Clinical Focus

  • Medical Oncology

Academic Appointments

Honors & Awards

  • Young Investigator Award, Journal of Clinical Oncology, Conquer Cancer Foundation (2015)
  • Fellow Award, Leukemia and Lymphoma Society (2014-)
  • Dean's Postdoctoral Fellowship, Stanford University (2014)
  • Distinction in Academics and Research, University of Michigan, Ann Arbor (2010)
  • Wiliam Dodd Robinson Award, University of Michigan, Ann Arbor (2010)
  • Membership, Alpha Omega Alpha (2009)
  • Predoctoral Fellowship Award, National Science Foundation (2002)

Boards, Advisory Committees, Professional Organizations

  • Member, Research Advisory Council, Cutaneous Lymphoma Foundation (2019 - Present)
  • Steering Committee, Chair, San Francisco Lymphoma Rounds, Lymphoma Research Foundation (2020 - Present)
  • Board Member, International Society of Cutaneous Lymphomas (2020 - Present)

Professional Education

  • Fellowship: Stanford University Hematology and Oncology Fellowship (2015) CA
  • Residency: Stanford University Internal Medicine Residency (2012) CA
  • Internship: Stanford University Internal Medicine Residency (2011) CA
  • Board Certification: American Board of Internal Medicine, Medical Oncology (2017)
  • Board Certification, Oncology, American Board of Internal Medicine (2017)
  • Board Certification: American Board of Internal Medicine, Internal Medicine (2013)
  • PhD, University of Michigan, Immunology (2010)
  • Medical Education: University of Michigan Health System (2010) MI

Clinical Trials

  • Clinical and Pathologic Studies in Non-Hodgkin's Lymphoma and Hodgkin's Disease Recruiting

    The purpose of this study is to characterize the molecular and cell biology of the tumor cells in lymphoma.

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  • Testing the Combination of Two Experimental Drugs MK-3475 (Pembrolizumab) and Interferon-gamma for the Treatment of Mycosis Fungoides and Sézary Syndrome and Advanced Synovial Sarcoma Recruiting

    This phase II trial studies how well pembrolizumab and interferon gamma-1b work in treating patients with stage IB-IVB mycosis fungoides and Sezary syndrome that has come back (relapsed) or has not responded to previous treatment (refractory). Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Interferon gamma-1b may boost the immune system activity. Giving pembrolizumab and interferon gamma-1b together may work better in treating patients with stage IB-IVB mycosis fungoides and Sezary syndrome.

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  • A Multi-Center Study of Ibrutinib in Combination With MEDI4736 in Subjects With Relapsed or Refractory Lymphomas Not Recruiting

    The purpose of this study is to evaluate the efficacy, safety and tolerability of the combination treatment of ibrutinib and MEDI4736 in subjects with relapsed or refractory lymphomas.

    Stanford is currently not accepting patients for this trial. For more information, please contact Cancer Clinical Trials Office (CCTO), 650-498-7061.

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  • A Phase I/II Study of Intratumoral Injection of SD-101 Not Recruiting

    This phase 1-2 trial studies the side effects and best dose of ipilimumab in combination with toll-like receptor 9 (TLR9) agonist SD-101 and radiation therapy in treating patients with recurrent low-grade B-cell lymphoma.

    Stanford is currently not accepting patients for this trial. For more information, please contact Kathleen McDonald, 650-725-8589.

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  • A Safety, Efficacy and Pharmacokinetics Study of CD11301 for the Treatment of Cutaneous T-Cell Lymphoma (CTCL) Not Recruiting

    To assess the efficacy, safety and pharmacokinetics in participants treated with CD11301 gel vs. placebo for early stage CTCL (IA, IB, or IIA).

    Stanford is currently not accepting patients for this trial. For more information, please contact Cancer Clinical Trials Office (CCTO), 650-498-7061.

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  • Efficacy of Axicabtagene Ciloleucel Compared to Standard of Care Therapy in Subjects With Relapsed/Refractory Diffuse Large B Cell Lymphoma Not Recruiting

    The purpose of this study is to evaluate whether axicabtagene ciloleucel therapy improves the clinical outcome compared with standard of care second-line therapy in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL).

    Stanford is currently not accepting patients for this trial. For more information, please contact Cancer Clinical Trials Office (CCTO), 650-498-7061.

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  • NM-IL-12 in Cutaneous T-Cell Lymphoma (CTCL) Undergoing Total Skin Electron Beam Therapy (TSEBT) Not Recruiting

    In the proposed study, NM-IL-12 will be evaluated as immunotherapy to increase antitumor efficacy against CTCL, while reducing skin-related toxicity, when combined with low-dose TSEBT therapy. Determination of the maximum tolerated dose (MTD) for NM-IL-12 is not planned in this study, rather, a pre-defined starting dose will be explored; this dose is based on two safety and tolerability studies of NM-IL-12 in healthy volunteers.

    Stanford is currently not accepting patients for this trial. For more information, please contact Eric Hong, 650-725-2142.

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  • Pembrolizumab in Treating Patients With Relapsed or Refractory Stage IB-IVB Mycosis Fungoides or Sezary Syndrome Not Recruiting

    This phase II trial studies how well pembrolizumab works in treating patients with stage IB-IVB mycosis fungoides or Sezary syndrome that has returned after a period of improvement or has not responded to at least one type of treatment. Monoclonal antibodies, such as pembrolizumab, may block cancer growth in different ways by targeting certain cells.

    Stanford is currently not accepting patients for this trial. For more information, please contact Illisha Rajasansi, 650-421-1397.

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  • Phase 1-2 of a CpG-Activated Whole Cell Vaccine Followed by Autologous Immunotransplant for MCL Not Recruiting

    Mantle cell lymphoma (MCL) is a sub-type of non-Hodgkin's lymphoma (NHL) which is generally considered incurable with current therapy. Participants will receive an autologous vaccine against their individual lymphoma after undergoing stem cell transplantation. This vaccination may prolong the time which patients will stay in remission from their disease.

    Stanford is currently not accepting patients for this trial. For more information, please contact Ami Okada, (650) 725 - 4968.

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  • Phase 1/2a Dose Escalation Study in Participants With CLL, SLL, or NHL Not Recruiting

    This study will identify the highest dose, and assess the safety, of cerdulatinib (PRT062070) that may be given in participants with relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma or non-hodgkin lymphoma.

    Stanford is currently not accepting patients for this trial. For more information, please contact Cancer Clinical Trials Office (CCTO), 650-498-7061.

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  • Safety and Efficacy of KTE-C19 in Combination With Atezolizumab in Adults With Refractory Diffuse Large B-Cell Lymphoma (DLBCL) Not Recruiting

    The primary objective of phase 1 is to evaluate the safety of KTE-C19 and atezolizumab combination regimens. The primary objective of phase 2 is to evaluate the efficacy of KTE-C19 and atezolizumab, as measured by complete response rate in participants with refractory diffuse large B-cell lymphoma (DLBCL). Subjects who received an infusion of KTE-C19 will complete the remainder of the 15 year follow-up assessments in a separate long-term follow-up study, KT-US-982-5968

    Stanford is currently not accepting patients for this trial. For more information, please contact Cancer Clinical Trials Office (CCTO), 650-498-7061.

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  • Study Evaluating the Safety and Efficacy of KTE-C19 in Adult Participants With Refractory Aggressive Non-Hodgkin Lymphoma Not Recruiting

    This study will be separated into 3 distinct phases designated as the Phase 1 study, Phase 2 pivotal study (Cohort 1 and Cohort 2), and Phase 2 safety management study (Cohort 3 and Cohort 4, Cohort 5 and Cohort 6). The primary objectives of this study are: - Phase 1 Study: Evaluate the safety of axicabtagene ciloleucel regimens - Phase 2 Pivotal Study; Evaluate the efficacy of axicabtagene ciloleucel - Phase 2 Safety Management Study: Assess the impact of prophylactic regimens or earlier interventions on the rate and severity of cytokine release syndrome (CRS) and neurologic toxicities Subjects who received an infusion of KTE-C19 will complete the remainder of the 15 year follow-up assessments in a separate long-term follow-up study, KT-US-982-5968.

    Stanford is currently not accepting patients for this trial. For more information, please contact Physician Referrals, 650-723-0822.

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  • Study of IPH4102 in Patients With Relapsed/Refractory Cutaneous T-cell Lymphomas (CTCL) Not Recruiting

    The primary objective of this first in human study is to assess the safety and tolerability of increasing intravenous (IV) doses of single agent IPH4102 administered to patients with relapsed/refractory CTCL to characterize the dose limiting toxicities (DLT) and identify a Maximum Tolerated Dose (MTD).

    Stanford is currently not accepting patients for this trial. For more information, please contact Illisha Rajasansi, 650-421-1397.

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  • Study of SD-101 in Combination With Localized Low-dose Radiation in Patients With Untreated Low-grade B-cell Lymphoma Not Recruiting

    To assess the safety and tolerability of escalating doses of SD-101 in combination with localized low-dose radiation therapy in adult subjects with untreated low-grade B-cell lymphoma.

    Stanford is currently not accepting patients for this trial. For more information, please contact Kathleen McDonald, 650-725-8589.

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  • Testing the Addition of an Anti-cancer Drug, Hu5F9-G4 (Magrolimab), to the Usual Chemotherapy Treatment (Mogamulizumab) in T-Cell (a Type of Immune Cell) Lymphoma That Has Returned After Treatment or Does Not Respond to Treatment Not Recruiting

    This phase Ib/II trial identifies the best dose and possible benefits and/or side effects of magrolimab when given in combination with mogamulizumab in treating patients with stage IB-IV mycosis fungoides or Sezary syndrome types of T-cell lymphoma that has come back (relapsed) or does not respond to treatment (refractory). Magrolimab and mogamulizumab are monoclonal antibodies that may interfere with the ability of cancer cells to grow and spread. Treatment with magrolimab in combination with mogamulizumab may stabilize cancer for longer period than the usual treatment in patients with relapsed/refractory T-cell lymphoma who have been previously treated.

    Stanford is currently not accepting patients for this trial. For more information, please contact Site Public Contact, 650-498-7061.

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  • TLR9 Agonist SD-101, Anti-OX40 Antibody BMS 986178, and Radiation Therapy in Treating Patients With Low-Grade B-Cell Non-Hodgkin Lymphomas Not Recruiting

    This phase I trial studies the side effects and best dose of the anti-OX40 antibody BMS-986178 when given together with the TLR9 agonist SD-101 and radiation therapy in treating patients with low-grade B-cell Non-Hodgkin lymphomas. TLR9 agonist SD-101 may stimulate the immune system in different ways and stop cancer cells from growing. Anti-OX40 antibody is a monoclonal antibody that enhances the activation of T cells, immune cells that are important for fighting tumors Radiation therapy uses high energy x-rays to kill cancer cells and may make them more easily detected by the immune system. Giving TLR9 agonist SD-101 together with anti-OX40 antibody BMS 986178 and radiation therapy may work better in treating patients with low-grade B-cell non-hodgkin lymphomas.

    Stanford is currently not accepting patients for this trial. For more information, please contact Destiny Phillips, 650-498-1313.

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  • TLR9 Agonist SD-101, Ibrutinib, and Radiation Therapy in Treating Patients With Relapsed or Refractory Grade 1-3A Follicular Lymphoma Not Recruiting

    This phase Ib/II trial studies the side effects and best dose of toll-like receptor 9 (TLR9) agonist SD-101 when given together with ibrutinib and radiation therapy and to see how well they work in treating patients with Low Grade Follicular Lymphoma, Marginal Zone Lymphoma, or Mantle Cell Lymphoma that has come back after a period of improvement or no longer responds to treatment. Immunostimulants such as TLR9 agonist SD-101 may increase the ability of the immune system to fight infection and disease. Ibrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Giving TLR9 agonist SD-101 with ibrutinib and radiation therapy may induce an immune response and prolong anti-tumor response.

    Stanford is currently not accepting patients for this trial. For more information, please contact Ami Okada, 650-725-4968.

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  • Trial of Duvelisib in Combination With Either Romidepsin or Bortezomib in Relapsed/Refractory T-cell Lymphomas Not Recruiting

    The purpose of this study is to test the safety of a study drug called duvelisib.

    Stanford is currently not accepting patients for this trial. For more information, please contact Cancer Clinical Trials Office (CCTO), 650-498-7061.

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2022-23 Courses

Stanford Advisees

Graduate and Fellowship Programs

All Publications

  • 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


    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


    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


    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-?


    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

  • 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


    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
  • 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
  • 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
  • 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

  • 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
  • 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
  • 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
  • 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. 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


    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


    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


    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


    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

  • 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
  • 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


    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


    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


    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
  • 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


    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

  • 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


    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

  • 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


    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 as #NCT00896493.

    View details for DOI 10.1182/bloodadvances.2020001627

    View details for PubMedID 32941647

  • 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)


    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

  • 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
  • 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
  • Determining cell type abundance and expression from bulk tissues with digital cytometry NATURE BIOTECHNOLOGY Newman, A. M., Steen, C. B., Liu, C., Gentles, A. J., Chaudhuri, A. A., Scherer, F., Khodadoust, M. S., Esfahani, M. S., Luca, B. A., Steiner, D., Diehn, M., Alizadeh, A. A. 2019; 37 (7): 773-+
  • 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; 9 (4): 220–25
  • 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


    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, 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


    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

  • 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


    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

  • 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

  • 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


    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

  • 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


    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

  • 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


    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; ), 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

  • 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
  • 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
  • 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
  • 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
  • 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


    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

  • 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
  • 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
  • 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
  • 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


    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


    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
  • 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


    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

  • 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


    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

  • 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


    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

  • 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


    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

  • 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

  • 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


    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

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


    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


    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

  • 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


    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

  • 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


    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

  • 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


    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

  • 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


    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

  • 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


    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