Michael Khodadoust

All Publications

• Genetic alteration of class I HLA in cutaneous T-cell lymphoma. Blood Kwang, A. C., Duran, G. E., Fernandez-Pol, S., Najidh, S., Li, S., Bastidas Torres, A. N., Wang, E. B., Herrera, M., Bandali, T. I., Kurtz, D. M., Kim, Y. H., Khodadoust, M. S. 2024

  Abstract

  Abnormalities involving class I HLA are frequent in many lymphoma subtypes but have not yet been extensively studied in cutaneous T-cell lymphomas (CTCL). We characterized the occurrence of class I HLA abnormalities in 65 patients with advanced mycosis fungoides (MF) or Sézary syndrome (SS). Targeted DNA sequencing including coverage of HLA loci revealed at least one HLA abnormality in 26/65 patients (40%). Twelve unique somatic HLA mutations were identified across nine patients, and loss of heterozygosity or biallelic loss of HLA was found to affect 24 patients. Although specific HLA alleles were commonly disrupted, these events did not associate with decreased total class I HLA expression. Genetic events preferentially disrupted HLA alleles capable of presentation of greater numbers of putative neoantigens. HLA abnormalities co-occurred with other genetic immune evasion events and were associated with worse progression-free survival. Single-cell analyses demonstrated HLA abnormalities were frequently subclonal. Through analysis of serial samples, we observed disrupting class I HLA events change dynamically over the disease course. The dynamics of HLA disruption are highlighted in a patient receiving pembrolizumab, where resistance to pembrolizumab was associated with elimination of an HLA mutation. Overall, our findings show that genomic class I HLA abnormalities are common in advanced CTCL and may be an important consideration in understanding the effects of immunotherapy in CTCL.

  View details for DOI 10.1182/blood.2024024817

  View details for PubMedID 39388712

• Clinical characteristics, treatment patterns, and outcomes of cytotoxic cutaneous T-cell lymphomas. American journal of hematology Mou, E., Fernandez-Pol, S., Li, S., Rieger, K. E., Novoa, R., Suarez, C. J., Wieland, R., Weng, W., Kim, Y. H., Khodadoust, M. S. 2024

  View details for DOI 10.1002/ajh.27266

  View details for PubMedID 38391088

• Integrating Novel Agents into the Treatment of Advanced Mycosis Fungoides and Sézary Syndrome. Blood Khodadoust, M. S., Mou, E., Kim, Y. H. 2022

  Abstract

  Agents targeting the unique biology of mycosis fungoides and Sézary syndrome are quickly being incorporated into clinical management. With these new therapies, we are now capable of inducing more durable responses and even complete remissions in advanced disease, outcomes which were exceedingly rare with prior therapies. Yet, even this new generation of therapies typically produces objective responses in only a minority of patients. As our therapeutic options increase, we are now challenged with selecting treatments from a growing list of options. To gain the full benefit of these novel agents, we must develop strategies to match treatments to the patients most likely to benefit from them. Here, we consider both the current approaches to treatment selection based on clinical features and the future of molecular biomarker-guided therapy for patients with this heterogeneous disease.

  View details for DOI 10.1182/blood.2020008241

  View details for PubMedID 36379025

• Single-cell RNA-sequencing reveals predictive features of response to pembrolizumab in Sézary syndrome. Oncoimmunology Su, T., Duran, G. E., Kwang, A. C., Ramchurren, N., Fling, S. P., Kim, Y. H., Khodadoust, M. S. 2022; 11 (1): 2115197

  Abstract

  The PD-1 inhibitor pembrolizumab is effective in treating Sézary syndrome, a leukemic variant of cutaneous T-cell lymphoma. Our purpose was to investigate the effects of pembrolizumab on healthy and malignant T cells in Sézary syndrome and to discover characteristics that predict pembrolizumab response. Samples were analyzed before and after 3 weeks of pembrolizumab treatment using single-cell RNA-sequencing of 118,961 peripheral blood T cells isolated from six Sézary syndrome patients. T-cell receptor clonotyping, bulk RNA-seq signatures, and whole-exome data were integrated to classify malignant T-cells and their underlying subclonal heterogeneity. We found that responses to pembrolizumab were associated with lower KIR3DL2 expression within Sézary T cells. Pembrolizumab modulated Sézary cell gene expression of T-cell activation associated genes. The CD8 effector populations included clonally expanded populations with a strong cytotoxic profile. Expansions of CD8 terminal effector and CD8 effector memory T-cell populations were observed in responding patients after treatment. We observed intrapatient Sézary cell heterogeneity including subclonal segregation of a coding mutation and copy number variation. Our study reveals differential effects of pembrolizumab in both malignant and healthy T cells. These data support further study of KIR3DL2 expression and CD8 immune populations as predictive biomarkers of pembrolizumab response in Sézary syndrome.

  View details for DOI 10.1080/2162402X.2022.2115197

  View details for PubMedID 36046812

  View details for PubMedCentralID PMC9423847

• Resistance to mogamulizumab is associated with loss of CCR4 in Cutaneous T-cell Lymphoma. Blood Beygi, S., Duran, G. E., Fernandez-Pol, S., Rook, A. H., Kim, Y. H., Khodadoust, M. S. 2022

  Abstract

  Mogamulizumab is a humanized anti-CCR4 antibody approved for the treatment of mycosis fungoides and Sezary Syndrome. Despite almost universal expression of CCR4 in these diseases, most patients eventually develop resistance to mogamulizumab. We tested whether resistance to mogamulizumab is associated with loss of CCR4 expression. We identified 17 patients with mycosis fungoides or Sezary syndrome who either were intrinsically resistant or acquired resistance to mogamulizumab. Low expression of CCR4 by immunohistochemistry or flow cytometry was found in 65% of patients. Novel emergent CCR4 mutations targeting the N-terminal and transmembrane domains were found in 3 patients after disease progression. Emerging CCR4 copy number loss was detected in 2 patients with CCR4 mutations. Acquisition of CCR4 genomic alterations corresponded with loss of CCR4 antigen expression. We also report on outcomes of three cutaneous T-cell lymphoma patients with gain-of-function CCR4 mutations treated with mogamulizumab. Our study indicates that resistance to mogamulizumab in CTCL frequently involves loss of CCR4 expression and emergence of CCR4 genomic alterations. This finding has implications for management and monitoring of CTCL patients on mogamulizumab and development of future CCR4-directed therapies.

  View details for DOI 10.1182/blood.2021014468

  View details for PubMedID 35436328

• Pembrolizumab in mycosis fungoides with PD-L1 structural variants. Blood advances Beygi, S. n., Fernandez-Pol, S. n., Duran, G. n., Wang, E. B., Stehr, H. n., Zehnder, J. L., Ramchurren, N. n., Fling, S. P., Cheever, M. A., Weng, W. K., Kim, Y. H., Khodadoust, M. S. 2021; 5 (3): 771–74

  View details for DOI 10.1182/bloodadvances.2020002371

  View details for PubMedID 33560388

• Pembrolizumab in Relapsed and Refractory Mycosis Fungoides and Sézary Syndrome: A Multicenter Phase II Study. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Khodadoust, M. S., Rook, A. H., Porcu, P. n., Foss, F. n., Moskowitz, A. J., Shustov, A. n., Shanbhag, S. n., Sokol, L. n., Fling, S. P., Ramchurren, N. n., Pierce, R. n., Davis, A. n., Shine, R. n., Li, S. n., Fong, S. n., Kim, J. n., Yang, Y. n., Blumenschein, W. M., Yearley, J. H., Das, B. n., Patidar, R. n., Datta, V. n., Cantu, E. n., McCutcheon, J. N., Karlovich, C. n., Williams, P. M., Subrahmanyam, P. B., Maecker, H. T., Horwitz, S. M., Sharon, E. n., Kohrt, H. E., Cheever, M. A., Kim, Y. H. 2019: JCO1901056

  Abstract

  To assess the efficacy of pembrolizumab in patients with advanced relapsed or refractory mycosis fungoides (MF) or Sézary syndrome (SS).CITN-10 is a single-arm, multicenter phase II trial of 24 patients with advanced MF or SS. Patients were treated with pembrolizumab 2 mg/kg every 3 weeks for up to 24 months. The primary end point was overall response rate by consensus global response criteria.Patients had advanced-stage disease (23 of 24 with stage IIB to IV MF/SS) and were heavily pretreated with a median of four prior systemic therapies. The overall response rate was 38% with two complete responses and seven partial responses. Of the nine responding patients, six had 90% or more improvement in skin disease by modified Severity Weighted Assessment Tool, and eight had ongoing responses at last follow-up. The median duration of response was not reached, with a median response follow-up time of 58 weeks. Immune-related adverse events led to treatment discontinuation in four patients. A transient worsening of erythroderma and pruritus occurred in 53% of patients with SS. This cutaneous flare reaction did not result in treatment discontinuation for any patient. The flare reaction correlated with high PD-1 expression on Sézary cells but did not associate with subsequent clinical responses or lack of response. Treatment responses did not correlate with expression of PD-L1, total mutation burden, or an interferon-γ gene expression signature.Pembrolizumab demonstrated significant antitumor activity with durable responses and a favorable safety profile in patients with advanced MF/SS.

  View details for DOI 10.1200/JCO.19.01056

  View details for PubMedID 31532724

• B cell lymphomas present immunoglobulin neoantigens. Blood Khodadoust, M. S., Olsson, N. n., Chen, B. n., Sworder, B. n., Shree, T. n., Liu, C. L., Zhang, L. n., Czerwinski, D. K., Davis, M. M., Levy, R. n., Elias, J. E., Alizadeh, A. A. 2018

  View details for PubMedID 30545830

• Antigen presentation profiling reveals recognition of lymphoma immunoglobulin neoantigens NATURE Khodadoust, M. S., Olsson, N., Wagar, L. E., Haabeth, O. A., Chen, B., Swaminathan, K., Rawson, K., Liu, C. L., Steiner, D., Lund, P., Rao, S., Zhang, L., Marceau, C., Stehr, H., Newman, A. M., Czerwinski, D. K., Carlton, V. E., Moorhead, M., Faham, M., Kohrt, H. E., Carette, J., Green, M. R., Davis, M. M., Levy, R., Elias, J. E., Alizadeh, A. A. 2017; 543 (7647): 723-?

  Abstract

  Cancer somatic mutations can generate neoantigens that distinguish malignant from normal cells. However, the personalized identification and validation of neoantigens remains a major challenge. Here we discover neoantigens in human mantle-cell lymphomas by using an integrated genomic and proteomic strategy that interrogates tumour antigen peptides presented by major histocompatibility complex (MHC) class I and class II molecules. We applied this approach to systematically characterize MHC ligands from 17 patients. Remarkably, all discovered neoantigenic peptides were exclusively derived from the lymphoma immunoglobulin heavy- or light-chain variable regions. Although we identified MHC presentation of private polymorphic germline alleles, no mutated peptides were recovered from non-immunoglobulin somatically mutated genes. Somatic mutations within the immunoglobulin variable region were almost exclusively presented by MHC class II. We isolated circulating CD4(+) T cells specific for immunoglobulin-derived neoantigens and found these cells could mediate killing of autologous lymphoma cells. These results demonstrate that an integrative approach combining MHC isolation, peptide identification, and exome sequencing is an effective platform to uncover tumour neoantigens. Application of this strategy to human lymphoma implicates immunoglobulin neoantigens as targets for lymphoma immunotherapy.

  View details for DOI 10.1038/nature21433

  View details for PubMedID 28329770

• ASTCT and USCLC Clinical Practice Recommendations for Allogeneic Stem Cell Transplant in Mycosis Fungoides and Sézary Syndrome. Transplantation and cellular therapy Goyal, A., O'Leary, D., Dabaja, B., Weng, W. K., Zain, J., Cutler, C., Guitart, J., Kim, Y. H., Geskin, L. J., Hoppe, R. T., Wilson, L. D., Beaven, A. W., Horwitz, S., Allen, P. B., Barta, S. K., Bohjanen, K., Brammer, J. E., Carter, J. B., Comfere, N., DeSimone, J. A., Dusenbery, K., Duvic, M., Huen, A., Jagadeesh, D., Kelsey, C. R., Khodadoust, M. S., Lechowicz, M. J., Mehta-Shah, N., Moskowitz, A. J., Olsen, E. A., Poh, C., Pro, B., Querfeld, C., Sauter, C., Sokol, L., Sokumbi, O., Wilcox, R. A., Zic, J. A., Hamadani, M., Foss, F. 2024

  Abstract

  Mycosis fungoides (MF) and Sézary syndrome (SS) are the most common subtypes of cutaneous T-cell lymphoma (CTCL). While MF generally follows an indolent course, a subset of patients will experience progressive and/or treatment-refractory disease. Sézary syndrome is an aggressive CTCL associated with high morbidity and mortality secondary to immune compromise and opportunistic infection. Although allogeneic hematopoietic cell transplant (allo-HCT) is currently the only available potentially curative treatment modality for MF/SS and is included in NCCN and ASTCT treatment guidelines, there is no published guidance regarding referral criteria, timing and allo-HCT approach to help guide clinicians caring for these patients.Delphi survey of 32 specialists in dermatology (n=9), transplant hematology/oncology (n=10), non-transplant hematology/oncology (n=8), and radiation oncology (n=5) from across the United States. Consensus required agreement of ≥75% of participants.Sixteen consensus statements were generated on four topics: 1) criteria for referral for consideration for allo-HCT, 2) allo-HCT preparative regimens and procedures 3) disease status at the time of allo-HCT, and 4) multidisciplinary management in the pre- and post-transplant settings.These clinical practice guidelines provide a framework for decision-making regarding allo-HCT for MF/SS and highlight areas for future prospective investigation.

  View details for DOI 10.1016/j.jtct.2024.08.020

  View details for PubMedID 39222792

• Duvelisib plus romidepsin in relapsed/refractory T cell lymphomas: a phase 1b/2a trial. Nature medicine Horwitz, S. M., Nirmal, A. J., Rahman, J., Xu, R., Drill, E., Galasso, N., Ganesan, N., Davey, T., Hancock, H., Perez, L., Maccaro, C., Bahgat, A., Marzouk, E., Cathcart, E., Moskowitz, A., Noy, A., Kumar, A., Jacobsen, E., Fisher, D. C., Mehta-Shah, N., Kim, Y. H., Khodadoust, M., Kotlov, N., Nikitina, A., Kudryashova, O., Zubareva, V., Zornikova, K., Shin, N., Sorokina, M., Degryse, S., Postovalova, E., Bagaev, A., Hosszu, K., McAvoy, D., Boelens, J. J., Wu, W., Ciantra, Z., Appelt, J. W., Trevisani, C., Amaka, S., Weinstock, D. M., Vardhana, S. A. 2024

  Abstract

  PI3K-δ inhibitors have shown impressive activity in lymphoid malignancies but have been hampered by autoimmune and infectious toxicities, leading to market withdrawals. We previously demonstrated activity of the PI3K-δγ inhibitor duvelisib in T cell lymphomas (TCLs) that was associated with inflammatory adverse events. As reported here, we conducted a phase 1b/2a study of duvelisib in combination with either romidepsin (n = 66) or bortezomib (n = 32) in patients with relapsed/refractory TCL and found that the addition of romidepsin, but not bortezomib, appeared to increase efficacy while attenuating PI3K inhibitor-driven toxicity. The primary endpoint of the study was to determine the safety and maximum tolerated dose of duvelisib, which was 75 mg twice daily when combined with romidepsin versus 25 mg twice daily when combined with bortezomib. The most common adverse events were neutropenia (42%, 25/59) and fatigue (37%, 22/59) in patients treated with duvelisib and romidepsin and diarrhea (48%, 11/23) and neutropenia (30%, 7/23) in patients treated with duvelisib and bortezomib. Duvelisib and romidepsin resulted in less grade 3/4 hepatotoxicity (14%, 8/59) compared to 40% (14/35) in our previous study with duvelisib monotherapy. This was associated with reductions in circulating inflammatory mediators and myeloid cell inflammatory gene expression. Secondary endpoints of overall and complete response rates were 55% (35/64) and 34% (22/64) for patients treated with duvelisib and romidepsin and 34% (11/32) and 13% (4/32) for patients treated with duvelisib and bortezomib. Among patients with peripheral T cell lymphomas (PTCLs), overall and complete response rates of duvelisib and romidepsin were 56% (27/48) and 44% (21/48), respectively, with exploratory analyses showing increased response rates in patients with a follicular helper T cell subtype. These findings support further development of combined PI3K and histone deacetylase (HDAC) inhibition in TCLs and suggest a unique strategy to enable PI3K inhibitor-based combinations for additional patient populations. ClinicalTrials.gov identifier: NCT02783625 .

  View details for DOI 10.1038/s41591-024-03076-6

  View details for PubMedID 38886623

  View details for PubMedCentralID 1895501

• Multi-omic profiling reveals the endogenous and neoplastic responses to immunotherapies in cutaneous T cell lymphoma. Cell reports. Medicine Glass, D. R., Mayer-Blackwell, K., Ramchurren, N., Parks, K. R., Duran, G. E., Wright, A. K., Bastidas Torres, A. N., Islas, L., Kim, Y. H., Fling, S. P., Khodadoust, M. S., Newell, E. W. 2024: 101527

  Abstract

  Cutaneous T cell lymphomas (CTCLs) are skin cancers with poor survival rates and limited treatments. While immunotherapies have shown some efficacy, the immunological consequences of administering immune-activating agents to CTCL patients have not been systematically characterized. We apply a suite of high-dimensional technologies to investigate the local, cellular, and systemic responses in CTCL patients receiving either mono- or combination anti-PD-1 plus interferon-gamma (IFN-γ) therapy. Neoplastic T cells display no evidence of activation after immunotherapy. IFN-γ induces muted endogenous immunological responses, while anti-PD-1 elicits broader changes, including increased abundance of CLA+CD39+ T cells. We develop an unbiased multi-omic profiling approach enabling discovery of immune modules stratifying patients. We identify an enrichment of activated regulatory CLA+CD39+ T cells in non-responders and activated cytotoxic CLA+CD39+ T cells in leukemic patients. Our results provide insights into the effects of immunotherapy in CTCL patients and a generalizable framework for multi-omic analysis of clinical trials.

  View details for DOI 10.1016/j.xcrm.2024.101527

  View details for PubMedID 38670099

• A human lymphoma organoid model for evaluating and targeting the follicular lymphoma tumor immune microenvironment. Cell stem cell Kastenschmidt, J. M., Schroers-Martin, J. G., Sworder, B. J., Sureshchandra, S., Khodadoust, M. S., Liu, C. L., Olsen, M., Kurtz, D. M., Diehn, M., Wagar, L. E., Alizadeh, A. A. 2024

  Abstract

  Heterogeneity in the tumor microenvironment (TME) of follicular lymphomas (FLs) can affect clinical outcomes. Current immunotherapeutic strategies, including antibody- and cell-based therapies, variably overcome pro-tumorigenic mechanisms for sustained disease control. Modeling the intact FL TME, with its native, syngeneic tumor-infiltrating leukocytes, is a major challenge. Here, we describe an organoid culture method for cultivating patient-derived lymphoma organoids (PDLOs), which include cells from the native FL TME. We define the robustness of this method by successfully culturing cryopreserved FL specimens from diverse patients and demonstrate the stability of TME cellular composition, tumor somatic mutations, gene expression profiles, and B/T cell receptor dynamics over 3 weeks. PDLOs treated with CD3:CD19 and CD3:CD20 therapeutic bispecific antibodies showed B cell killing and T cell activation. This stable system offers a robust platform for advancing precision medicine efforts in FL through patient-specific modeling, high-throughput screening, TME signature identification, and treatment response evaluation.

  View details for DOI 10.1016/j.stem.2024.01.012

  View details for PubMedID 38402619

• Specificity of Immunoglobulin High-Throughput Sequencing Minimal Residual Disease Monitoring in Non-Hodgkin Lymphomas. Blood advances Shukla, N., Schroers-Martin, J., Sworder, B., Kathuria, K. R., Alig, S., Frank, M. J., Miklos, D. B., Coutre, S. E., Diehn, M., Khodadoust, M. S., Roschewski, M. J., Kurtz, D. M., Alizadeh, A. A. 2023

  View details for DOI 10.1182/bloodadvances.2023011997

  View details for PubMedID 38147627

• Two cases of mycosis fungoides with large cell transformation with KMT2A rearrangements. Journal of hematopathology Wadsworth, P. A., Lawrence, L., Suarez, C. J., Saleem, A., Khodadoust, M. S., Kim, Y. H., Rieger, K. E., Fernandez-Pol, S. 2023; 16 (4): 227-234

  Abstract

  Cutaneous T-cell lymphomas (CTCL) are a clinically and molecularly heterogeneous class of lymphomas of the skin-homing T cell, and their genetic profiles are not fully characterized. Previously, rearrangements of the Lysine Methyltransferase 2A (KMT2A) gene have been identified as driver mutations only in acute leukemias. KMT2A plays a role in epigenetic regulation, and cancers with such rearrangements are responsive to epigenetic therapy including hypomethylating agents. Here, we report two cases of CTCL with novel genetic profiles. KMT2A rearrangements were identified in two aggressive cases of mycosis fungoides with large cell transformation. A KMT2A::DSCAML1 gene rearrangement was seen in Case 1, while a KMT2A::MAPRE1 fusion was identified in Case 2. These cases demonstrate that KMT2A rearrangements can be found in primary CTCLs rather than solely acute leukemias, illustrating the importance of correlating molecular findings with clinical and histologic features in diagnosis. Additionally, this finding suggests that the subset of CTCLs driven by aberrancy of the KMT2A pathway may be responsive to therapy with hypomethylating agents or menin inhibitors, as seen in acute leukemias.

  View details for DOI 10.1007/s12308-023-00567-2

  View details for PubMedID 38175436

  View details for PubMedCentralID 5854542

• A clinical trial of therapeutic vaccination in lymphoma with serial tumor sampling and single cell analysis. Blood advances Shree, T., Haebe, S. E., Czerwinski, D. K., Eckhert, E., Day, G., Sathe, A., Grimes, S. M., Frank, M. J., Maeda, L., Alizadeh, A. A., Advani, R. H., Hoppe, R. T., Long, S. R., Martin, B. A., Ozawa, M. G., Khodadoust, M. S., Ji, H. P., Levy, R. 2023

  Abstract

  In situ vaccination (ISV) triggers an immune response to tumor-associated antigens at one tumor site that can then tackle disease throughout the body. Here we report clinical and biological results of a phase I/II ISV trial in patients with low-grade lymphoma (NCT02927964) combining an intratumoral TLR9 agonist with local low-dose radiation, and ibrutinib (an inhibitor of B and T cell kinases). Adverse events were predominately low grade. The overall response rate was 50%, including one complete response. All patients experienced tumor reduction at distant sites. Single cell analyses of serial fine needle aspirates from injected and uninjected tumors revealed correlates of clinical response, such as lower CD47 and higher MHCII expression on tumor cells, enhanced T and NK cell effector function, and reduced immune suppression from TGFß and inhibitory T regulatory 1 cells. While changes at the local injected site were more pronounced, changes at distant uninjected sites more often associated with clinical responses. Functional immune response assays and tracking of T cell receptor sequences provided evidence of treatment-induced tumor-specific T cell responses. Induction of immune effectors and reversal of negative regulators were both important in producing clinically meaningful tumor responses. NCT02927964.

  View details for DOI 10.1182/bloodadvances.2023011589

  View details for PubMedID 37939259

• Reduced Dose Brentuximab Vedotin for Mycosis Fungoides Appears to Prolong Response Duration By Balancing Efficacy and Tolerability Munayirji, B., Khan, N., Myskowski, P., Geller, S., Noor, S., Kheterpal, M., Davey, T., Hancock, H., Perez, L., Miller, T., Brutus, J., Ganesan, N., Chang, T., Mangiaracina, G., Patel, R., Galasso, N., Casper, E., Ghione, P., Stuver, R., Epstein-Peterson, Z. D., Pulitzer, M., Khodadoust, M. S., Kim, Y. H., Horwitz, S. M., Moskowitz, A. AMER SOC HEMATOLOGY. 2023

  View details for DOI 10.1182/blood-2023-184898

  View details for Web of Science ID 001159306706173

• Lacutamab in Patients with Relapsed and Refractory Sezary Syndrome: Results from the Tellomak Phase 2 Trial Bagot, M., Kim, Y. H., Geskin, L. J., Ortiz-Romero, P. L., Kim, E., Mehta-Shah, N., Dereure, O., Oro, S., Beylot-Barry, M., Dalle, S., Jacobsen, E., Lansigan, F., Ram-Wolff, C., Khodadoust, M. S., Battistella, M., Gru, A. A., Moins-Teisserenc, H., Zinzani, P., Viotti, J., Paiva, C., Muller, M., Porcu, P. AMER SOC HEMATOLOGY. 2023

  View details for DOI 10.1182/blood-2023-173806

  View details for Web of Science ID 001159306700186

• Development of Circulating Tumor DNA (ctDNA) for Molecular Measurable Residual Disease (MRD) in Acute Myeloid Leukemia (AML) Gunaratne, R., Zhou, C., Tai, J. W., Schwede, M., Tanaka, K., Alkaitis, M., Yin, R., Sworder, B. J., Mannis, G., Majeti, R., Khodadoust, M. S., Kurtz, D. M., Zhang, T. Y. AMER SOC HEMATOLOGY. 2023

  View details for DOI 10.1182/blood-2023-181459

  View details for Web of Science ID 001159740307053

• An Integrated Multimodal Framework for Noninvasive TCL Disease Detection and Monitoring Sugio, T., Shukla, N., Khodadoust, M. S., Nesselbush, M., Kato, K., Alig, S. K., Boegeholz, J., Schroers-Martin, J., Esfahani, M., Mutter, J. A., Garofalo, A., Jun, S., Hamilton, M. P., Rossi, C., Olsen, M., Liu, C., Akashi, K., Diehn, M., Alizadeh, A. A. AMER SOC HEMATOLOGY. 2023

  View details for DOI 10.1182/blood-2023-180492

  View details for Web of Science ID 001159306706091

• Machine Learning-Based Survival Analysis Reveals Prognostic Clinical and Genetic Insights for Patients with Cutaneous T-Cell Lymphoma Schreidah, C. M., DeStephano, D. M., Pan, S. S., Wang, S., Shen, H., Ta, C. N., Reynolds, G., Fahmy, L. M., Gordon, E. R., Adeuyan, O., Kwinta, B. D., Stonesifer, C. J., Chan, W. H., Choi, J., Duvic, M., Gallardo, F., Girardi, M., Guitart, J., Kim, Y. H., Khodadoust, M. S., Najidh, S., Ni, X., Pujol, R. M., Tensen, C. P., Vermeer, M. H., Whittaker, S., Tatonetti, N. P., Chase, H. S., Pe'er, I., Geskin, L. J. AMER SOC HEMATOLOGY. 2023

  View details for DOI 10.1182/blood-2023-190775

  View details for Web of Science ID 001159306706186

• Elucidating genetic factors of cutaneous T-cell lymphoma staging and disease severity through machine learning Schreidah, C. M., Reynolds, G., Shen, H., Fahmy, L. M., Choi, J., Duvic, M., Gallardo, F., Girardi, M., Guitart, J., Kim, Y. H., Khodadoust, M., Najidh, S., Ni, X., Pujol, R. M., Tensen, C. P., Vermeer, M. H., Whittaker, S., Tatonetti, N. P., Chase, H. S., Pe'er, I., Geskin, L. J. ELSEVIER SCI LTD. 2023: S15

  View details for DOI 10.1016/j.ejca.2023.113022

  View details for Web of Science ID 001077487800035

• Lacutamab in patients with mycosis fungoides: efficacy results according to updated lymph node classification in the TELLOMAK study Bagot, M., Kim, Y. H., Ortiz-Romero, P. L., Zinzani, P., Beylot-Barry, M., Dalle, S., Jacobsen, E., Combalia, A., Huen, A., Mehta-Shah, N., Khodadoust, M., Mehta, A., Dereure, O., Battistella, M., Gru, A., Moins-Teisserenc, H., Viotti, J., Paiva, C., Boyer-Chammard, A., Porcu, P. ELSEVIER SCI LTD. 2023: S19-S20

  View details for DOI 10.1016/j.ejca.2023.113032

  View details for Web of Science ID 001077487800045

• Genomic abnormalities involving class I HLA are common in advanced cutaneous T-cell lymphoma Kwang, A., Duran, G., Fernandez-Pol, S., Li, S., Najidh, S., Torres, A., Herrera, M., Wang, E., Kurtz, D., Kim, Y. H., Khodadoust, M. ELSEVIER SCI LTD. 2023: S14

  View details for DOI 10.1016/j.ejca.2023.113019

  View details for Web of Science ID 001077487800032

• Identification and confirmation via in situ hybridization of Merkel cell polyomavirus in rare cases of posttransplant cutaneous T-cell lymphoma. Journal of cutaneous pathology Lawrence, L., Wang, A., Charville, G., Liu, C. L., Garofalo, A., Alizadeh, A., Jangam, D., Pinsky, B. A., Sahoo, M., Gratzinger, D., Khodadoust, M., Kim, Y., Novoa, R., Stehr, H. 2023

  Abstract

  Viral infection is an oncogenic factor in many hematolymphoid malignancies. We sought to determine the diagnostic yield of aligning off-target reads incidentally obtained during targeted hematolymphoid next-generation sequencing to a large database of viral genomes to screen for viral sequences within tumor specimens.Alignment of off-target reads to viral genomes was performed using magicBLAST. Localization of Merkel cell polyomavirus (MCPyV) RNA was confirmed by RNAScope in situ hybridization. Integration analysis was performed using Virus-Clip.Four cases of post-cardiac-transplant folliculotropic mycosis fungoides (fMF) and one case of peripheral T-cell lymphoma (PTCL) were positive in off-target reads for MCPyV DNA. Two of the four cases of posttransplant fMF and the case of PTCL showed localization of MCPyV RNA to malignant lymphocytes, whereas the remaining two cases of posttransplant fMF showed MCPyV RNA in keratinocytes.Our findings raise the question of whether MCPyV may play a role in rare cases of T-lymphoproliferative disorders, particularly in the skin and in the heavily immunosuppressed posttransplant setting.

  View details for DOI 10.1111/cup.14486

  View details for PubMedID 37394808

• Tracing founder mutations in circulating and tissue-resident follicular lymphoma precursors. Cancer discovery Schroers-Martin, J. G., Soo, J., Brisou, G., Scherer, F., Kurtz, D. M., Sworder, B. J., Khodadoust, M. S., Jin, M. C., Bru, A., Liu, C. L., Stehr, H., Vineis, P., Natkunam, Y., Teras, L. R., Song, J. Y., Nadel, B., Diehn, M., Roulland, S., Alizadeh, A. A. 2023

  Abstract

  Follicular lymphomas (FL) are characterized by BCL2 translocations, often detectable in blood years before FL diagnosis, but also observed in aging healthy individuals suggesting additional lesions are required for lymphomagenesis. We directly characterized early cooperating mutations by ultra-deep sequencing of pre-diagnostic blood and tissue specimens from 48 subjects who ultimately developed FL. Strikingly, CREBBP lysine acetyltransferase (KAT) domain mutations were the most commonly observed precursor lesions, and largely distinguished patients developing FL (14/48, 29%) from healthy adults with or without detected BCL2 rearrangements (0/13, p=0.03 and 0/20, p=0.007, respectively). CREBBP variants were detectable a median of 5.8 years before FL diagnosis, were clonally selected in FL tumors, and appeared restricted to the committed B-cell lineage. These results suggest that mutations affecting the CREBBP KAT domain are common lesions in FL cancer precursor cells (CPC), with potential for discriminating subjects at risk of developing FL or monitoring residual disease.

  View details for DOI 10.1158/2159-8290.CD-23-0111

  View details for PubMedID 36939219

• Minimal/measurable residual disease (MRD) monitoring in patients with lymphoid neoplasms by high-throughput sequencing of the T-cell receptor. The Journal of molecular diagnostics : JMD Tung, J. K., Jangam, D., Ho, C. C., Fung, E., Khodadoust, M. S., Kim, Y. H., Zehnder, J. L., Stehr, H., Zhang, B. M. 2023

  Abstract

  High-throughput sequencing of the T-cell receptor beta (TRB) and gamma (TRG) loci is increasingly utilized due to its high sensitivity, specificity, and versatility in the diagnosis of various T-cell malignancies. Application of these technologies for tracking disease burden can be valuable in detecting recurrence, determining response to therapy, guiding future management of patients, and establishing endpoints for clinical trials. In this study, the performance of the commercially available LymphoTrack high-throughput sequencing assay was assessed for determining residual disease burden in patients with various T-cell malignancies seen at our institution. A custom bioinformatics pipeline and database was also developed to facilitate MRD analysis and clinical reporting. This assay demonstrated excellent test performance characteristics, achieving a sensitivity of 1 out of 100,000 T-cell equivalents for the DNA inputs evaluated and high concordance with orthogonal testing methods. This assay was further utilized to correlate disease burden in several patients, demonstrating its potential utility for monitoring patients with T-cell malignancies.

  View details for DOI 10.1016/j.jmoldx.2023.02.002

  View details for PubMedID 36870603

• Hepatosplenic T-cell lymphoma with STAT5B and SETD2 mutations recurring as cells with NK-cell immunophenotype. Blood Khodadoust, M., Silva, O. 2023; 141 (5): 555

  View details for DOI 10.1182/blood.2022018200

  View details for PubMedID 36729542

• Determinants of resistance to engineered T cell therapies targeting CD19 in large B cell lymphomas. Cancer cell Sworder, B. J., Kurtz, D. M., Alig, S. K., Frank, M. J., Shukla, N., Garofalo, A., Macaulay, C. W., Shahrokh Esfahani, M., Olsen, M. N., Hamilton, J., Hosoya, H., Hamilton, M., Spiegel, J. Y., Baird, J. H., Sugio, T., Carleton, M., Craig, A. F., Younes, S. F., Sahaf, B., Sheybani, N. D., Schroers-Martin, J. G., Liu, C. L., Oak, J. S., Jin, M. C., Beygi, S., Hüttmann, A., Hanoun, C., Dührsen, U., Westin, J. R., Khodadoust, M. S., Natkunam, Y., Majzner, R. G., Mackall, C. L., Diehn, M., Miklos, D. B., Alizadeh, A. A. 2022

  Abstract

  Most relapsed/refractory large B cell lymphoma (r/rLBCL) patients receiving anti-CD19 chimeric antigen receptor (CAR19) T cells relapse. To characterize determinants of resistance, we profiled over 700 longitudinal specimens from two independent cohorts (n = 65 and n = 73) of r/rLBCL patients treated with axicabtagene ciloleucel. A method for simultaneous profiling of circulating tumor DNA (ctDNA), cell-free CAR19 (cfCAR19) retroviral fragments, and cell-free T cell receptor rearrangements (cfTCR) enabled integration of tumor and both engineered and non-engineered T cell effector-mediated factors for assessing treatment failure and predicting outcomes. Alterations in multiple classes of genes are associated with resistance, including B cell identity (PAX5 and IRF8), immune checkpoints (CD274), and those affecting the microenvironment (TMEM30A). Somatic tumor alterations affect CAR19 therapy at multiple levels, including CAR19 T cell expansion, persistence, and tumor microenvironment. Further, CAR19 T cells play a reciprocal role in shaping tumor genotype and phenotype. We envision these findings will facilitate improved chimeric antigen receptor (CAR) T cells and personalized therapeutic approaches.

  View details for DOI 10.1016/j.ccell.2022.12.005

  View details for PubMedID 36584673

• Specificity & Precision of Minimal Residual Disease Monitoring in DLBCL Using Ig-HTS Shukla, N. D., Schroers-Martin, J., Kathuria, K. R., Sworder, B., Alig, S. K., Frank, M. J., Miklos, D. B., Coutre, S., Diehn, M., Khodadoust, M. S., Roschewski, M., Kurtz, D. M., Alizadeh, A. A. AMER SOC HEMATOLOGY. 2022: 6403-6404

  View details for DOI 10.1182/blood-2022-165656

  View details for Web of Science ID 000893223206185

• ITK Inhibitor Induces Dose-Dependent Th1 Skewing in Normal T Cells and Is Active in Refractory T Cell Lymphomas Song, Y., Ding, N., Yoon, D., Reneau, J. C., Wilcox, R. A., Kim, W., Kim, Y. H., Khodadoust, M. S., Feldman, T. A., Yannakou, C. K., Giri, P., Brammer, J. E., Hsu, L., Yuan, H., Verner, E., Mahabhashyam, S., Miller, R. A. AMER SOC HEMATOLOGY. 2022: 8857-8859

  View details for DOI 10.1182/blood-2022-159177

  View details for Web of Science ID 000893230301424

• Disease Characterization and Response Prediction in Myeloma Patients Undergoing Conventional and Cellular Therapies from Circulating Tumor DNA Hosoya, H., Carleton, M., Tanaka, K. L., Sworder, B., Hovanky, V., Duran, G. E., Zhang, T. Y., Khodadoust, M. S., Miklos, D. B., Arai, S., Iberri, D., Liedtke, M., Sidana, S., Kurtz, D. M. AMER SOC HEMATOLOGY. 2022: 1546-1548

  View details for DOI 10.1182/blood-2022-160370

  View details for Web of Science ID 000893223201226

• Activating Immune Effectors and Dampening Immune Suppressors Generates Successful Therapeutic Cancer Vaccination in Patients with Lymphoma Shree, T., Haebe, S., Czerwinski, D. K., Eckhert, E., Day, G., Sathe, A., Grimes, S. M., Frank, M. J., Maeda, L. S., Alizadeh, A. A., Advani, R. H., Hoppe, R., Long, S. R., Martin, B., Ozawa, M. G., Khodadoust, M. S., Ji, H. P., Levy, R. AMER SOC HEMATOLOGY. 2022: 6450-6451

  View details for DOI 10.1182/blood-2022-167469

  View details for Web of Science ID 000893223206208

• Clinical Characteristics, Treatment Patterns, and Outcomes of Cytotoxic Cutaneous T-Cell Lymphomas Mou, E., Fernandez-Pol, S., Li, S., Kim, Y. H., Khodadoust, M. S. AMER SOC HEMATOLOGY. 2022: 6552-6553

  View details for DOI 10.1182/blood-2022-158610

  View details for Web of Science ID 000893223206251

• Lacutamab in Patients with Advanced Sezary Syndrome: Results from an Interim Analysis of the Tellomak Phase 2 Trial Bagot, M., Kim, Y. H., Ortiz-Romero, P. L., Zinzani, P., Mehta-Shah, N., Dereure, O., Beylot-Barry, M., Dalle, S., Jacobsen, E. D., Huen, A., Combalia, A., Battistella, M., Gru, A. A., Moins-Teisserenc, H., Khodadoust, M. S., Viotti, J., Paiva, C., Muller, M., Porcu, P. AMER SOC HEMATOLOGY. 2022: 3760-3761

  View details for DOI 10.1182/blood-2022-160239

  View details for Web of Science ID 000893223203349

• Determinants of Resistance to Engineered T-Cell Therapies Targeting CD19 in Large B-Cell Lymphomas Sworder, B., Kurtz, D. M., Alig, S. K., Frank, M. J., Shukla, N. D., Garofalo, A., Macaulay, C., Esfahani, M., Olsen, M., Hamilton, J., Hosoya, H., Hamilton, M. P., Spiegel, J. Y., Baird, J. H., Carleton, M., Craig, A. M., Younes, S. F., Sahaf, B., Sheybani, N., Schroers-Martin, J., Liu, C., Oak, J. S., Jin, M. C., Beygi, S., Huttmann, A., Hanoun, C., Duhrsen, U., Westin, J., Khodadoust, M. S., Natkunam, Y., Majzner, R. G., Mackall, C. L., Diehn, M., Miklos, D. B., Alizadeh, A. A. AMER SOC HEMATOLOGY. 2022: 1301-1303

  View details for DOI 10.1182/blood-2022-165545

  View details for Web of Science ID 000893223201129

• CYTOF AND SERUM PROTEOMICS SHOW DISTINCT DIFFERENCES IN IMMUNE RESPONSES BETWEEN MYCOSIS FUNGOIDES AND SEZARY SYNDROME TO MONO- AND COMBINATION ANTI-PD-1 IMMUNOTHERAPY Ramchurren, N., Parks, R., Islas, L., Fling, S., Khodadoust, M., Newell, E., Glass, D. BMJ PUBLISHING GROUP. 2022: A103

  View details for DOI 10.1136/jitc-2022-SITC2022.0094

  View details for Web of Science ID 000919423400093

• Correlation of sTNFR2 elevation and disease progression in cutaneous T cell lymphomas Lee, A., Kim, Y., Khodadoust, M., Faustman, D. L. AMER ASSOC CANCER RESEARCH. 2022

  View details for Web of Science ID 000892509504201

• CD20-Targeted Therapy Ablates De Novo Antibody Response to Vaccination but Spares Pre-Established Immunity. Blood cancer discovery Shree, T., Shankar, V., Lohmeyer, J. J., Czerwinski, D. K., Schroers-Martin, J. G., Rodriguez, G. M., Beygi, S., Kanegai, A. M., Corbelli, K. S., Gabriel, E., Kurtz, D. M., Khodadoust, M. S., Gupta, N. K., Maeda, L. S., Advani, R. H., Alizadeh, A. A., Levy, R. 2022

  Abstract

  To obtain a deeper understanding of poor responses to COVID-19 vaccination in lymphoma patients, we assessed blocking antibodies, total anti-spike IgG, and spike-specific memory B cells in the peripheral blood of 126 patients with lymphoma and 20 age-matched healthy controls 1 and 4 months after COVID-19 vaccination. Fifty-five percent of patients developed blocking antibodies post-vaccination, compared to 100% of controls. Evaluating patients last treated from days to nearly 18 years prior to vaccination, time since last anti-CD20 was a significant independent predictor of vaccine response. None of 31 patients who had received anti-CD20 treatment within 6 months prior to vaccination developed blocking antibodies. In contrast, patients who initiated anti-CD20 treatment shortly after achieving a vaccine-induced antibody response tended to retain that response during treatment, suggesting a policy of immunizing prior to treatment whenever possible.

  View details for DOI 10.1158/2643-3230.BCD-21-0222

  View details for PubMedID 35015688

• Time Since Last Anti-CD20 Treatment Is a Major Determinant of Sars-Cov-2 Vaccine Response in a Large Cohort of Patients with B-Cell Lymphoma Shree, T., Shankar, V., Czerwinski, D. K., Rodriguez, G., Beygi, S., Schroers-Martin, J. G., Advani, R., Maeda, L. S., Gupta, N. K., Khodadoust, M. S., Kurtz, D. M., Corbelli, K. S., Gabriel, E., Kanegai, A. M., Alizadeh, A. A., Levy, R. AMER SOC HEMATOLOGY. 2021

  View details for DOI 10.1182/blood-2021-153901

  View details for Web of Science ID 000736413900065

• Phase 2a Study of the Dual SYK/JAK Inhibitor Cerdulatinib (ALXN2075) As Monotherapy in Patients with Relapsed/Refractory Peripheral TCell Lymphoma Horwitz, S. M., Feldman, T. A., Ye, J. C., Khodadoust, M. S., Munoz, J., Hamlin, P. A., Kim, Y. H., Wilcox, R. A., Patel, M. R., Coffey, G. P., Osman, M., Holland, J. S., Guzman, C. B., Smith, S. M. AMER SOC HEMATOLOGY. 2021

  View details for DOI 10.1182/blood-2021-148352

  View details for Web of Science ID 000736398802162

• Therapeutic and Immunologic Responses Elicited By in Situ Vaccination with CpG, Ibrutinib, and Low-Dose Radiation Shree, T., Haebe, S., Czerwinski, D. K., Day, G., Sathe, A., Khodadoust, M. S., Frank, M. J., Beygi, S., Hoppe, R., Long, S. R., Martin, B., Ji, H. P., Levy, R. AMER SOC HEMATOLOGY. 2021

  View details for DOI 10.1182/blood-2021-154017

  View details for Web of Science ID 000736413906106

• Two Cases of Mycosis Fungoides With PCM1-JAK2 Fusion. JCO precision oncology Fernandez-Pol, S., Neishaboori, N., Chapman, C. M., Khodadoust, M. S., Kim, Y. H., Rieger, K. E., Suarez, C. J. 2021; 5: 646-652

  View details for DOI 10.1200/PO.20.00366

  View details for PubMedID 34994608

• Patient characteristics of long-term responders to mogamulizumab: results from the MAVORIC study. European journal of cancer (Oxford, England : 1990) Kim, Y. H., Khodadoust, M., de Masson, A., Moins-Teisserenc, H., Ito, T., Dwyer, K., Herr, F., Bagot, M. 2021; 156 Suppl 1: S48-S49

  View details for DOI 10.1016/S0959-8049(21)00715-2

  View details for PubMedID 34649658

• Primary cytotoxic T cell lymphomas harbor recurrent targetable alterations in the JAK-STAT pathway Lee, K., Evans, M. G., Yang, L., Ng, S., Snowden, C., Khodadoust, M., Brown, R. A., Trum, N., Querfeld, C., Doan, L. T., Song, J., Zhang, H., Wood, G. S., Wada, D. A., Shanmugam, V., Haun, P. L., Duncan, L. M., Guitart, J., Weinstock, D. M., Nardi, V., Choi, J. ELSEVIER SCI LTD. 2021: S8-S9

  View details for Web of Science ID 000719152800017

• Patient characteristics of long-term responders to mogamulizumab: results from the MAVORIC study Kim, Y. H., Khodadoust, M., de Masson, A., Moins-Teisserenc, H., Ito, T., Dwyer, K., Herr, F., Bagot, M. ELSEVIER SCI LTD. 2021: S48-S49

  View details for Web of Science ID 000719152800090

• Mechanisms of resistance to anti-CCR4 antibody, mogamulizumab, in cutaneous T cell lymphoma Beygi, S., Fernandez-Pol, S., Duran, G., Wang, E. B., Kim, Y., Khodadoust, M. ELSEVIER SCI LTD. 2021: S8

  View details for Web of Science ID 000719152800016

• Primary Cytotoxic T Cell Lymphomas Harbor Recurrent Targetable Alterations in the JAK-STAT Pathway. Blood Lee, K., Evans, M. G., Yang, L., Ng, S., Snowden, C., Khodadoust, M. S., Brown, R. A., Trum, N. A., Querfeld, C., Doan, L. T., Song, J., Zhang, H., Gru, A., Wood, G. S., Wada, D. A., Shanmugam, V., Haun, P. L., Aster, J. C., Duncan, L. M., Guitart, J., Weinstock, D. M., Nardi, V., Choi, J. 2021

  View details for DOI 10.1182/blood.2021012536

  View details for PubMedID 34432866

• Highly Multiplexed Phenotyping of Immunoregulatory Proteins in the Tumor Microenvironment by CODEX Tissue Imaging FRONTIERS IN IMMUNOLOGY Phillips, D., Schuerch, C. M., Khodadoust, M. S., Kim, Y. H., Nolan, G. P., Jiang, S. 2021; 12: 687673

  Abstract

  Immunotherapies are revolutionizing cancer treatment by boosting the natural ability of the immune system. In addition to antibodies against traditional checkpoint molecules or their ligands (i.e., CTLA-4, PD-1, and PD-L1), therapies targeting molecules such as ICOS, IDO-1, LAG-3, OX40, TIM-3, and VISTA are currently in clinical trials. To better inform clinical care and the design of therapeutic combination strategies, the co-expression of immunoregulatory proteins on individual immune cells within the tumor microenvironment must be robustly characterized. Highly multiplexed tissue imaging platforms, such as CO-Detection by indEXing (CODEX), are primed to meet this need by enabling >50 markers to be simultaneously analyzed in single-cells on formalin-fixed paraffin-embedded (FFPE) tissue sections. Assembly and validation of antibody panels is particularly challenging, with respect to the specificity of antigen detection and robustness of signal over background. Herein, we report the design, development, optimization, and application of a 56-marker CODEX antibody panel to eight cutaneous T cell lymphoma (CTCL) patient samples. This panel is comprised of structural, tumor, and immune cell markers, including eight immunoregulatory proteins that are approved or currently undergoing clinical trials as immunotherapy targets. Here we provide a resource to enable extensive high-dimensional, spatially resolved characterization of the tissue microenvironment across tumor types and imaging modalities. This framework provides researchers with a readily applicable blueprint to study tumor immunology, tissue architecture, and enable mechanistic insights into immunotherapeutic targets.

  View details for DOI 10.3389/fimmu.2021.687673

  View details for Web of Science ID 000657048100001

  View details for PubMedID 34093591

  View details for PubMedCentralID PMC8170307

• Low-Dose Total Skin Electron Beam Therapy Combined With Mogamulizumab for Refractory Mycosis Fungoides and Sezary Syndrome. Advances in radiation oncology Fong, S., Hong, E. K., Khodadoust, M. S., Li, S., Hoppe, R. T., Kim, Y. H., Hiniker, S. M. 2021; 6 (3): 100629

  Abstract

  Purpose: Management of patients with refractory mycosis fungoides and Sezary syndrome (SS) is often challenging, as available therapies lack durable response and consistent activity across disease compartments. Combining low-dose total skin electron beam therapy (LD-TSEBT) upfront with mogamulizumab could optimize the clinical outcome of these patients. LD-TSEBT is effective in clearing skin disease, and mogamulizumab is an antitumor immunotherapy with long-term tolerability, suggesting its potential as a maintenance therapy after maximal response. We examine the combination regimen in patients with SS who were previously treated.Methods and Materials: Two patients with SS were treated with combination LD-TSEBT and mogamulizumab. Both patients received mogamulizumab 1 mg/kg weekly * 4 and then bi-weekly; LD-TSEBT (12 Gy) was initiated within 2 days of starting mogamulizumab and given over 2-3 weeks. Safety and clinical response were evaluated.Results: Total skin electron beam therapy plus mogamulizumab (TSE-Moga) was well-tolerated without any unanticipated adverse events. Patient 1 (T4N2bM0B2) was a 63-year-old woman with 4 prior systemic therapies; time to global response with TSE-Moga was 9 weeks. Patient 2 (T4NxM0B2) was a 75-year-old man with 5 prior systemic therapies; time to global response was 4 weeks. Both patients lacked global response to their prior therapies but achieved global complete response (blood and skin) with TSE-Moga. After a follow-up of 72 weeks and 43 weeks, respectively, global complete response continued.Conclusions: TSE-Moga demonstrated excellent tolerability and promising clinical activity with ongoing global complete responses in 2 patients with refractory SS. This encouraging experience supports our ongoing clinical trial evaluating the efficacy and safety of TSE-Moga in mycosis fungoides and SS.

  View details for DOI 10.1016/j.adro.2020.11.014

  View details for PubMedID 33748543

• Radiation Therapy for Primary Cutaneous Gamma Delta Lymphoma Prior to Stem Cell Transplantation. Cancer investigation Wu, Y. F., Skinner, L., Lewis, J., Khodadoust, M. S., Kim, Y. H., Kwong, B. Y., Weng, W., Hoppe, R. T., Sodji, Q., Hui, C., Kastelowitz, N., Fernandez-Pol, S., Hiniker, S. M. 2021: 1–11

  Abstract

  We present a patient with widespread PCGD-TCL of the bilateral arms and legs, who underwent radiotherapy with 34Gy in 17 fractions using circumferential VMAT and 3-D printed bolus to the 4 extremities prior to planned stem cell transplant, who was then found to have progression in the liver, lung, and skin, followed by drastic regression of all in and out-of-field lesions on imaging 1.5months later. The cause of regression may be related to a radiation-induced abscopal effect from the immunomodulatory effects of radiation, or related to immune reactivation in the setting of cessation of systemic immunosuppressive agents.

  View details for DOI 10.1080/07357907.2021.1919696

  View details for PubMedID 33899635

• Clinical Characterization of Mogamulizumab-Associated Rash During Treatment of Mycosis Fungoides or Sezary Syndrome. JAMA dermatology Hirotsu, K. E., Neal, T. M., Khodadoust, M. S., Wang, J. Y., Rieger, K. E., Strelo, J., Hong, E., Kim, Y. H., Kwong, B. Y. 2021

  Abstract

  Importance: Mogamulizumab is a monoclonal antibody against CCR4 approved for treatment for mycosis fungoides (MF) and Sezary syndrome (SS). Mogamulizumab-associated rash (MAR) is difficult to differentiate from cutaneous MF or SS, which can lead to unnecessary discontinuation of drug use because of concern for severe drug reaction or incorrect presumption of disease relapse or progression in the skin.Objective: To examine the most common clinical presentations of MAR in patients with MF or SS and the diagnostic and management challenges.Design, Setting, and Participants: This retrospective case series assessed patients from a multidisciplinary cutaneous lymphoma clinic and supportive oncodermatology clinic at a major academic referral center who had a diagnosis of MF or SS and received mogamulizumab from January 1, 2013, to January 1, 2020. Treatment was followed by new or worsening rash with skin biopsy results compatible with drug eruption determined by clinicopathologic correlation and molecular testing to exclude active malignant disease.Exposures: At least 1 dose of mogamulizumab.Main Outcomes and Measures: Mogamulizumab-associated rash was characterized by clinical features, including time to onset, clinical presentation, histopathologic features, and management approach.Results: The study included 19 patients with MF or SS who developed MAR (median age, 65 years; age range, 38-82 years; 10 [52.6%] male). Median time to MAR onset was 119 days (range, 56 days to 3.8 years). Patients with MAR exhibited 4 predominant clinical presentations: (1) folliculotropic MF-like scalp plaques with alopecia, (2) papules and/or plaques, (3) photoaccentuated dermatitis, and (4) morbilliform or erythrodermic dermatitis. The most common anatomical region involved was the head and neck, including the scalp. Histopathologic findings were variable and did not correspond to primary clinical morphologic findings. Immunohistochemistry and T-cell clonality ancillary testing were helpful to distinguish MAR from disease. Most patients with MAR (14 of 19) discontinued mogamulizumab treatment; however, no life-threatening severe cutaneous adverse drug reactions occurred, and the decision for drug therapy cessation was usually multifactorial. Four patients were treated again with mogamulizumab with no life-threatening drug-related events. Approaches to management of MAR include topical corticosteroids, systemic corticosteroids, and/or methotrexate.Conclusions and Relevance: This case series found that mogamulizumab-associated rash had a heterogeneous clinical presentation with variable and delayed onset in patients with MF or SS. Mogamulizumab-associated rash exhibited a predilection for the head and neck and was difficult to clinically distinguish from relapse or progression of disease. Recognition of the most common clinical presentations can help prevent unnecessary discontinuation of mogamulizumab treatment. The presence of MAR does not necessitate permanent discontinuation of or avoidance of retreatment with mogamulizumab.

  View details for DOI 10.1001/jamadermatol.2021.0877

  View details for PubMedID 33881447

• Immune cell topography predicts response to PD-1 blockade in cutaneous T cell lymphoma. Nature communications Phillips, D., Matusiak, M., Gutierrez, B. R., Bhate, S. S., Barlow, G. L., Jiang, S., Demeter, J., Smythe, K. S., Pierce, R. H., Fling, S. P., Ramchurren, N., Cheever, M. A., Goltsev, Y., West, R. B., Khodadoust, M. S., Kim, Y. H., Schürch, C. M., Nolan, G. P. 2021; 12 (1): 6726

  Abstract

  Cutaneous T cell lymphomas (CTCL) are rare but aggressive cancers without effective treatments. While a subset of patients derive benefit from PD-1 blockade, there is a critically unmet need for predictive biomarkers of response. Herein, we perform CODEX multiplexed tissue imaging and RNA sequencing on 70 tumor regions from 14 advanced CTCL patients enrolled in a pembrolizumab clinical trial (NCT02243579). We find no differences in the frequencies of immune or tumor cells between responders and non-responders. Instead, we identify topographical differences between effector PD-1+ CD4+ T cells, tumor cells, and immunosuppressive Tregs, from which we derive a spatial biomarker, termed the SpatialScore, that correlates strongly with pembrolizumab response in CTCL. The SpatialScore coincides with differences in the functional immune state of the tumor microenvironment, T cell function, and tumor cell-specific chemokine recruitment and is validated using a simplified, clinically accessible tissue imaging platform. Collectively, these results provide a paradigm for investigating the spatial balance of effector and suppressive T cell activity and broadly leveraging this biomarker approach to inform the clinical use of immunotherapies.

  View details for DOI 10.1038/s41467-021-26974-6

  View details for PubMedID 34795254

• Two Cases With Features of Lymphocyte Variant Hypereosinophilic Syndrome With STAT3 SH2 Domain Mutations. The American journal of surgical pathology Fernandez-Pol, S., Petersen, B., Murphy, J., Oak, J. S., Wang, E. B., Rieger, K. E., Kim, Y. H., Khodadoust, M. S., Suarez, C. J. 2020

  Abstract

  Lymphocyte variant hypereosinophilic syndrome (LV-HES) is a rare cause of eosinophilia that is due to eosinophilipoietic cytokine production by an immunophenotypically abnormal T-cell clone. The molecular pathogenesis of this disorder is largely unknown and only 1 case of LV-HES with a pathogenic STAT3 mutation has been described thus far. Here we report 2 cases of LV-HES with STAT3 SH2 domain mutations. These cases further support the model that activation of STAT3 signaling through STAT3 SH2 domain mutations is a recurrent event in LV-HES.

  View details for DOI 10.1097/PAS.0000000000001604

  View details for PubMedID 33060403

• Cutaneous T-cell lymphomas with pathogenic somatic mutations and absence of detectable clonal T-cell receptor gene rearrangement: two case reports. Diagnostic pathology Rojansky, R., Fernandez-Pol, S., Wang, E., Rieger, K. E., Novoa, R. A., Zehnder, J. L., Kunder, C. A., Kim, Y. H., Khodadoust, M. S., Brown, R. A. 2020; 15 (1): 122

  Abstract

  BACKGROUND: Cutaneous T-cell lymphomas (CTCL) are a heterogeneous group of extranodal non-Hodgkin lymphomas for which diagnosis can be challenging given the potential for overlap with inflammatory dermatoses. Current diagnostic criteria for CTCL incorporate clinical and histopathologic findings as well as results of T-cell receptor (TCR) gene sequencing. Molecular interrogation of TCR genes, TRG and TRB, has provento be a critical tool for confirming diagnoses of CTCL and for disease tracking after initiation of therapy or after stem cell transplant. Methods for confirming a diagnosis of lymphoma in the absence of TCR gene clonality are lacking. We present two patients with CTCL with pathogenic somatic mutations in the absence of TRG and TRB clonality.CASE PRESENTATIONS: Case 1: A 38-year-old male had a 19-year history of a diffuse skin rash with papulosquamous, granulomatous, and verrucous features and progressive ulcerated plaques and tumors demonstrating an atypical CD4+ T-cell infiltrate with expression of cytotoxic markers CD56, TIA-1, granzyme, and perforin on histopathology. No definitive evidence for T-cell clonality was detected by conventional PCR of 6 biopsies or by next-generation sequencing (NGS) of 14 biopsies. Somatic mutational profiling of a skin biopsy revealed pathogenic mutations in PIKC3D and TERT promoter hotspots, confirming the presence of a clonal process. Case 2: A 69-year-old male with a 13-year history of progressive, diffuse hypertrophic and eroded plaques showed an atypical CD4+ T-cell infiltrate with subset expression of TIA-1 and granzyme on histopathology. No TCR clonality was detected by TCR-NGS of 6 biopsies. Somatic mutational profiling of a skin biopsy detected a pathogenic mutation in TP53, confirming the presence of a clonal process.CONCLUSIONS: These cases highlight how detection of pathogenic somatic mutations can confirma diagnosis of lymphoma in a clinically and histopathologically suspicious cutaneous lymphoid proliferation without detectable TCR clonality.

  View details for DOI 10.1186/s13000-020-01022-x

  View details for PubMedID 32988392

• Cellular neighborhoods predict pembrolizumab response in cutaneous T cell lymphoma Schurch, C. M., Phillips, D. J., Gutierrez, B., Matusiak, M., Bhate, S. S., Barlow, G. L., Fling, S. P., Ramchurren, N., Pierce, R. H., Cheever, M. A., Khodadoust, M. S., West, R., Kim, Y. H., Nolan, G. P. AMER ASSOC CANCER RESEARCH. 2020

  View details for DOI 10.1158/1538-7445.AM2020-6669

  View details for Web of Science ID 000590059307310

• Autologous tumor cell vaccine induces antitumor T cell immune responses in patients with mantle cell lymphoma: A phase I/II trial. The Journal of experimental medicine Frank, M. J., Khodadoust, M. S., Czerwinski, D. K., Haabeth, O. A., Chu, M. P., Miklos, D. B., Advani, R. H., Alizadeh, A. A., Gupta, N. K., Maeda, L. S., Reddy, S. A., Laport, G. G., Meyer, E. H., Negrin, R. S., Rezvani, A. R., Weng, W. K., Sheehan, K. n., Faham, M. n., Okada, A. n., Moore, A. H., Phillips, D. L., Wapnir, I. L., Brody, J. D., Levy, R. n. 2020; 217 (9)

  Abstract

  Here, we report on the results of a phase I/II trial (NCT00490529) for patients with mantle cell lymphoma who, having achieved remission after immunochemotherapy, were vaccinated with irradiated, CpG-activated tumor cells. Subsequently, vaccine-primed lymphocytes were collected and reinfused after a standard autologous stem cell transplantation (ASCT). The primary endpoint was detection of minimal residual disease (MRD) within 1 yr after ASCT at the previously validated threshold of ≥1 malignant cell per 10,000 leukocyte equivalents. Of 45 evaluable patients, 40 (89%) were found to be MRD negative, and the MRD-positive patients experienced early subsequent relapse. The vaccination induced antitumor CD8 T cell immune responses in 40% of patients, and these were associated with favorable clinical outcomes. Patients with high tumor PD-L1 expression after in vitro exposure to CpG had inferior outcomes. Vaccination with CpG-stimulated autologous tumor cells followed by the adoptive transfer of vaccine-primed lymphocytes after ASCT is feasible and safe.

  View details for DOI 10.1084/jem.20191712

  View details for PubMedID 32558897

• Histopathologic Characterization of Mogamulizumab-associated Rash. The American journal of surgical pathology Wang, J. Y., Hirotsu, K. E., Neal, T. M., Raghavan, S. S., Kwong, B. Y., Khodadoust, M. S., Brown, R. A., Novoa, R. A., Kim, Y. H., Rieger, K. E. 2020

  Abstract

  Rash is one of the most common adverse events observed with mogamulizumab, an anti-C-C chemokine receptor 4 monoclonal antibody approved for previously treated mycosis fungoides (MF) and Sezary syndrome (SS). Given the nonspecific clinical presentations of this rash, histopathologic distinction from MF/SS is critical for informing clinical management. We performed a comprehensive characterization of the histopathologic findings in mogamulizumab-associated rash (MAR) with the integration of high-throughput sequencing of T-cell receptor (TCR) genes. Fifty-two biopsy specimens from 19 patients were evaluated retrospectively. Three major histologic reaction patterns were identified: spongiotic/psoriasiform dermatitis (33/52), interface dermatitis (11/52), and granulomatous dermatitis (8/52). Almost half of the specimens (21/52) showed at least 2 of these reaction patterns concurrently. Dermal eosinophils were not a consistent feature, being present in only half (27/52) of specimens and prominent in only 3. Features mimicking MF/SS, including lymphocyte exocytosis, lamellar fibroplasia, and adnexal involvement, were commonly seen but tended to be focal and mild. In 38/43 specimens with available immunohistochemistry, intraepidermal lymphocytes demonstrated a CD4:CD8 ratio ≤1 : 1. Low background levels of the patient's previously identified MF/SS-associated TCR sequence(s) were demonstrated in 20/46 specimens analyzed by high-throughput sequencing of TCR. We conclude that MAR may demonstrate diverse histologic features. Findings that may distinguish MAR from MF/SS include the inverted or normalized CD4:CD8 ratio within intraepidermal lymphocytes and demonstration of absent or nondominant levels of disease-associated TCR sequences. Correlation with the clinical findings and immunohistochemical and molecular characterization of the patient's MF/SS before mogamulizumab, when possible, may facilitate recognition of MAR.

  View details for DOI 10.1097/PAS.0000000000001587

  View details for PubMedID 32976123

• Nonmyeloablative allogeneic transplantation achieves clinical and molecular remission in cutaneous T-cell lymphoma. Blood advances Weng, W. K., Arai, S. n., Rezvani, A. n., Johnston, L. n., Lowsky, R. n., Miklos, D. n., Shizuru, J. n., Muffly, L. n., Meyer, E. n., Negrin, R. S., Wang, E. n., Almazan, T. n., Million, L. n., Khodadoust, M. n., Li, S. n., Hoppe, R. T., Kim, Y. H. 2020; 4 (18): 4474–82

  Abstract

  The majority of patients with refractory, advanced-stage mycosis fungoides (MF) or Sézary syndrome (SS) have a life expectancy of <5 years. Here, we report a phase 2 study of a novel nonmyeloablative allogeneic transplantation strategy tailored for this patient population. This study has completed the enrollment, and 35 patients (13 MF, 22 SS) have undergone transplant as planned. The majority (80%) of the patients had stage IV disease and received multiple previous systemic therapies. All patients had active disease at the time of conditioning using total skin electron beam therapy, total lymphoid irradiation, and antithymocyte globulin, and received allograft infusion as outpatients. Cyclosporine or tacrolimus and mycophenolate mofetil were used for graft-versus-host disease (GVHD) prophylaxis. Patients tolerated the transplant well, with 1- and 2-year nonrelapse mortality of 3% and 14%, respectively. The day +180 cumulative incidence of grade 2 to 4 acute GVHD was 16%, and the 2-year incidence of moderate/severe chronic GVHD was 32%. With a median posttransplant follow-up of 5.4 years, the 2-, 3-, and 5-year overall survival rates were 68%, 62%, and 56%. Using high-throughput sequencing of the T-cell receptor for minimal residual disease monitoring, we observed that 43% achieved molecular remission, which was associated with a lower incidence of disease progression or relapse (9% vs 87%; P = .02). Our study also showed that patients who were aged ≥65 years at the time of allotransplant had similar clinical outcomes compared with younger patients. Thus, we have developed an alternative and potentially curative nonmyeloablative allogeneic transplant regimen for patients with advanced stage MF/SS. This trial was registered at www.clinicaltrials.gov as #NCT00896493.

  View details for DOI 10.1182/bloodadvances.2020001627

  View details for PubMedID 32941647

• A Long-Term Study of Persistent Sézary Syndrome: Evidence for Antigen Shift by Multiparameter Flow Cytometry and Its Significance in Overall Survival. The American Journal of dermatopathology Hoffmann, J. C., Atwater, S. K., Hong, E. n., Kumar, J. n., Khodadoust, M. n., Kim, Y. n., Ohgami, R. S. 2020; 42 (6): 389–96

  Abstract

  Sézary syndrome (SS) is a peripheral T-cell lymphoma characterized by erythroderma, diffuse lymphadenopathy, and circulating neoplastic T cells, which classically show a helper T-cell immunophenotype with loss of CD7 and CD26. Flow cytometry is often used to identify and enumerate populations of Sézary cells in the peripheral blood; however, the significance and frequency of antigen shift over time is unclear. In this article, we follow the immunophenotype of the neoplastic T-cell population from 28 patients with SS across 415 flow cytometry studies. Antigen shift for each patient was assigned as none, minimal = 1-2 markers by 1°, moderate = up to 3 markers, or marked ≥ 4 markers. Sixty-four percent (18/28) of patients showed antigen shift, and among those with antigen shift, the majority showed minimal (8/18) or moderate antigen shift (7/18) with fewer demonstrating marked shift (3/18). Patients without antigen shift showed a trend toward improved overall survival in comparison with patients demonstrating any degree of antigen shift. Antigen shift is seen in a significant proportion of cases of SS with long-term follow-up and may be a marker of more aggressive disease.

  View details for DOI 10.1097/DAD.0000000000001637

  View details for PubMedID 32433315

• Maria-I: A Deep-Learning Approach for Accurate Prediction of MHC Class I Tumor Neoantigen Presentation Kathuria, K. R., Chen, B., Khodadoust, M. S., Olsson, N., Davis, M. M., Elias, J. E., Levy, R., Altman, R. B., Alizadeh, A. A. AMER SOC HEMATOLOGY. 2019

  View details for DOI 10.1182/blood-2019-129334

  View details for Web of Science ID 000518218500130

• A Phase I/II Trial of Intratumoral CpG, Local Low-Dose Radiation, and Oral Ibrutinib in Patients with Low-Grade B-Cell Lymphoma Shree, T., Khodadoust, M. S., Czerwinski, D. K., Frank, M. J., Hong, W. X., Greenstein, R., Long, S. R., Martin, B., Levy, R. AMER SOC HEMATOLOGY. 2019

  View details for DOI 10.1182/blood-2019-129661

  View details for Web of Science ID 000577160406206

• Follicular Lymphoma Organoids for Investigating the Tumor Microenvironment Wagar, L. E., Sworder, B., Khodadoust, M. S., Davis, M. M., Alizadeh, A. A. AMER SOC HEMATOLOGY. 2019

  View details for DOI 10.1182/blood-2019-131192

  View details for Web of Science ID 000577160406180

• A Phase 1/1b Dose-Escalation Trial Evaluating Cpi-818, an Oral Interleukin-2-Inducible T-Cell Kinase Inhibitor, in Subjects with Relapsed/Refractory T-Cell Lymphoma Mobasher, M., Miller, R. A., Janc, J. W., Kwei, L., Buggy, J. J., Luciano, G., Mohammady, A., Kim, W., Kim, Y. H., Khodadoust, M. S., Horwitz, S. M., Radeski, D. AMER SOC HEMATOLOGY. 2019

  View details for DOI 10.1182/blood-2019-124958

  View details for Web of Science ID 000577164602053

• Preliminary Clinical Data from a Phase 1 Trial with CPI-818, a Selective ITK Inhibitor That Preferentially Blocks the Growth of T Lymphoma Cells Ng, P. P., Mobasher, M., Yeung, K. S., Hotson, A. N., Hill, C. M., Madriaga, A., Dao-Pick, T. P., Verner, E., Radeski, D., Khodadoust, M. S., Kim, Y. H., Miller, R. A., Buggy, J. J., Janc, J. W. AMER SOC HEMATOLOGY. 2019

  View details for DOI 10.1182/blood-2019-127338

  View details for Web of Science ID 000577160402124

• Dynamics of the Cutaneous T Cell Lymphoma Microenvironment in Patients Treated with Pembrolizumab Revealed By Highly Multiplexed Tissue Imaging Schuerch, C. M., Phillips, D. J., Bhate, S. S., Barlow, G. L., Fling, S. P., Ramchurren, N., Pierce, R., Cheever, M. A., Khodadoust, M. S., Kim, Y. H., Nolan, G. P. AMER SOC HEMATOLOGY. 2019

  View details for DOI 10.1182/blood-2019-125315

  View details for Web of Science ID 000577160403194

• A Phase 2 Study of the Dual SYK/JAK Inhibitor Cerdulatinib Demonstrates Good Tolerability and Clinical Response in Relapsed/Refractory Peripheral T-Cell Lymphoma and Cutaneous T-Cell Lymphoma Horwitz, S. M., Feldman, T. A., Hess, B. T., Khodadoust, M. S., Kim, Y. H., Munoz, J., Patel, M. R., Phillips, T. J., Smith, S. D., Smith, S. M., Wilcox, R. A., Birrell, M. R., Leeds, J. M., Conley, P. B., Michelson, G. C., Coffey, G. P., Curnutte, J. T., Hamlin, P. A. AMER SOC HEMATOLOGY. 2019

  View details for DOI 10.1182/blood-2019-123986

  View details for Web of Science ID 000518218500569

• Antagonism of TNFR2: Focus on novel antibodies with preference for tumor microenvironment Tregs and oncogenes expressed on the tumor Khodadoust, M., Kim, Y., Yang, M., Torrey, H., Tran, L., Faustman, D. BMC. 2019

  View details for Web of Science ID 000496473200268

• Interim results of a Phase I/II trial of intratumoral CpG, local low-dose radiation, and oral ibrutinib in patients with low-grade B-cell lymphoma Shree, T., Khodadoust, M. S., Czerwinski, D., Frank, M. J., Hong, W. X., Greenstein, R., Guo, S., Long, S., Martin, B. A., Levy, R. AMER ASSOC CANCER RESEARCH. 2019

  View details for DOI 10.1158/1538-7445.AM2019-CT133

  View details for Web of Science ID 000488129900119

• IPH4102, a first-in-class anti-KIR3DL2 monoclonal antibody, in patients with relapsed or refractory cutaneous T-cell lymphoma: an international, first-in-human, open-label, phase 1 trial. The Lancet. Oncology Bagot, M., Porcu, P., Marie-Cardine, A., Battistella, M., William, B. M., Vermeer, M., Whittaker, S., Rotolo, F., Ram-Wolff, C., Khodadoust, M. S., Bensussan, A., Paturel, C., Bonnafous, C., Sicard, H., Azim, H. A., Kim, Y. H. 2019

  Abstract

  BACKGROUND: IPH4102 is a first-in-class monoclonal antibody targeting KIR3DL2, a cell surface protein that is expressed in cutaneous T-cell lymphoma, and predominantly in its leukaemic form, Sezary syndrome. We aimed to assess the safety and activity of IPH4102 in cutaneous T-cell lymphoma.METHODS: We did an international, first-in-human, open-label, phase 1 clinical trial with dose-escalation and cohort-expansion parts in five academic hospitals in the USA, France, the UK, and the Netherlands. Eligible patients had histologically confirmed relapsed or refractory primary cutaneous T-cell lymphoma, an Eastern Cooperative Oncology group performance score of 2 or less, were aged 18 years or older, and had received at least two previous systemic therapies. Ten dose levels of IPH4102, administered as an intravenous infusion, ranging from 0·0001 mg/kg to 10 mg/kg, were assessed using an accelerated 3 + 3 design. The primary endpoint was the occurrence of dose-limiting toxicities during the first 2 weeks of treatment, defined as toxicity grade 3 or worse lasting for 8 or more days, except for lymphopenia. Global overall response by cutaneous T-cell lymphoma subtype was a secondary endpoint. Safety and activity analyses were done in the per-protocol population. The study is ongoing and recruitment is complete. This trial is registered with ClinicalTrials.gov, number NCT02593045.FINDINGS: Between Nov 4, 2015, and Nov 20, 2017, 44 patients were enrolled. 35 (80%) patients had Sezary syndrome, eight (18%) had mycosis fungoides, and one (2%) had primary cutaneous T-cell lymphoma, not otherwise specified. In the dose-escalation part, no dose limiting toxicity was reported and the trial's safety committee recommended a flat dose of 750 mg for the cohort-expansion, corresponding to the maximum administered dose. The most common adverse events were peripheral oedema (12 [27%] of 44 patients) and fatigue (nine [20%]), all of which were grade 1-2. Lymphopenia was the most common grade 3 or worse adverse event (three [7%]). One patient developed possibly treatment-related fulminant hepatitis 6 weeks after IPH4102 discontinuation and subsequently died. However, the patient had evidence of human herpes virus-6B infection. Median follow-up was 14·1 months (IQR 11·3-20·5). A confirmed global overall response was achieved in 16 (36·4% [95% CI 23·8-51·1]) of 44 patients, and of those, 15 responses were observed in 35 patients with Sezary syndrome (43% [28·0-59·1]).INTERPRETATION: IPH4102 is safe and shows encouraging clinical activity in patients with relapsed or refractory cutaneous T-cell lymphoma, particularly those with Sezary syndrome. If confirmed in future trials, IPH4102 could become a novel treatment option for these patients. A multi-cohort, phase 2 trial (TELLOMAK) is underway to confirm the activity in patients with Sezary syndrome and explore the role of IPH4102 in other subtypes of T-cell lymphomas that express KIR3DL2.FUNDING: Innate Pharma.

  View details for DOI 10.1016/S1470-2045(19)30320-1

  View details for PubMedID 31253572

• Low-dose Total Skin Electron Beam Therapy for Refractory Cutaneous CD30 Positive Lymphoproliferative Disorders. The Journal of dermatological treatment Panjwani, N., Yoo, C. H., Wang, E., Khodadoust, M. S., Kim, Y. H., Hoppe, R. T., Hiniker, S. M. 2019: 1–5

  Abstract

  We describe a case of a 48-year-old woman with a refractory cutaneous CD30 positive lymphoproliferative disorder treated successfully with total skin electron beam radiotherapy (TSEBT).

  View details for DOI 10.1080/09546634.2019.1628913

  View details for PubMedID 31179774

• Prognostic Value of Circulating Tumor DNA in Diffuse Large B-Cell Lymphoma Reply JOURNAL OF CLINICAL ONCOLOGY Kurtz, D. M., Scherer, F., Jin, M. C., Soo, J., Craig, A. M., Esfahani, M. S., Chabon, J. J., Stehr, H., Liu, C., Tibshirani, R., Maeda, L. S., Gupta, N. K., Khodadoust, M. S., Advani, R. H., Newman, A. M., Duehrsen, U., Huettmann, A., Meignan, M., Casasnovas, O., Westin, J. R., Roschewski, M., Wilson, W. H., Gaidano, G., Rossi, D., Diehn, M., Alizadeh, A. A. 2019; 37 (9): 755-+

  View details for DOI 10.1200/JCO.18.01907

  View details for Web of Science ID 000462408300010

• Volumetric modulated arc therapy and 3-dimensional printed bolus in the treatment of refractory primary cutaneous gamma delta lymphoma of the bilateral legs. Practical radiation oncology Obeid, J., Gutkin, P. M., Lewis, J., Skinner, L., Wang, E. B., Khodadoust, M. S., Kim, Y. H., Weng, W., Hoppe, R. T., Hiniker, S. M. 2019

  Abstract

  Patients with extensive dermal and subcutaneous disease present a technical challenge for treatment with radiation therapy (RT). Volumetric arc therapy (VMAT) can effectively treat disease on circumferential surfaces while minimizing dose to the core structures. However, treatment of extensive areas of the bilateral lower extremities with this technique has not been previously reported. Here we report the successful treatment of a patient with primary cutaneous gamma-delta T-cell lymphoma of the bilateral legs using VMAT and a custom 3-dimensional printed bolus. This approach is applicable for the treatment of cutaneous malignancies of the lower extremities.

  View details for PubMedID 30836188

• B-cell lymphomas present immunoglobulin neoantigens BLOOD Khodadoust, M. S., Olsson, N., Chen, B., Sworder, B., Shree, T., Liu, C., Zhang, L., Czerwinski, D. K., Davis, M. M., Levy, R., Elias, J. E., Alizadeh, A. A. 2019; 133 (8): 878–81

  View details for DOI 10.1182/blood-2018-06-845156

  View details for Web of Science ID 000459264700019

• Reply to J. Wang et al. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Kurtz, D. M., Scherer, F., Jin, M. C., Soo, J., Craig, A. F., Esfahani, M. S., Chabon, J. J., Stehr, H., Liu, C. L., Tibshirani, R., Maeda, L. S., Gupta, N. K., Khodadoust, M. S., Advani, R. H., Newman, A. M., Duhrsen, U., Huttmann, A., Meignan, M., Casasnovas, O., Westin, J. R., Roschewski, M., Wilson, W. H., Gaidano, G., Rossi, D., Diehn, M., Alizadeh, A. A. 2019: JCO1801907

  View details for PubMedID 30753108

• Circulating DNA for Molecular Response Prediction, Characterization of Resistance Mechanisms and Quantification of CAR T-Cells during Axicabtagene Ciloleucel Therapy American Society of Hematology Sworder, B., Kurtz, D. M., Macaulay, C., Frank, M. J., Alig, S., Garofalo, A., Sahaf, B., Esfahani, M. S., Spiegel, J. Y., Oak, J., Beygi, S., Jin, M. C., Chabon, J. J., Khodadoust, M. S., Majzner, R. G., Mackall, C. L., Diehn, M., Miklos, D. B., Alizadeh, A. A. 2019

  View details for DOI 10.1182/blood-2019-129015

• Predicting HLA class II antigen presentation through integrated deep learning. Nature biotechnology Chen, B. n., Khodadoust, M. S., Olsson, N. n., Wagar, L. E., Fast, E. n., Liu, C. L., Muftuoglu, Y. n., Sworder, B. J., Diehn, M. n., Levy, R. n., Davis, M. M., Elias, J. E., Altman, R. B., Alizadeh, A. A. 2019

  Abstract

  Accurate prediction of antigen presentation by human leukocyte antigen (HLA) class II molecules would be valuable for vaccine development and cancer immunotherapies. Current computational methods trained on in vitro binding data are limited by insufficient training data and algorithmic constraints. Here we describe MARIA (major histocompatibility complex analysis with recurrent integrated architecture; https://maria.stanford.edu/ ), a multimodal recurrent neural network for predicting the likelihood of antigen presentation from a gene of interest in the context of specific HLA class II alleles. In addition to in vitro binding measurements, MARIA is trained on peptide HLA ligand sequences identified by mass spectrometry, expression levels of antigen genes and protease cleavage signatures. Because it leverages these diverse training data and our improved machine learning framework, MARIA (area under the curve = 0.89-0.92) outperformed existing methods in validation datasets. Across independent cancer neoantigen studies, peptides with high MARIA scores are more likely to elicit strong CD4+ T cell responses. MARIA allows identification of immunogenic epitopes in diverse cancers and autoimmune disease.

  View details for DOI 10.1038/s41587-019-0280-2

  View details for PubMedID 31611695

• Acute myeloid leukemia immunopeptidome reveals HLA presentation of mutated nucleophosmin. PloS one Narayan, R. n., Olsson, N. n., Wagar, L. E., Medeiros, B. C., Meyer, E. n., Czerwinski, D. n., Khodadoust, M. S., Zhang, L. n., Schultz, L. n., Davis, M. M., Elias, J. E., Levy, R. n. 2019; 14 (7): e0219547

  Abstract

  Somatic mutations in cancer are a potential source of cancer specific neoantigens. Acute myeloid leukemia (AML) has common recurrent mutations shared between patients in addition to private mutations specific to individuals. We hypothesized that neoantigens derived from recurrent shared mutations would be attractive targets for future immunotherapeutic approaches. Here we sought to study the HLA Class I and II immunopeptidome of thirteen primary AML tumor samples and two AML cell lines (OCI-AML3 and MV4-11) using mass spectrometry to evaluate for endogenous mutation-bearing HLA ligands from common shared AML mutations. We identified two endogenous, mutation-bearing HLA Class I ligands from nucleophosmin (NPM1). The ligands, AVEEVSLRK from two patient samples and C(cys)LAVEEVSL from OCI-AML3, are predicted to bind the common HLA haplotypes, HLA-A*03:01 and HLA-A*02:01 respectively. Since NPM1 is mutated in approximately one-third of patients with AML, the finding of endogenous HLA ligands from mutated NPM1 supports future studies evaluating immunotherapeutic approaches against this shared target, for this subset of patients with AML.

  View details for DOI 10.1371/journal.pone.0219547

  View details for PubMedID 31291378

• Determining cell type abundance and expression from bulk tissues with digital cytometry. Nature biotechnology Newman, A. M., Steen, C. B., Liu, C. L., Gentles, A. J., Chaudhuri, A. A., Scherer, F. n., Khodadoust, M. S., Esfahani, M. S., Luca, B. A., Steiner, D. n., Diehn, M. n., Alizadeh, A. A. 2019

  Abstract

  Single-cell RNA-sequencing has emerged as a powerful technique for characterizing cellular heterogeneity, but it is currently impractical on large sample cohorts and cannot be applied to fixed specimens collected as part of routine clinical care. We previously developed an approach for digital cytometry, called CIBERSORT, that enables estimation of cell type abundances from bulk tissue transcriptomes. We now introduce CIBERSORTx, a machine learning method that extends this framework to infer cell-type-specific gene expression profiles without physical cell isolation. By minimizing platform-specific variation, CIBERSORTx also allows the use of single-cell RNA-sequencing data for large-scale tissue dissection. We evaluated the utility of CIBERSORTx in multiple tumor types, including melanoma, where single-cell reference profiles were used to dissect bulk clinical specimens, revealing cell-type-specific phenotypic states linked to distinct driver mutations and response to immune checkpoint blockade. We anticipate that digital cytometry will augment single-cell profiling efforts, enabling cost-effective, high-throughput tissue characterization without the need for antibodies, disaggregation or viable cells.

  View details for PubMedID 31061481

• Durable Responses with Pembrolizumab in Relapsed/Refractory Mycosis Fungoides and Sezary Syndrome: Final Results from a Phase 2 Multicenter Study Khodadoust, M. S., Rook, A., Porcu, P., Foss, F. M., Moskowitz, A. J., Shustov, A. R., Shanbhag, S., Sokol, L., Fling, S. P., Li, S., Davis, A., Fong, S., Kim, J., Yang, Y., Yearley, J. H., Subrahmanyam, P. B., Maecker, H. T., Budovskaya, Y., Das, B., Patidar, R., Datta, V., Karlovich, C., Horwitz, S. M., Sharon, E., Kohrt, H., Cheever, M. A., Kim, Y. H. AMER SOC HEMATOLOGY. 2018

  View details for DOI 10.1182/blood-2018-99-117244

  View details for Web of Science ID 000454842800095

• The Combination of Duvelisib, a PI3K-delta,gamma Inhibitor, and Romidepsin Is Highly Active in Relapsed/Refractory Peripheral T-Cell Lymphoma with Low Rates of Transaminitis: Results of Parallel Multicenter, Phase 1 Combination Studies with Expansion Cohorts Horwitz, S. M., Moskowitz, A. J., Jacobsen, E. D., Mehta-Shah, N., Khodadoust, M. S., Fisher, D. C., Myskowski, P., Wang, E. K., Tawa, M., Davey, T., Blouin, W., Hancock, H., Ganesan, N., Galasso, N., Marzouk, E., Bahgat, A., Jester, H., Fong, S., Butt, A., Dogan, A., Kim, Y. H., Weinstock, D. M. AMER SOC HEMATOLOGY. 2018

  View details for DOI 10.1182/blood-2018-99-115241

  View details for Web of Science ID 000454837602061

• IPH4102; An Anti-KIR3DL2 Monoclonal Antibody in Refractory Sezary Syndrome: Results from a Multicenter Phase 1 Trial Bagot, M., Porcu, P., William, B. M., Battistella, M., Vermeer, M., Whittaker, S., Ram-Wolff, C., Khodadoust, M. S., Sicard, H., Azim, H. A., Kim, Y. H. AMER SOC HEMATOLOGY. 2018

  View details for DOI 10.1182/blood-2018-99-118021

  View details for Web of Science ID 000454837602062

• The Novel SYK/JAK Inhibitor Cerdulatinib Demonstrates Good Tolerability and Clinical Response in a Phase 2a Study in Relapsed/Refractory Peripheral T-Cell Lymphoma and Cutaneous T-Cell Lymphoma Horwitz, S. M., Feldman, T. A., Hess, B. T., Khodadoust, M. S., Kim, Y. H., Munoz, J., Patel, M. R., Phillips, T. J., Smith, S. D., Smith, S. M., Wilcox, R. A., Steele, A., Pandey, A., Birrell, M. R., Leeds, J. M., Conley, P. B., Michelson, G., Coffey, G. P., Curnutte, J. T., Hamlin, P. A. AMER SOC HEMATOLOGY. 2018

  View details for DOI 10.1182/blood-2018-99-119944

  View details for Web of Science ID 000454837603031

• Targeted killing of TNFR2-expressing tumor cells and Tregs by TNFR2 antagonistic antibodies in advanced Sézary syndrome. Leukemia Torrey, H., Khodadoust, M., Tran, L., Baum, D., Defusco, A., Kim, Y. H., Faustman, D. L. 2018

  Abstract

  Sézary syndrome (SS) is a rare form of cutaneous T-cell lymphoma often refractory to treatment. SS is defined as adenopathy, erythroderma with high numbers of atypical T cells. This offers an opportunity for new interventions and perhaps antibody-based therapeutic by virtue of its high expression of the TNFR2 oncogene on the tumor cells and on T-regulatory cells (Tregs). Potent human-directed TNFR2 antagonistic antibodies have been created that preferentially target the TNFR2 oncogene and tumor-infiltrating TNFR2+ Tregs. Here we test the therapeutic potential of TNFR2 antagonists on freshly isolated lymphocytes from patients with Stage IVA SS and from healthy controls. SS patients were on a variety of end-stage multi-drug therapies. Baseline burden Treg/T effector (Teff) ratios and the responsiveness of tumor and infiltrating Tregs to TNFR2 antibody killing was studied. We show dose-escalating concentrations of a dominant TNFR2 antagonistic antibody killed TNFR2+ SS tumor cells and thus restored CD26- subpopulations of lymphocyte cell numbers to normal. The abundant TNFR2+ Tregs of SS subjects are also killed with TNFR2 antagonism. Beneficial and rapid expansion of Teff was observed. The combination of Treg inhibition and Teff expansion brought the high Treg/Teff ratio to normal. Our findings suggest a marked responsiveness of SS tumor cells and Tregs, to targeting with TNFR2 antagonistic antibodies. These results show TNFR2 antibodies are potent and efficacious in vitro.

  View details for DOI 10.1038/s41375-018-0292-9

  View details for PubMedID 30356161

• Circulating Tumor DNA Measurements As Early Outcome Predictors in Diffuse Large B-Cell Lymphoma JOURNAL OF CLINICAL ONCOLOGY Kurtz, D. M., Scherer, F., Jin, M. C., Soo, J., Craig, A. M., Esfahani, M., Chabon, J. J., Stehr, H., Liu, C., Tibshirani, R., Maeda, L. S., Gupta, N. K., Khodadoust, M. S., Advani, R. H., Levy, R., Newman, A. M., Duehrsen, U., Huettmann, A., Meignan, M., Casasnovas, R., Westin, J. R., Roschewski, M., Wilson, W. H., Gaidano, G., Rossi, D., Diehn, M., Alizadeh, A. A. 2018; 36 (28): 2845-+

  View details for DOI 10.1200/JCO.2018.78.5246

  View details for Web of Science ID 000451485300005

• Pembrolizumab in mycosis fungoides and Sezary syndrome: Updated results of the CITN multicenter Phase 2 study Khodadoust, M. S., Rook, A. H., Porcu, P., Foss, F., Moskowitz, A., Shustov, A. R., Shanbhag, S., Sokol, L., Fling, S. P., Li, S., Fong, S., Kim, J., Yang, Y., Yearley, J., Subrahmanyam, P., Maecker, H., Horwitz, S. M., Sharon, E., Cheever, M. A., Kim, Y. H. ELSEVIER SCI LTD. 2018: S37

  View details for DOI 10.1016/j.ejca.2018.07.304

  View details for Web of Science ID 000443008600101

• Novel treatment of cutaneous T cell lymphoma: Targeting TNFR2, an oncogene and marker of potent Tregs, with anti-TNFR2 antibodies Torrey, H., Defusco, A., Baum, D., Rhabar, Z., Khodadoust, M., Kim, Y. H., Faustman, D. L. AMER ASSOC CANCER RESEARCH. 2018

  View details for DOI 10.1158/2326-6074.TUMIMM17-B18

  View details for Web of Science ID 000456801700070

• IPH4102 in relapsed/refractory cutaneous T cell lymphoma (CTCL): Results of the first-in-human multicenter phase 1 study Bagot, M., Porcu, P., William, B., Vermeer, M., Whittaker, S., Wolff, C., Khodadoust, M., Battistella, M., Paiva, C., Sicard, H., Azim, H., Kim, Y. ELSEVIER SCI LTD. 2018: S29

  View details for DOI 10.1016/j.ejca.2018.07.282

  View details for Web of Science ID 000443008600079

• Circulating Tumor DNA Measurements As Early Outcome Predictors in Diffuse Large B-Cell Lymphoma. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Kurtz, D. M., Scherer, F., Jin, M. C., Soo, J., Craig, A. F., Esfahani, M. S., Chabon, J. J., Stehr, H., Liu, C. L., Tibshirani, R., Maeda, L. S., Gupta, N. K., Khodadoust, M. S., Advani, R. H., Levy, R., Newman, A. M., Duhrsen, U., Huttmann, A., Meignan, M., Casasnovas, R., Westin, J. R., Roschewski, M., Wilson, W. H., Gaidano, G., Rossi, D., Diehn, M., Alizadeh, A. A. 2018: JCO2018785246

  Abstract

  Purpose Outcomes for patients with diffuse large B-cell lymphoma remain heterogeneous, with existing methods failing to consistently predict treatment failure. We examined the additional prognostic value of circulating tumor DNA (ctDNA) before and during therapy for predicting patient outcomes. Patients and Methods We studied the dynamics of ctDNA from 217 patients treated at six centers, using a training and validation framework. We densely characterized early ctDNA dynamics during therapy using cancer personalized profiling by deep sequencing to define response-associated thresholds within a discovery set. These thresholds were assessed in two independent validation sets. Finally, we assessed the prognostic value of ctDNA in the context of established risk factors, including the International Prognostic Index and interim positron emission tomography/computed tomography scans. Results Before therapy, ctDNA was detectable in 98% of patients; pretreatment levels were prognostic in both front-line and salvage settings. In the discovery set, ctDNA levels changed rapidly, with a 2-log decrease after one cycle (early molecular response [EMR]) and a 2.5-log decrease after two cycles (major molecular response [MMR]) stratifying outcomes. In the first validation set, patients receiving front-line therapy achieving EMR or MMR had superior outcomes at 24 months (EMR: EFS, 83% v 50%; P = .0015; MMR: EFS, 82% v 46%; P < .001). EMR also predicted superior 24-month outcomes in patients receiving salvage therapy in the first validation set (EFS, 100% v 13%; P = .011). The prognostic value of EMR and MMR was further confirmed in the second validation set. In multivariable analyses including International Prognostic Index and interim positron emission tomography/computed tomography scans across both cohorts, molecular response was independently prognostic of outcomes, including event-free and overall survival. Conclusion Pretreatment ctDNA levels and molecular responses are independently prognostic of outcomes in aggressive lymphomas. These risk factors could potentially guide future personalized risk-directed approaches.

  View details for PubMedID 30125215

• Surgical and molecular characterization of primary and metastatic disease in a neuroendocrine tumor arising in a tailgut cyst. Cold Spring Harbor molecular case studies Erdrich, J., Schaberg, K., Khodadoust, M. S., Zhou, L., Shelton, A. A., Visser, B. C., Ford, J. M., Alizadeh, A. A., Quake, S. R., Kunz, P. L., Beausang, J. F. 2018

  Abstract

  Neuroendocrine tumors arising from tailgut cysts are rare but increasingly reported entity with gene expression profiles that may be indicative of the gastrointestinal cell of origin. We present a case report describing the unique pathological and genomic characteristics of a tailgut cyst neuroendocrine tumor that metastasized to liver. The histologic and immunohistochemical findings were consistent with a well-differentiated neuroendocrine tumor. Genomic testing indicates a germline frame-shift in BRCA1 and a few somatic mutations of unknown significance. Transcriptomic analysis suggests an enteroendocrine L-cell in the tailgut as a putative cell-of-origin. Genomic profiling of a rare neuroendocrine tumor and metastasis provides insight into its origin, development and potential therapeutic options.

  View details for PubMedID 30087100

• TNFR2-targeted elimination of Tregs and tumor-residing T cells in advanced cutaneous T cell lymphoma Faustman, D. L., Torrey, H., Khodadoust, M., Defusco, A., Baum, D., Rahbar, Z., Kim, Y. H. AMER ASSOC CANCER RESEARCH. 2018

  View details for DOI 10.1158/1538-7445.AM2018-1790

  View details for Web of Science ID 000468818904182

• Profiling Tumor Infiltrating Immune Cells with CIBERSORT. Methods in molecular biology (Clifton, N.J.) Chen, B. n., Khodadoust, M. S., Liu, C. L., Newman, A. M., Alizadeh, A. A. 2018; 1711: 243–59

  Abstract

  Tumor infiltrating leukocytes (TILs) are an integral component of the tumor microenvironment and have been found to correlate with prognosis and response to therapy. Methods to enumerate immune subsets such as immunohistochemistry or flow cytometry suffer from limitations in phenotypic markers and can be challenging to practically implement and standardize. An alternative approach is to acquire aggregative high dimensional data from cellular mixtures and to subsequently infer the cellular components computationally. We recently described CIBERSORT, a versatile computational method for quantifying cell fractions from bulk tissue gene expression profiles (GEPs). Combining support vector regression with prior knowledge of expression profiles from purified leukocyte subsets, CIBERSORT can accurately estimate the immune composition of a tumor biopsy. In this chapter, we provide a primer on the CIBERSORT method and illustrate its use for characterizing TILs in tumor samples profiled by microarray or RNA-Seq.

  View details for PubMedID 29344893

• Potential Association of Anti-CCR4 Antibody Mogamulizumab and Graft-vs-Host Disease in Patients With Mycosis Fungoides and Sézary Syndrome. JAMA dermatology Dai, J. n., Almazan, T. H., Hong, E. K., Khodadoust, M. S., Arai, S. n., Weng, W. K., Kim, Y. H. 2018

  View details for PubMedID 29800117

• Transcript-indexed ATAC-seq for precision immune profiling. Nature medicine Satpathy, A. T., Saligrama, N. n., Buenrostro, J. D., Wei, Y. n., Wu, B. n., Rubin, A. J., Granja, J. M., Lareau, C. A., Li, R. n., Qi, Y. n., Parker, K. R., Mumbach, M. R., Serratelli, W. S., Gennert, D. G., Schep, A. N., Corces, M. R., Khodadoust, M. S., Kim, Y. H., Khavari, P. A., Greenleaf, W. J., Davis, M. M., Chang, H. Y. 2018

  Abstract

  T cells create vast amounts of diversity in the genes that encode their T cell receptors (TCRs), which enables individual clones to recognize specific peptide-major histocompatibility complex (MHC) ligands. Here we combined sequencing of the TCR-encoding genes with assay for transposase-accessible chromatin with sequencing (ATAC-seq) analysis at the single-cell level to provide information on the TCR specificity and epigenomic state of individual T cells. By using this approach, termed transcript-indexed ATAC-seq (T-ATAC-seq), we identified epigenomic signatures in immortalized leukemic T cells, primary human T cells from healthy volunteers and primary leukemic T cells from patient samples. In peripheral blood CD4+ T cells from healthy individuals, we identified cis and trans regulators of naive and memory T cell states and found substantial heterogeneity in surface-marker-defined T cell populations. In patients with a leukemic form of cutaneous T cell lymphoma, T-ATAC-seq enabled identification of leukemic and nonleukemic regulatory pathways in T cells from the same individual by allowing separation of the signals that arose from the malignant clone from the background T cell noise. Thus, T-ATAC-seq is a new tool that enables analysis of epigenomic landscapes in clonal T cells and should be valuable for studies of T cell malignancy, immunity and immunotherapy.

  View details for PubMedID 29686426

• T-cell immunopeptidomes reveal cell subtype surface markers derived from intracellular proteins. Proteomics Olsson, N. n., Schultz, L. M., Zhang, L. n., Khodadoust, M. S., Narayan, R. n., Czerwinski, D. K., Levy, R. n., Elias, J. E. 2018

  Abstract

  Immunopeptidomes promise novel surface markers as ideal immunotherapy targets, but their characterization by mass spectrometry (MS) remains challenging. Until recently, cell numbers exceeding 109were needed to survey thousands of HLA ligands. Such limited analytical sensitivity has historically constrained the types of clinical specimens that can be evaluated to cell cultures or bulk tissues. Measuring immunopeptidomes from purified cell subpopulations would be preferable for many applications, particularly those evaluating rare, primary hematopoietic cell lineages. Here, we test the feasibility of immunopeptidome profiling from limited numbers of primary purified human regulatory T cells (TReg), conventional T cells (Tconv) and activated T cells. The combined T-cell immunopeptide dataset reported here contains 13,804 unique HLA ligands derived from 5,049 proteins. Of these, more than 700 HLA ligands were derived from 82 proteins that we exclusively identified from TReg-enriched cells. This study 1) demonstrates that primary, lineage-enriched T cell supbopulations recovered from single donors are compatible with immunopeptidome analysis; 2) presents new TReg-biased ligand candidates; and 3) supports immunopeptidome surveys value for revealing T cell biology that may not be apparent from expression data alone. Taken together, these findings open up new avenues for targeting TRegand abrogating their suppressive functions to treat cancer. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1002/pmic.201700410

  View details for PubMedID 29493099

• Development of a Dynamic Model for Personalized Risk Assessment in Large B-Cell Lymphoma Kurtz, D. M., Scherer, F., Jin, M., Soo, J., Craig, A., Esfahani, M. S., Chabon, J. J., Stehr, H., Liu, C., Tibshirani, R., Maeda, L. S., Gupta, N. K., Khodadoust, M., Advani, R. H., Levy, R., Newman, A., Westin, J. R., Gaidano, G., Rossi, D., Diehn, M., Alizadeh, A. A. AMER SOC HEMATOLOGY. 2017

  View details for Web of Science ID 000432419402076

• In Vitro, In Vivo, and Parallel Phase I Evidence Support the Safety and Activity of Duvelisib, a PI3K-delta,gamma Inhibitor, in Combination with Romidepsin or Bortezomib in Relapsed/Refractory T-Cell Lymphoma Moskowitz, A. J., Koch, R., Mehta-Shah, N., Myskowski, P., Kheterpal, M., Dogan, A., Davey, T., Galasso, N., Evan, M., Shah, M., Ganesan, N., Lubin, L., Kim, Y. H., Khodadoust, M., Almazan, T., Dai, J., Jacobsen, E. D., Weinstock, D. M., Horwitz, S. M. AMER SOC HEMATOLOGY. 2017

  View details for Web of Science ID 000432419402069

• Maria: Accurate Prediction of MHC-II Peptide Presentation with Deep-Learning and Lymphoma Patient MHC-II Ligandome Chen, B., Khodadoust, M., Olsson, N., Fast, E., Wagar, L. E., Liu, C., Davis, M., Levy, R., Elias, J. E., Altman, R. B., Alizadeh, A. A. AMER SOC HEMATOLOGY. 2017

  View details for Web of Science ID 000432419403310

• Novel treatment of cutaneous T cell lymphoma: Targeting TNFR2, an oncogene and marker of potent Tregs, with anti-TNFR2 antibodies Torrey, H., Defusco, A., Baum, D., Rahbar, Z., Khodadoust, M., Kim, Y. H., Faustman, D. BMC. 2017

  View details for Web of Science ID 000460207200103

• On the hunt for cancer neoantigens: is mass spectrometry the solution? Elias, J., Olsson, N., Khodadoust, M., Wagar, L., Swaminathan, K., Green, M. R., Davis, M. M., Levy, R., Alizadeh, A. A. AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC. 2017: S65

  View details for Web of Science ID 000407623600102

• Noninvasive detection of clinically relevant copy number alterations in diffuse large B-cell lymphoma. Jin, M. C., Kurtz, D., Esfahani, M., Scherer, F., Craig, A. M., Soo, J., Khodadoust, M., Saganty, R., Chabon, J. J., Schroers-Martin, J., Stehr, H., Advani, R. H., Rossi, D., Gaidano, G., Westin, J. R., Diehn, M., Alizadeh, A. A. AMER SOC CLINICAL ONCOLOGY. 2017

  View details for DOI 10.1200/JCO.2017.35.15_suppl.7507

  View details for Web of Science ID 000411931708176

• Antigen presentation profiling reveals T-cell recognition of lymphoma imrnunoglobuhn neoantigens Olsson, N., Khodadoust, M., Wagar, L., Swaminathan, K., Haabeth, O., Chen, B., Rawson, K., Liu, C., Steiner, D., Lund, P. J., Rao, S., Zhang, L., Marceau, C., Stehr, H., Newman, A. M., Czerwinski, D. K., Carlton, V., Moorhead, M., Faham, M., Kohrt, H. E., Carette, J., Green, M. R., Davis, M. M., Levy, R., Alizadeh, A. A., Elias, J. E. AMER ASSOC IMMUNOLOGISTS. 2017

  View details for Web of Science ID 000407750400169

• Early detection of molecular residual disease in localized lung cancer by circulating tumor DNA profiling. Cancer discovery Chaudhuri, A. A., Chabon, J. J., Lovejoy, A. F., Newman, A. M., Stehr, H. n., Azad, T. D., Khodadoust, M. S., Esfahani, M. S., Liu, C. L., Zhou, L. n., Scherer, F. n., Kurtz, D. M., Say, C. n., Carter, J. N., Merriott, D. J., Dudley, J. C., Binkley, M. S., Modlin, L. n., Padda, S. K., Gensheimer, M. F., West, R. B., Shrager, J. B., Neal, J. W., Wakelee, H. A., Loo, B. W., Alizadeh, A. A., Diehn, M. n. 2017

  Abstract

  Identifying molecular residual disease (MRD) after treatment of localized lung cancer could facilitate early intervention and personalization of adjuvant therapies. Here we apply Cancer Personalized Profiling by Deep Sequencing (CAPP-Seq) circulating tumor DNA (ctDNA) analysis to 255 samples from 40 patients treated with curative intent for stage I-III lung cancer and 54 healthy adults. In 94% of evaluable patients experiencing recurrence, ctDNA was detectable in the first post-treatment blood sample, indicating reliable identification of MRD. Post-treatment ctDNA detection preceded radiographic progression in 72% of patients by a median of 5.2 months and 53% of patients harbored ctDNA mutation profiles associated with favorable responses to tyrosine kinase inhibitors or immune checkpoint blockade. Collectively, these results indicate that ctDNA MRD in lung cancer patients can be accurately detected using CAPP-Seq and may allow personalized adjuvant treatment while disease burden is lowest.

  View details for PubMedID 28899864

• Antigen Presentation Profiling Reveals T-Cell Recognition of Lymphoma Immunoglobulin Neoantigens Khodadoust, M., Olsson, N., Wagar, L., Chen, B., Rawson, K., Liu, C., Steiner, D., Rao, S., Zhang, L., Stehr, H., Newman, A. M., Czerwinski, D. K., Carlton, V., Moorhead, M., Faham, M., Kohrt, H., Green, M. R., Davis, M. M., Levy, R., Elias, J., Alizadeh, A. A. AMER SOC HEMATOLOGY. 2016

  View details for Web of Science ID 000394446803106

• Examining the Heterogeneity of Follicular Lymphoma By Multi-Parameter Flow Cyotmetry in Previously Untreated Patients Czerwinski, D. K., Long, S. R., Khodadoust, M., Frank, M. J., Kardosh, A., Okada, A., Robinson, S., Levy, R. AMER SOC HEMATOLOGY. 2016

  View details for Web of Science ID 000394452307082

• SD-101, a Novel Class C CpG-Oligodeoxynucleotide (ODN) Toll-like Receptor 9 (TLR9) Agonist, Given with Low Dose Radiation for Untreated Low Grade B-Cell Lymphoma: Interim Results of a Phase 1/2 Trial Levy, R., Reagan, P. M., Friedberg, J. W., Bartlett, N. L., Gordon, L. I., Leung, A., Peterkin, J., Xing, B., Coffman, R., Janssen, R., Candia, A., Khodadoust, M., Frank, M. J., Long, S. R., Czerwinski, D. K., Chu, M. AMER SOC HEMATOLOGY. 2016

  View details for Web of Science ID 000394452307156

• Pembrolizumab for Treatment of Relapsed/Refractory Mycosis Fungoides and Sezary Syndrome: Clinical Efficacy in a Citn Multicenter Phase 2 Study Khodadoust, M., Rook, A. H., Porcu, P., Foss, F. M., Moskowitz, A. J., Shustov, A. R., Shanbhag, S., Sokol, L., Shine, R., Fling, S. P., Li, S., Rabhar, Z., Kim, J., Yang, Y., Yearley, J., Chartash, E., Townson, S. M., Subrahmanyam, P. B., Maecker, H., Alizadeh, A. A., Dai, J., Horwitz, S. M., Sharon, E., Kohrt, H., Cheever, M. A., Kim, Y. AMER SOC HEMATOLOGY. 2016

  View details for Web of Science ID 000394446803144

• First-in-Human, Multicenter Phase I Study of IPH4102, First-in-Class Humanized Anti-KIR3DL2 Monoclonal Antibody, in Relapsed/Refractory Cutaneous T-Cell Lymphomas: Preliminary Safety, Exploratory and Clinical Activity Results Bagot, M., Porcu, P., Ram-Wolff, C., Khodadoust, M., Battistella, M., Marie-Cardine, A., Mathieu, S., Vermeer, M. H., Whittaker, S., Duvic, M., Bensussan, A., Paturel, C., Bonnafous, C., Thonnart, N., Widemann, A., Bonin, C., Sicard, H., Paiva, C., Pilz, K., Kim, Y. AMER SOC HEMATOLOGY. 2016

  View details for Web of Science ID 000394452308018

• A Single-Arm PHASE 2A Study of NM-IL-12 (rHu-IL12) in Patients with Mycosis Fungoides-Type CTCL (MF) Undergoing Low-Dose TOTAL Skin Electron BEAM Therapy (LD-TSEBT) Kim, Y. H., Hoppe, R. T., Rook, A. H., Maity, A., Geskin, L. J., Horowitz, D. P., Finnegan, G., Khodadoust, M., Weng, W., Lares, A., Hong, E., Buchanan, M., Ma, V., Kha, H., Lawrence, C. E., Vainstein, V., Basile, L. A. AMER SOC HEMATOLOGY. 2016

  View details for Web of Science ID 000394452308077

• SD-101, a novel intratumoral class C CpG-ODN, given with low-dose radiation in patients with untreated low-grade B-cell lymphoma: interim results of a phase I trial Levy, R., Bartlett, N., Friedberg, J., Reagan, P., Gordon, L., Bergman, C., Coffman, R., Janssen, R., Candia, A., Khodadoust, M., Frank, M., Long, S., Czerwinski, D., Chu, M., Kohrt, H. AMER ASSOC CANCER RESEARCH. 2016

  View details for DOI 10.1158/1538-7445AM2016-CT047

  View details for Web of Science ID 000389940603166

• Prediction of therapeutic outcomes in DLBCL from circulating tumor DNA dynamics. Kurtz, D., Scherer, F., Newman, A. M., Craig, A. M., Khodadoust, M., Lovejoy, A. F., Klass, D. M., Chabon, J. J., Glover, C., Zhou, L., Liu, C., Gupta, N. K., Maeda, L., Advani, R. H., Levy, R., Diehn, M., Alizadeh, A. A. AMER SOC CLINICAL ONCOLOGY. 2016

  View details for DOI 10.1200/JCO.2016.34.15_suppl.7511

  View details for Web of Science ID 000404711505025

• Clinical activity of ponatinib in a patient with FGFR1-rearranged mixed-phenotype acute leukemia. Leukemia Khodadoust, M. S., Luo, B., Medeiros, B. C., Johnson, R. C., Ewalt, M. D., Schalkwyk, A. S., Bangs, C. D., Cherry, A. M., Arai, S., Arber, D. A., Zehnder, J. L., Gotlib, J. 2016; 30 (4): 947-950

  View details for DOI 10.1038/leu.2015.136

  View details for PubMedID 26055304

• Phase I/II Clinical Trial of CpG-Activated Whole Cell Vaccine in Mantle Cell Lymphoma (MCL): Results in Safety and Efficacy from Planned Interim Analysis Chu, M. P., Brody, J., Kohrt, H. E., Frank, M. J., Khodadoust, M., Reddy, S., Advani, R. H., Gupta, N. K., Laport, G., Maeda, L. S., Meyer, E., Miklos, D. B., Negrin, R., Rezvani, A. R., Weng, W., Sheehan, K., Faham, M., Czerwinski, D. K., Okada, A., Levy, R. AMER SOC HEMATOLOGY. 2015

  View details for Web of Science ID 000368019005014

• T Regulatory Cells Exhibit Surface Expression of FoxP3 Derived Peptides Presented within Class I MHC Schultz, L. M., Olsson, N., Khodadoust, M., Narayan, R., Sagiv-Barfi, I., Elias, J., Levy, R. AMER SOC HEMATOLOGY. 2015

  View details for Web of Science ID 000368020101066

• Regulatory T Cells Are Depleted in Low-Grade Lymphoma By the Combination of Local Low-Dose Radiation Followed By Intratumoral CpG-ODN Czerwinski, D. K., Long, S. R., Khodadoust, M., Frank, M. J., Chu, M. P., Okada, A., McDonald, K. A., Kohrt, H. E., Bartlett, N. L., Reagan, P. M., Friedberg, J. W., Gordon, L. I., Coffman, R., Janssen, R., Levy, R. AMER SOC HEMATOLOGY. 2015

  View details for Web of Science ID 000368019005017

• Phase I/II study of intratumoral injection of SD-101, an immunostimulatory CpG, and intratumoral injection of ipillumumab, an anti-CTLA-4 monoclonal antibody, in combination with local radiation in low-grade B-cell lymphomas. Khodadoust, M., Chu, M., Czerwinski, D., McDonald, K., Long, S., Kohrt, H., Hoppe, R. T., Advani, R. H., Lowsky, R., Levy, R. AMER SOC CLINICAL ONCOLOGY. 2015

  View details for Web of Science ID 000358036904866

• Distinct early response dynamics of circulating tumor DNA and circulating tumor cells during therapy of B-cell NHL. Kurtz, D., Scherer, F., Green, M., Khodadoust, M., Klass, D. M., Zhou, L., Krishnan, R., Glover, C., Liu, C., Kong, K. A., Faham, M., Levy, R., Diehn, M., Alizadeh, A. A. AMER SOC CLINICAL ONCOLOGY. 2015

  View details for Web of Science ID 000358036901882

• Value of Surveillance Studies for Patients With Stage I to II Diffuse Large B-Cell Lymphoma in the Rituximab Era. International journal of radiation oncology, biology, physics Hiniker, S. M., Pollom, E. L., Khodadoust, M. S., Kozak, M. M., Xu, G., Quon, A., Advani, R. H., Hoppe, R. T. 2015; 92 (1): 99-106

  Abstract

  The role of surveillance studies in limited-stage diffuse large B-cell lymphoma (DLBCL) in the rituximab era has not been well defined. We sought to evaluate the use of imaging (computed tomography [CT] and positron emission tomography [PET]-CT) scans and lactate dehydrogenase (LDH) in surveillance of patients with stage I to II DLBCL.A retrospective analysis was performed of patients who received definitive treatment between 2000 and 2013.One hundred sixty-two consecutive patients with stage I to II DLBCL were treated with chemotherapy +/- rituximab, radiation, or combined modality therapy. The 5-year rates of overall survival (OS) and freedom from progression (FFP) were 81.2% and 80.8%, respectively. Of the 162 patients, 124 (77%) were followed up with at least 1 surveillance PET scan beyond end-of-treatment scans; of those, 94 of 124 (76%) achieved a complete metabolic response on PET scan after completion of chemotherapy, and this was associated with superior FFP (P=.01, HR=0.3) and OS (P=.01, HR 0.3). Eighteen patients experienced relapse after initial response to therapy. Nine relapses were initially suspected by surveillance imaging studies (8 PET, 1 CT), and 9 were suspected clinically (5 by patient-reported symptoms and 4 by symptoms and physical examination). No relapses were detected by surveillance LDH. The median duration from initiation of treatment to relapse was 14.3 months among patients with relapses suspected by imaging, and 59.8 months among patients with relapses suspected clinically (P=.077). There was no significant difference in OS from date of first therapy or OS after relapse between patients whose relapse was suspected by imaging versus clinically. Thirteen of 18 patients underwent successful salvage therapy after relapse.A complete response on PET scan immediately after initial chemotherapy is associated with superior FFP and OS in stage I to II DLBCL. The use of PET scans as posttreatment surveillance is not associated with a survival advantage. LDH is not a sensitive marker for relapse. Our results argue for limiting the use of posttreatment surveillance in patients with limited-stage DLBCL.

  View details for DOI 10.1016/j.ijrobp.2015.01.039

  View details for PubMedID 25863757

• Prognostic Factors, Treatment, and Outcomes of Limited-Stage Diffuse Large B-Cell Lymphoma (DLBCL) in the Rituximab (R) Era Hiniker, S. M., Pollom, E. L., Khodadoust, M. S., Kozak, M. M., Advani, R. H., Hoppe, R. T. ELSEVIER SCIENCE INC. 2014: S677–S678

  View details for DOI 10.1016/j.ijrobp.2014.05.1993

  View details for Web of Science ID 000342331402400

• Value of surveillance studies for patients (pts) with stage I-II diffuse large B-cell lymphoma (DLBCL) in the rituximab (R) era. Hiniker, S. M., Pollom, E. L., Khodadoust, M. S., Kozak, M. M., Advani, R. H., Hoppe, R. T. AMER SOC CLINICAL ONCOLOGY. 2014

  View details for Web of Science ID 000358613204223

• Tumor antigen discovery through translation of the cancer genome. Immunologic research Khodadoust, M. S., Alizadeh, A. A. 2014; 58 (2-3): 292-299

  Abstract

  Cancer cells harbor unique mutations that theoretically create corresponding unique tumor-specific antigens. This class of mutated antigens represents an attractive target for cancer immunotherapy, but their identification has been cumbersome. By combining cancer genome sequencing with computational analysis of MHC binding, it is possible to predict and rank all of the possible mutated tumor antigens. This form of antigen screen is being combined with high throughput methods to measure the immune response to each candidate mutated antigen. Using these techniques, it is possible to systematically test each mutated tumor antigens for an associated immune response. Only a small fraction of the putative mutated antigens tested in this manner have been found to elicit an immune response, yet these responses appear to be both robust and durable. It is becoming increasingly clear that these mutated tumor antigens are an important target in the antitumor response. Studies incorporating this approach promise to improve our understanding of the inherent immunogenicity of individual cancers, potentially providing an explanation for the varying clinical responses to novel immunotherapeutic agents.

  View details for DOI 10.1007/s12026-014-8505-4

  View details for PubMedID 24718952

• DEK expression in melanocytic lesions HUMAN PATHOLOGY Kappes, F., Khodadoust, M. S., Yu, L., Kim, D. S., Fullen, D. R., Markovitz, D. M., Ma, L. 2011; 42 (7): 932-938

  Abstract

  The diagnosis of malignant melanoma presents a clinical challenge and relies principally on histopathological evaluation. Previous studies have indicated that increased expression of the DEK oncogene, a chromatin-bound factor, could contribute to the development of melanoma and may be a frequent event in melanoma progression. Here, we investigated DEK expression by immunohistochemistry in a total of 147 melanocytic lesions, including ordinary nevi, dysplastic nevi, Spitz nevi, melanoma in situ, primary invasive melanomas, and metastatic melanomas. Most benign nevi (ordinary, dysplastic, and Spitz nevi) were negative or exhibited weak staining for DEK, with only 4 of 49 cases showing strong staining. Similar to benign nevi, melanoma in situ also demonstrated low levels of DEK expression. In contrast, the expression of DEK in primary invasive melanomas was significantly higher than benign nevi (P < .0001). Moreover, DEK expression was significantly increased in deep melanomas (Breslow depth >1 mm) and metastatic melanomas as compared with superficial melanomas (Breslow depth ≤1 mm) (P < .05). Our findings indicate that DEK overexpression may be a frequent event in invasive melanomas, and further augmentation of DEK expression may be associated with the acquisition of ominous features such as deep dermal invasion and metastasis. These data suggest a role of DEK in melanoma progression.

  View details for DOI 10.1016/j.humpath.2010.10.022

  View details for Web of Science ID 000292231800003

  View details for PubMedID 21316078

  View details for PubMedCentralID PMC3162348

• The DEK oncoprotein is a Su(var) that is essential to heterochromatin integrity GENES & DEVELOPMENT Kappes, F., Waldmann, T., Mathew, V., Yu, J., Zhang, L., Khodadoust, M. S., Chinnaiyan, A. M., Luger, K., Erhardt, S., Schneider, R., Markovitz, D. M. 2011; 25 (7): 673-678

  Abstract

  Heterochromatin integrity is crucial for genome stability and regulation of gene expression, but the factors involved in mammalian heterochromatin biology are only incompletely understood. Here we identify the oncoprotein DEK, an abundant nuclear protein with a previously enigmatic in vivo function, as a Suppressor of Variegation [Su(var)] that is crucial to global heterochromatin integrity. We show that DEK interacts directly with Heterochromatin Protein 1 α (HP1α) and markedly enhances its binding to trimethylated H3K9 (H3K9me3), which is key for maintaining heterochromatic regions. Loss of Dek in Drosophila leads to a Su(var) phenotype and global reduction in heterochromatin. Thus, these findings show that DEK is a key factor in maintaining the balance between heterochromatin and euchromatin in vivo.

  View details for DOI 10.1101/gad.2036411

  View details for Web of Science ID 000289062700002

  View details for PubMedID 21460035

  View details for PubMedCentralID PMC3070930

• Melanoma Proliferation and Chemoresistance Controlled by the DEK Oncogene CANCER RESEARCH Khodadoust, M. S., Verhaegen, M., Kappes, F., Riveiro-Falkenbach, E., Cigudosa, J. C., Kim, D. S., Chinnaiyan, A. M., Markovitz, D. M., Soengas, M. S. 2009; 69 (16): 6405-6413

  Abstract

  Gain of chromosome 6p is a consistent feature of advanced melanomas. However, the identity of putative oncogene(s) associated with this amplification has remained elusive. The chromatin remodeling factor DEK is an attractive candidate as it maps to 6p (within common melanoma-amplified loci). Moreover, DEK expression is increased in metastatic melanomas, although the functional relevance of this induction remains unclear. Importantly, in other tumor types, DEK can display various tumorigenic effects in part through its ability to promote proliferation and inhibit p53-dependent apoptosis. Here, we report a generalized up-regulation of DEK protein in aggressive melanoma cells and tumors. In addition, we provide genetic and mechanistic evidence to support a key role of DEK in the maintenance of malignant phenotypes of melanoma cells. Specifically, we show that long-term DEK down-regulation by independent short hairpin RNAs resulted in premature senescence of a variety of melanoma cell lines. Short-term abrogation of DEK expression was also functionally relevant, as it attenuated the traditional resistance of melanomas to DNA-damaging agents. Unexpectedly, DEK short hairpin RNA had no effect on p53 levels or p53-dependent apoptosis. Instead, we identified a new role for DEK in the transcriptional activation of the antiapoptotic MCL-1. Other MCL-1-related factors such as BCL-2 or BCL-xL were unaffected by changes in the endogenous levels of DEK, indicating a selective effect of this gene on the apoptotic machinery of melanoma cells. These results provide support for DEK as a long sought-after oncogene mapping at chromosome 6, with novel functions in melanoma proliferation and chemoresistance.

  View details for DOI 10.1158/0008-5472.CAN-09-1063

  View details for Web of Science ID 000269064600007

  View details for PubMedID 19679545

  View details for PubMedCentralID PMC2727675

• DEK is a poly(ADP-ribose) acceptor in apoptosis and mediates resistance to genotoxic stress MOLECULAR AND CELLULAR BIOLOGY Kappes, F., Fahrer, J., Khodadoust, M. S., Tabbert, A., Strasser, C., Mor-Vaknin, N., Moreno-Villanueva, M., Buerkle, A., Markovitz, D. M., Ferrando-May, E. 2008; 28 (10): 3245-3257

  Abstract

  DEK is a nuclear phosphoprotein implicated in oncogenesis and autoimmunity and a major component of metazoan chromatin. The intracellular cues that control the binding of DEK to DNA and its pleiotropic functions in DNA- and RNA-dependent processes have remained mainly elusive so far. Our recent finding that the phosphorylation status of DEK is altered during death receptor-mediated apoptosis suggested a potential involvement of DEK in stress signaling. In this study, we show that in cells committed to die, a portion of the cellular DEK pool is extensively posttranslationally modified by phosphorylation and poly(ADP-ribosyl)ation. Through interference with DEK expression, we further show that DEK promotes the repair of DNA lesions and protects cells from genotoxic agents that typically trigger poly(ADP-ribose) polymerase activation. The posttranslational modification of DEK during apoptosis is accompanied by the removal of the protein from chromatin and its release into the extracellular space. Released modified DEK is recognized by autoantibodies present in the synovial fluids of patients affected by juvenile rheumatoid arthritis/juvenile idiopathic arthritis. These findings point to a crucial role of poly(ADP-ribosyl)ation in shaping DEK's autoantigenic properties and in its function as a promoter of cell survival.

  View details for DOI 10.1128/MCB.01921-07

  View details for Web of Science ID 000255600800014

  View details for PubMedID 18332104

  View details for PubMedCentralID PMC2423161

• The DEK nuclear autoantigen is a secreted chemotactic factor MOLECULAR AND CELLULAR BIOLOGY Mor-Vaknin, N., Punturieri, A., Sitwala, K., Faulkner, N., Legendre, M., Khodadoust, M. S., Kappes, F., Ruth, J. H., Koch, A., Glass, D., Petruzzelli, L., Adams, B. S., Markovitz, D. M. 2006; 26 (24): 9484-9496

  Abstract

  The nuclear DNA-binding protein DEK is an autoantigen that has been implicated in the regulation of transcription, chromatin architecture, and mRNA processing. We demonstrate here that DEK is actively secreted by macrophages and is also found in synovial fluid samples from patients with juvenile arthritis. Secretion of DEK is modulated by casein kinase 2, stimulated by interleukin-8, and inhibited by dexamethasone and cyclosporine A, consistent with a role as a proinflammatory molecule. DEK is secreted in both a free form and in exosomes, vesicular structures in which transcription-modulating factors such as DEK have not previously been found. Furthermore, DEK functions as a chemotactic factor, attracting neutrophils, CD8+ T lymphocytes, and natural killer cells. Therefore, the DEK autoantigen, previously described as a strictly nuclear protein, is secreted and can act as an extracellular chemoattractant, suggesting a direct role for DEK in inflammation.

  View details for DOI 10.1128/MCB.01030-06

  View details for Web of Science ID 000242859200029

  View details for PubMedID 17030615

  View details for PubMedCentralID PMC1698538

• The DEK nuclear protein autoantigen is secreted chemotactic factor Mor-Vaknin, N., Puntuieri, A., Sitwala, K., Faulkner, N., Legendre, M., Khodadoust, M. S., Burrell, B. E., Ruth, J. H., Koch, A., Glass, D., Petruzzelli, L., Adams, B., Markovitz, D. M. AMER ASSOC IMMUNOLOGISTS. 2006: S132

  View details for Web of Science ID 000238837101109

• p300/CBP-associated factor drives DEK into interchromatin granule clusters JOURNAL OF BIOLOGICAL CHEMISTRY Cleary, J., Sitwala, K. V., Khodadoust, M. S., Kwok, R. P., Mor-Vaknin, N., Cebrat, M., Cole, P. A., Markovitz, D. M. 2005; 280 (36): 31760-31767

  Abstract

  DEK is a mammalian protein that has been implicated in the pathogenesis of autoimmune diseases and cancer, including acute myeloid leukemia, melanoma, glioblastoma, hepatocellular carcinoma, and bladder cancer. In addition, DEK appears to participate in multiple cellular processes, including transcriptional repression, mRNA processing, and chromatin remodeling. Sub-nuclear distribution of this protein, with the attendant functional ramifications, has remained a controversial topic. Here we report that DEK undergoes acetylation in vivo at lysine residues within the first 70 N-terminal amino acids. Acetylation of DEK decreases its affinity for DNA elements within the promoter, which is consistent with the involvement of DEK in transcriptional repression. Furthermore, deacetylase inhibition results in accumulation of DEK within interchromatin granule clusters (IGCs), sub-nuclear structures that contain RNA processing factors. Overexpression of P/CAF acetylase drives DEK into IGCs, and addition of a newly developed, synthetic, cell-permeable P/CAF inhibitor blocks this movement. To our knowledge, this is the first reported example of acetylation playing a direct role in relocation of a protein to IGCs, and this may explain how DEK can function in multiple pathways that take place in distinct sub-nuclear compartments. These findings also suggest that DEK-associated malignancies and autoimmune diseases might be amenable to treatment with agents that alter acetylation.

  View details for DOI 10.1074/jbc.M500884200

  View details for Web of Science ID 000231665200054

  View details for PubMedID 15987677

• The nuclear protein DEK, a putative autoantigen in JRA, is secreted by activated human macrophages and exhibits chemokine activity. Mor-Vaknin, N., Punturieri, A., Sitwala, K., Faulkner, N., Legendre, M., Cleary, J., Khodadoust, M. S., Burrell, B., Ruth, J. H., Koch, A. E., Glass, D. N., Petruzzelli, L., Adams, B. S., Markovitz, D. M. WILEY-BLACKWELL. 2005: S442

  View details for Web of Science ID 000232207802183

• Induction of apoptosis in lymphoid cell lines and primary CLL by HA14-1, a cell permeable organic small molecule that binds to the BH1 to BH3 surface pocket of Bcl-2 protein. Hu, G. Y., Khodadoust, M., Konopleva, M., Huang, Z. W., Andreeff, M. AMER SOC HEMATOLOGY. 2001: 840A

  View details for Web of Science ID 000172134103504

• Bcl-2 antisense oligodeoxynucleotide (Genasense) enhances gemtuzumab ozogamicin (Mylotarg)-induced cytotoxicity in acute myeloid leukemia. Khodadoust, M., Konopleva, M., Leysath, C., Frankel, Giles, F. J., Andreeff, M. AMER SOC HEMATOLOGY. 2001: 102A

  View details for Web of Science ID 000172134100430

• Induction of apoptosis in primary human leukemia cells by HA14-1, a cell-permeable organic compound identified by protein structure-based computer screening that binds the BH1 to BH3 surface pocket of Bcl-2. Andreeff, M., Konopleva, M., Leysath, C., Khodadoust, M., Huang, Z. AMER ASSOC CANCER RESEARCH. 2001: 3722S

  View details for Web of Science ID 000172121800340