Matthew Frank

All Publications

• CD22-directed CAR T-cell therapy for large B-cell lymphomas progressing after CD19-directed CAR T-cell therapy: a dose-finding phase 1 study. Lancet (London, England) Frank, M. J., Baird, J. H., Kramer, A. M., Srinagesh, H. K., Patel, S., Brown, A. K., Oak, J. S., Younes, S. F., Natkunam, Y., Hamilton, M. P., Su, Y. J., Agarwal, N., Chinnasamy, H., Egeler, E., Mavroukakis, S., Feldman, S. A., Sahaf, B., Mackall, C. L., Muffly, L., Miklos, D. B. 2024

  Abstract

  Outcomes are poor for patients with large B-cell lymphoma who relapse after CD19-directed chimeric antigen receptor (CAR) T-cell therapy (CAR19). CD22 is a nearly universally expressed B-cell surface antigen and the efficacy of a CD22-directed CAR T-cell therapy (CAR22) in large B-cell lymphoma is unknown, which was what we aimed to examine in this study.In this single centre, open-label, dose-escalation phase 1 trial, we intravenously administered CAR22 at two dose levels (1 million and 3 million CAR22-positive T cells per kg of bodyweight) to adult patients (aged ≥18 years) who relapsed after CAR19 or had CD19-negative large B-cell lymphoma. The primary endpoints were manufacturing feasibility, safety measured by the incidence and severity of adverse events and dose-limiting toxicities, and identification of the maximum tolerated dose (ie, the recommended phase 2 dose). This study is registered with ClinicalTrials.gov (NCT04088890) and is active, but closed for enrolment.From Oct 17, 2019, to Oct 19, 2022, a total of 41 patients were assessed for eligibility; however, one patient withdrew. 40 patients underwent leukapheresis and 38 (95%) had CAR T-cell products manufactured successfully. The median age was 65 years (range 25-84), 17 (45%) were women, 32 (84%) had elevated pretreatment lactate dehydrogenase, 11 (29%) had refractory disease to all previous therapies, and patients had received a median of four lines of previous therapy (range 3-8). Of the 38 patients treated, 37 (97%) had relapsed after previous CAR19. The identified maximum tolerated dose was 1 million CAR T cells per kg. Of 29 patients who received the maximum tolerated dose, no patients developed a dose-limiting toxicity or grade 3 or higher cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, or immune effector cell-associated haemophagocytic lymphohistiocytosis-like syndrome.This trial identifies CD22 as an immunotherapeutic target in large B-cell lymphoma and demonstrates the durable clinical activity of CAR22 in patients with disease progression after CAR19 therapy. Although these findings are promising, it is essential to recognise that this is a phase 1 dose-finding study. Further investigations are warranted to establish the long-term efficacy and to delineate the patient subgroups that will derive the most benefit from this therapeutic approach.National Cancer Institute, National Institutes of Health, Stanford Cancer Institute, Leukemia & Lymphoma Society, Parker Institute for Cancer Immunotherapy, Lymph & Co, and the European Hematology Association.

  View details for DOI 10.1016/S0140-6736(24)00746-3

  View details for PubMedID 38996463

• Immune Effector Cell associated Hemophagocytic Lymphohistiocytosis-like Syndrome (IEC-HS). Transplantation and cellular therapy Hines, M. R., Knight, T. E., McNerney, K. O., Leick, M. B., Jain, T., Ahmed, S., Frigault, M. J., Hill, J. A., Jain, M. D., Johnson, W. T., Lin, Y., Mahadeo, K. M., Maron, G. M., Marsh, R. A., Neelapu, S. S., Nikiforow, S., Ombrello, A. K., Shah, N. N., Talleur, A. C., Turicek, D., Vatsayan, A., Wong, S. W., Maus, M. V., Komanduri, K. V., Berliner, N., Henter, J. I., Perales, M. A., Frey, N. V., Teachey, D. T., Frank, M. J., Shah, N. N. 2023

  Abstract

  T cell mediated hyperinflammatory responses such as cytokine release syndrome (CRS) and immune effector cell associated neurotoxicity syndrome (ICANS) are now well-established toxicities of chimeric antigen receptor (CAR) T cells. As the field of CAR T cells advances, however, there is increasing recognition that hemophagocytic lymphohistiocytosis (HLH)-like toxicities following CAR T cell infusions are occurring broadly across patient populations and CAR T cell constructs. Importantly, these HLH-like toxicities are often not as directly associated with CRS and/or its severity as initially described. This emergent toxicity, however ill-defined, is associated with life-threatening complications, creating an urgent need for improved identification and optimal management.With the goal to improve patient outcomes and formulate a framework to characterize and study this HLH-like syndrome, we established an American Society for Transplantation and Cellular Therapy (ASTCT) panel comprised of experts in primary and secondary HLH, pediatric and adult HLH, infectious disease, rheumatology and hematology, oncology, and cellular therapy.Through this effort, we provide an overview of the underlying biology of classical primary and secondary HLH, its relationship with similar manifestations following CAR T cell infusions and propose the term "immune effector cell (IEC) associated HLH-like syndrome (IEC-HS)" to describe this emergent toxicity. Further, we delineate a framework for identification of IEC-HS and put forward a grading schema which can be used to assess severity and facilitate cross-trial comparisons. Additionally, given the critical need to optimize outcomes for patients experiencing IEC-HS, we provide insights into potential treatment approaches, strategies to optimize supportive care and delineate alternate etiologies which should be considered in a patient presenting with IEC-HS.By collectively defining IEC-HS as a hyperinflammatory toxicity we can now embark on further study of the pathophysiology underlying this toxicity profile and make strides towards a more comprehensive assessment and treatment approach.

  View details for DOI 10.1016/j.jtct.2023.03.006

  View details for PubMedID 36906275

• 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

• CD22-CAR T-Cell Therapy Mediates High Durable Remission Rates in Adults with Large B-Cell Lymphoma Who Have Relapsed after CD19-CAR T-Cell Therapy Frank, M. J., Baird, J. H., Patel, S., Craig, J., Spiegel, J. Y., Ehlinger, Z., Chinnasamy, H., Younes, S. F., Oak, J. S., Natkunam, Y., Reynolds, W. D., Iglesias, M., Crawford, E., Srinagesh, H. K., Egeler, E. L., Arai, S., Johnston, L. J., Lowsky, R., Negrin, R. S., Rezvani, A. R., Shiraz, P., Sidana, S., Weng, W., Schultz, L. M., Ramakrishna, S., Davis, K. L., Sahaf, B., Feldman, S. A., Mackall, C. L., Miklos, D. B., Muffl, L. AMER SOC HEMATOLOGY. 2021

  View details for DOI 10.1182/blood-2021-152145

  View details for Web of Science ID 000736398803041

• Monitoring of Circulating Tumor DNA Improves Early Relapse Detection After Axicabtagene Ciloleucel Infusion in Large B-Cell Lymphoma: Results of a Prospective Multi-Institutional Trial. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Frank, M. J., Hossain, N. M., Bukhari, A., Dean, E., Spiegel, J. Y., Claire, G. K., Kirsch, I., Jacob, A. P., Mullins, C. D., Lee, L. W., Kong, K. A., Craig, J., Mackall, C. L., Rapoport, A. P., Jain, M. D., Dahiya, S., Locke, F. L., Miklos, D. B. 2021: JCO2100377

  Abstract

  PURPOSE: Although the majority of patients with relapsed or refractory large B-cell lymphoma respond to axicabtagene ciloleucel (axi-cel), only a minority of patients have durable remissions. This prospective multicenter study explored the prognostic value of circulating tumor DNA (ctDNA) before and after standard-of-care axi-cel for predicting patient outcomes.METHODS: Lymphoma-specific variable, diversity, and joining gene segments (VDJ) clonotype ctDNA sequences were frequently monitored via next-generation sequencing from the time of starting lymphodepleting chemotherapy until progression or 1 year after axi-cel infusion. We assessed the prognostic value of ctDNA to predict outcomes and axi-cel-related toxicity.RESULTS: A tumor clonotype was successfully detected in 69 of 72 (96%) enrolled patients. Higher pretreatment ctDNA concentrations were associated with progression after axi-cel infusion and developing cytokine release syndrome and/or immune effector cell-associated neurotoxicity syndrome. Twenty-three of 33 (70%) durably responding patients versus 4 of 31 (13%) progressing patients demonstrated nondetectable ctDNA 1 week after axi-cel infusion (P < .0001). At day 28, patients with detectable ctDNA compared with those with undetectable ctDNA had a median progression-free survival and OS of 3 months versus not reached (P < .0001) and 19 months versus not reached (P = .0080), respectively. In patients with a radiographic partial response or stable disease on day 28, 1 of 10 patients with concurrently undetectable ctDNA relapsed; by contrast, 15 of 17 patients with concurrently detectable ctDNA relapsed (P = .0001). ctDNA was detected at or before radiographic relapse in 29 of 30 (94%) patients. All durably responding patients had undetectable ctDNA at or before 3 months after axi-cel infusion.CONCLUSION: Noninvasive ctDNA assessments can risk stratify and predict outcomes of patients undergoing axi-cel for the treatment of large B-cell lymphoma. These results provide a rationale for designing ctDNA-based risk-adaptive chimeric antigen receptor T-cell clinical trials.

  View details for DOI 10.1200/JCO.21.00377

  View details for PubMedID 34133196

• 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

• Phase II study of novel CXCR2 agonist and Plerixafor for rapid stem cell mobilization in patients with multiple myeloma. Blood cancer journal Sidana, S., Bankova, A. K., Hosoya, H., Kumar, S. K., Holmes, T. H., Tamaresis, J., Le, A., Muffly, L. S., Maysel-Auslender, S., Johnston, L., Arai, S., Lowsky, R., Meyer, E., Rezvani, A., Weng, W. K., Frank, M. J., Shiraz, P., Maecker, H. T., Lu, Y., Miklos, D. B., Shizuru, J. A. 2024; 14 (1): 173

  Abstract

  MGTA-145 or GROβT, a CXCR2 agonist, has shown promising activity for hematopoietic stem cell (HSC) mobilization with plerixafor in pre-clinical studies and healthy volunteers. Twenty-five patients with multiple myeloma enrolled in a phase 2 trial evaluating MGTA-145 and plerixafor for HSC mobilization (NCT04552743). Plerixafor was given subcutaneously followed 2 h later by MGTA-145 (0.03 mg/kg) intravenously with same day apheresis. Mobilization/apheresis could be repeated for a second day in patients who collected <6 ×106 CD34+ cells/kg. Lenalidomide and anti-CD38 antibody were part of induction therapy in 92% (n = 23) and 24% (n = 6) of patients, respectively. Median total HSC cell yield (CD34+ cells/kg × 106) was 5.0 (range: 1.1-16.2) and day 1 yield was 3.4 (range: 0.3-16.2). 88% (n = 22) of patients met the primary endpoint of collecting 2 ×106 CD34+ cells/kg in ≤ two days, 68% (n = 17) in one day. Secondary endpoints of collecting 4 and 6 × 106 CD34+ cells/kg in ≤ two days were met in 68% (n = 17) and 40% (n = 10) patients. Grade 1 or 2 adverse events (AE) were seen in 60% of patients, the most common AE being grade 1 pain, usually self-limited. All 19 patients who underwent transplant with MGTA-145 and plerixafor mobilized HSCs engrafted successfully, with durable engraftment at day 100. 74% (17 of 23) of grafts with this regimen were minimal residual disease negative by next generation flow cytometry. Graft composition for HSCs and immune cells were similar to a contemporaneous cohort mobilized with G-CSF and plerixafor.

  View details for DOI 10.1038/s41408-024-01152-1

  View details for PubMedID 39384609

  View details for PubMedCentralID 10040899

• A Phase 1 Clinical Trial of NKTR-255 with CD19-22 CAR-T Cell Therapy for Refractory B-cell Acute Lymphoblastic Leukemia. Blood Srinagesh, H. K., Jackson, C., Shiraz, P., Jeyakumar, N., Hamilton, M. P., Egeler, E., Mavroukakis, S., Kuo, A., Cancilla, J., Sahaf, B., Agarwal, N., Kanegai, A. M., Kramer, A. M., Arai, S., Bharadwaj, S., Dahiya, S., Hosoya, H., Johnston, L. J., Kennedy, V. E., Liedtke, M., Lowsky, R., Mikkilineni, L., Negrin, R. S., Rezvani, A. R., Sidana, S., Shizuru, J. A., Smith, M., Weng, W. K., Feldman, S. A., Frank, M. J., Lee, Z., Tagliaferri, M., Marcondes, A. M., Miklos, D. B., Mackall, C. L., Muffly, L. 2024

  Abstract

  While chimeric antigen receptor T-cell (CAR-T) therapy has revolutionized the treatment of B-cell malignancies, many patients relapse and therefore strategies to improve antitumor immunity are needed. We previously designed a novel autologous bispecific CAR targeting CD19 and CD22 (CAR19-22), which was well tolerated and associated with high response rates but relapse was common. Interleukin-15 (IL15) induces proliferation of diverse immune cells and can augment lymphocyte trafficking. Here, we report the results of a phase 1 clinical trial of the first combination of a novel recombinant polymer-conjugated IL15 receptor agonist (NKTR-255), with CAR19-22, in adults with relapsed / refractory B-cell acute lymphoblastic leukemia. Eleven patients were enrolled, nine of whom successfully received CAR19-22 followed by NKTR-255. There were no dose limiting toxicities, with transient fever and myelosuppression as the most common possibly related toxicities. We observed favorable efficacy with eight out of nine patients (89%) achieving measurable residual disease negative remission. At 12 months, progression-free survival for NKTR-255 was double that of historical controls (67% vs 38%). We performed correlative analyses to investigate the effects of IL15 receptor agonism. Cytokine profiling showed significant increases in IL15 and the chemokines CXCL9 and CXCL10. The increase in chemokines was associated with decreases in absolute lymphocyte counts and CD8+ CAR T-cells in blood and ten-fold increases in CSF CAR-T cells, suggesting lymphocyte trafficking to tissue. Combining NKTR-255 with CAR19-22 was safe, feasible and associated with high rates of durable responses (NCT03233854).

  View details for DOI 10.1182/blood.2024024952

  View details for PubMedID 38968138

• Bendamustine is a safe and effective lymphodepletion agent for axicabtagene ciloleucel in patients with refractory or relapsed large B-cell lymphoma. Journal for immunotherapy of cancer Bharadwaj, S., Lau, E., Hamilton, M. P., Goyal, A., Srinagesh, H., Jensen, A., Lee, D., Mallampet, J., Elkordy, S., Syal, S., Patil, S., Latchford, T., Sahaf, B., Arai, S., Johnston, L. J., Lowsky, R., Negrin, R., Rezvani, A. R., Shizuru, J., Meyer, E. H., Shiraz, P., Mikkilineni, L., Weng, W. K., Smith, M., Sidana, S., Muffly, L., Maecker, H. T., Frank, M. J., Mackall, C., Miklos, D., Dahiya, S. 2024; 12 (7)

  Abstract

  Fludarabine in combination with cyclophosphamide (FC) is the standard lymphodepletion regimen for CAR T-cell therapy (CAR T). A national fludarabine shortage in 2022 necessitated the exploration of alternative regimens with many centers employing single-agent bendamustine as lymphodepletion despite a lack of clinical safety and efficacy data. To fill this gap in the literature, we evaluated the safety, efficacy, and expansion kinetics of bendamustine as lymphodepletion prior to axicabtagene ciloleucel (axi-cel) therapy.84 consecutive patients with relapsed or refractory large B-cell lymphoma treated with axi-cel and managed with a uniform toxicity management plan at Stanford University were studied. 27 patients received alternative lymphodepletion with bendamustine while 57 received FC.Best complete response rates were similar (73.7% for FC and 74% for bendamustine, p=0.28) and there was no significant difference in 12-month progression-free survival or overall survival estimates (p=0.17 and p=0.62, respectively). The frequency of high-grade cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome was similar in both the cohorts. Bendamustine cohort experienced lower proportions of hematological toxicities and antibiotic use for neutropenic fever. Immune reconstitution, as measured by quantitative assessment of cellular immunity, was better in bendamustine cohort as compared with FC cohort. CAR T expansion as measured by peak expansion and area under the curve for expansion was comparable between cohorts.Bendamustine is a safe and effective alternative lymphodepletion conditioning for axi-cel with lower early hematological toxicity and favorable immune reconstitution.

  View details for DOI 10.1136/jitc-2024-008975

  View details for PubMedID 38955420

• Risk of Second Tumors and T-Cell Lymphoma after CAR T-Cell Therapy. The New England journal of medicine Hamilton, M. P., Sugio, T., Noordenbos, T., Shi, S., Bulterys, P. L., Liu, C. L., Kang, X., Olsen, M. N., Good, Z., Dahiya, S., Frank, M. J., Sahaf, B., Mackall, C. L., Gratzinger, D., Diehn, M., Alizadeh, A. A., Miklos, D. B. 2024; 390 (22): 2047-2060

  Abstract

  The risk of second tumors after chimeric antigen receptor (CAR) T-cell therapy, especially the risk of T-cell neoplasms related to viral vector integration, is an emerging concern.We reviewed our clinical experience with adoptive cellular CAR T-cell therapy at our institution since 2016 and ascertained the occurrence of second tumors. In one case of secondary T-cell lymphoma, a broad array of molecular, genetic, and cellular techniques were used to interrogate the tumor, the CAR T cells, and the normal hematopoietic cells in the patient.A total of 724 patients who had received T-cell therapies at our center were included in the study. A lethal T-cell lymphoma was identified in a patient who had received axicabtagene ciloleucel therapy for diffuse large B-cell lymphoma, and both lymphomas were deeply profiled. Each lymphoma had molecularly distinct immunophenotypes and genomic profiles, but both were positive for Epstein-Barr virus and were associated with DNMT3A and TET2 mutant clonal hematopoiesis. No evidence of oncogenic retroviral integration was found with the use of multiple techniques.Our results highlight the rarity of second tumors and provide a framework for defining clonal relationships and viral vector monitoring. (Funded by the National Cancer Institute and others.).

  View details for DOI 10.1056/NEJMoa2401361

  View details for PubMedID 38865660

• Phase 2 open label, multicenter study evaluating CRG-022, a CD22-directed autologous CAR T-cell therapy, in patients (pts) with relapsed/refractory (R/R) large B-cell lymphoma (LBCL) after CD19-directed CAR T-cell therapy. Ghobadi, A., Jacobson, C., McGuirk, J., Shah, N., Rossi, J., Buchholz, T., Bachier-Rodriguez, L., Baird, J. H., Diefenbach, C. S., Farooq, U., Hernandez-Ilizaliturri, F. J., Isufi, I., Patel, K., Neelapu, S., Sauter, C., Spiegel, J. Y., Tees, M., Timmerman, J., Laport, G., Frank, M. LIPPINCOTT WILLIAMS & WILKINS. 2024

  View details for Web of Science ID 001275557406336

• Treatment strategies for progressive immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome: case series. Haematologica Scala, J. J., Eckrich, M. J., Lipak, K., Yates, B., Yuan, C., Wang, H. W., Dahiya, S., Henter, J. I., Huo, J. S., Frank, M. J., Shah, N. N. 2024

  Abstract

  Not available.

  View details for DOI 10.3324/haematol.2023.284784

  View details for PubMedID 38813719

• Management of post-autologous transplant relapse in patients with T-cell lymphomas. American journal of hematology Veilleux, O., Socola, F., Arai, S., Frank, M. J., Johnston, L., Lowsky, R., Shizuru, J., Meyer, E., Muffly, L., Rezvani, A. R., Shiraz, P., Sidana, S., Dahiya, S., Miklos, D. B., Negrin, R. S., Weng, W. K. 2024

  Abstract

  Autologous hematopoietic cell transplantation (AHCT) is often used as a consolidation for patients with peripheral T-cell lymphomas (PTCLs) due to the poor prognosis associated with this heterogenous group of disorders. However, a significant number of patients will experience post-AHCT disease relapse. Here, we report a retrospective study of consecutive 124 patients with PTCLs who underwent AHCT from 2008 to 2020. With a median follow-up of 6.01 years following AHCT, 49 patients (40%) experienced disease relapse. As expected, more patients who were not in first complete remission experienced post-AHCT relapse. Following relapse, majority of the patients (70%) receiving systemic therapies intended as bridging to curative allogeneic HCT. However, only 18 (53%) patients eventually underwent allogeneic HCT. The estimated 3-year OS among patients proceeding to allogeneic HCT was 72% (95% CI 46%-87%). Our report details the pattern of post-AHCT relapse and the management of relapsed disease using different therapeutic modalities.

  View details for DOI 10.1002/ajh.27345

  View details for PubMedID 38661220

• CAR19 monitoring by peripheral blood immunophenotyping reveals histology-specific expansion and toxicity. Blood advances Hamilton, M. P., Craig, E., Gentille Sanchez, C., Mina, A., Tamaresis, J., Kirmani, N., Ehlinger, Z., Syal, S., Good, Z., Sworder, B., Schroers-Martin, J., Lu, Y., Muffly, L., Negrin, R. S., Arai, S., Lowsky, R., Meyer, E., Rezvani, A. R., Shizuru, J. A., Weng, W. K., Shiraz, P., Sidana, S., Bharadwaj, S., Smith, M., Dahiya, S., Sahaf, B., Kurtz, D. M., Mackall, C. L., Tibshirani, R., Alizadeh, A. A., Frank, M. J., Miklos, D. B. 2024

  Abstract

  Chimeric antigen receptor (CAR) T cells directed against CD19 (CAR19) are a revolutionary treatment for B-cell lymphomas. CAR19 cell expansion is necessary for CAR19 function but is also associated with toxicity. To define the impact of CAR19 expansion on patient outcomes, we prospectively followed a cohort of 236 patients treated with CAR19 (brexucabtagene autoleucel or axicabtagene ciloleucel) for mantle cell (MCL), follicular (FL), and large B-cell lymphoma (LBCL) over the course of five years and obtained CAR19 expansion data using peripheral blood immunophenotyping for 188 of these patients. CAR19 expansion was higher in patients with MCL compared to other lymphoma histologic subtypes. Notably, patients with MCL had increased toxicity and required four-fold higher cumulative steroid doses than patients with LBCL. CAR19 expansion was associated with the development of cytokine release syndrome (CRS), immune effector cell associated neurotoxicity syndrome (ICANS), and the requirement for granulocyte colony stimulating factor (GCSF) after day 14 post-infusion. Younger patients and those with elevated lactate dehydrogenase (LDH) had significantly higher CAR19 expansion. In general, no association between CAR19 expansion and LBCL treatment response was observed. However, when controlling for tumor burden, we found that lower CAR19 expansion in conjunction with low LDH was associated with improved outcomes in LBCL. In sum, this study finds CAR19 expansion principally associates with CAR-related toxicity. Additionally, CAR19 expansion as measured by peripheral blood immunophenotyping may be dispensable to favorable outcomes in LBCL.

  View details for DOI 10.1182/bloodadvances.2024012637

  View details for PubMedID 38498731

• CD22 CAR T cells demonstrate high response rates and safety in pediatric and adult B-ALL: Phase 1b results. Leukemia Schultz, L. M., Jeyakumar, N., Kramer, A. M., Sahaf, B., Srinagesh, H., Shiraz, P., Agarwal, N., Hamilton, M., Erickson, C., Jacobs, A., Moon, J., Baggott, C., Arai, S., Bharadwaj, S., Johnston, L. J., Liedtke, M., Lowsky, R., Meyer, E., Negrin, R., Rezvani, A., Shizuru, J., Sidana, S., Egeler, E., Mavroukakis, S., Tunuguntla, R., Gkitsas-Long, N., Retherford, A., Brown, A. K., Gramstrap-Petersen, A. L., Ibañez, R. M., Feldman, S. A., Miklos, D. B., Mackall, C. L., Davis, K. L., Frank, M., Ramakrishna, S., Muffly, L. 2024

  Abstract

  Chimeric antigen receptor (CAR) T cells targeting CD22 (CD22-CAR) provide a therapeutic option for patients with CD22+ malignancies with progression after CD19-directed therapies. Using on-site, automated, closed-loop manufacturing, we conducted parallel Phase 1b clinical trials investigating a humanized CD22-CAR with 41BB costimulatory domain in children and adults with heavily treated, relapsed/refractory (r/r) B-ALL. Of 19 patients enrolled, 18 had successful CD22-CAR manufacturing, and 16 patients were infused. High grade (3-4) cytokine release syndrome (CRS) and immune effector-cell-associated neurotoxicity syndrome (ICANS) each occurred in only one patient; however, three patients experienced immune-effector-cell-associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS). Twelve of 16 patients (75%) achieved CR with an overall 56% MRD-negative CR rate. Duration of response was overall limited (median 77 days), and CD22 expression was downregulated in 4/12 (33%) available samples at relapse. In summary, we demonstrate that closed-loop manufacturing of CD22-CAR T cells is feasible and is associated with a favorable safety profile and high CR rates in pediatric and adult r/r B-ALL, a cohort with limited CD22-CAR reporting.

  View details for DOI 10.1038/s41375-024-02220-y

  View details for PubMedID 38491306

  View details for PubMedCentralID 4993814

• Clinical Features of Neurotoxicity Following CD19 CAR T-cell Therapy in Mantle Cell Lymphoma. Blood advances Nie, E. H., Su, Y. J., Baird, J. H., Agarwal, N., Bharadwaj, S., Weng, W. K., Smith, M., Dahiya, S., Han, M. H., Dunn, J. E., Kipp, L. B., Miklos, D. B., Scott, B. J., Frank, M. J. 2024

  Abstract

  CD19 chimeric antigen receptor (CAR) T-cell therapy has proven highly effective for treating relapsed/refractory mantle cell lymphoma (MCL). However, immune effector cell-associated neurotoxicity syndrome (ICANS) remains a significant concern. This study aimed to evaluate the clinical, radiological, and laboratory correlatives associated with ICANS development following CD19 CAR T-cell therapy in patients with MCL. All patients (n = 26) who received standard of care brexucabtagene autoleucel until July 2022 at our institution were evaluated. Laboratory and radiographic correlatives including brain magnetic resonance imaging (MRI) and electroencephalogram (EEG) were evaluated to determine the clinical impact of ICANS. Seventeen (65%) patients experienced ICANS after treatment, with a median onset on day 6. Ten (38%) patients experienced severe (≥ grade 3) ICANS. All ICANS patients had antecedent cytokine release syndrome (CRS), but no correlation was observed between ICANS severity and CRS grade. 92% of EEGs revealed interictal changes; no patients experienced frank seizures due to ICANS. 86% of severe ICANS patients with post-infusion brain MRIs demonstrated acute neuroimaging findings not seen on pretreatment MRI. Severe ICANS was also associated with higher rates of cytopenia, coagulopathy, increased cumulative steroid exposure, and prolonged hospitalization. However, severe ICANS did not affect treatment outcomes of patients with MCL. Severe ICANS is frequently associated with a range of post-infusion brain MRI changes and abnormal EEG findings. Longer hospitalization was observed in severe ICANS patients, especially those with abnormal acute MRI or EEG findings, but there was no discernible impact on overall treatment response and survival.

  View details for DOI 10.1182/bloodadvances.2023011896

  View details for PubMedID 38295285

• 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

• Single Center Randomized Trial of T-reg graft alone versus T-reg graft Plus Tacrolimus for the Prevention of Acute GVHD. Blood advances Bader, C. S., Pavlova, A., Lowsky, R., Muffly, L., Shiraz, P., Arai, S., Johnston, L. J., Rezvani, A. R., Weng, W. K., Miklos, D. B., Frank, M. J., Tamaresis, J. S., Agrawal, V., Bharadwaj, S., Sidana, S., Shizuru, J. A., Fernhoff, N. B., Putnam, A., Killian, S., Xie, B. J., Negrin, R. S., Meyer, E. 2023

  Abstract

  Allogeneic hematopoietic cell transplantation (HCT) is a curative therapy for hematological malignancies for which graft-versus-host disease (GVHD) remains a major complication. The use of donor T regulatory cells (Tregs) to prevent GVHD appears promising, including in our previous evaluation of an engineered graft product (T-reg graft) consisting of the timed, sequential infusion of CD34+ hematopoietic stem cells and high-purity Tregs followed by conventional T cells. However, whether immunosuppressive prophylaxis can be removed from this protocol remains unclear. We report the results of the first stage of an open-label single-center phase 2 study (NCT01660607) investigating T-reg graft in myeloablative HCT of HLA-matched and 9/10 matched recipients. Twenty-four patients were randomized to receive T-reg graft alone (n=12) or T-reg graft plus single-agent GVHD prophylaxis (n=12) to determine if T-reg graft alone was non-inferior in preventing acute GVHD. All patients developed full donor myeloid chimerism. Patients with T-reg graft alone versus with prophylaxis had an incidence of grade II-IV acute GVHD of 58% versus 8% (p=0.005) and grade III-IV of 17% versus 0% (p=0.149), respectively. The incidence of moderate to severe chronic GVHD was 28% in the T-reg graft alone arm versus 0% with prophylaxis (p=0.056). Among patients with T-reg graft and prophylaxis, CD4+ T cell:Treg ratios were reduced after transplantation, gene-expression profiles showed reduced CD4+ proliferation, and the achievement of full donor T cell chimerism was delayed. This study indicates that T-reg graft with single-agent tacrolimus is preferred to T-reg graft alone for the prevention of acute GVHD. Clinical Trial #: NCT01660607.

  View details for DOI 10.1182/bloodadvances.2023011625

  View details for PubMedID 38091578

• 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

• CAR19 Therapy Drives Expansion of Clonal Hematopoiesis and Associated Cytopenias Hamilton, M. P., Sworder, B. J., Alig, S. K., Good, Z., Boegeholz, J., Schroers-Martin, J., Tamaresis, J., Esfahani, M., Lu, Y., Olsen, M., Liu, C., Ehlinger, Z., Desai, M., Liu-Fei, F., Muffly, L. S., Negrin, R. S., Arai, S., Johnston, L., Lowsky, R., Meyer, E. H., Rezvani, A. R., Shizuru, J., Weng, W., Shiraz, P., Sidana, S., Bharadwaj, S., Smith, M., Dahiya, S., Sahaf, B., Diehn, M., Frank, M. J., Mackall, C. L., Kurtz, D. M., Miklos, D. B., Alizadeh, A. A. AMER SOC HEMATOLOGY. 2023

  View details for DOI 10.1182/blood-2023-182522

  View details for Web of Science ID 001159306701117

• Impact of Obesity on Efficacy, Safety, and Expansion Kinetics of Chimeric Antigen Receptor-T (CAR T) Therapy in Patients with Relapsed or Refractory Large B Cell Lymphoma (LBCL) Goyal, A., Bharadwaj, S., Lee, D., Lau, E., Hamilton, M. P., Jensen, A., Sahaf, B., Syal, S., Patil, S., Cancilla, J. E., Latchford, T., Weng, W., Smith, M., Frank, M. J., Miklos, D. B., Dahiya, S. AMER SOC HEMATOLOGY. 2023

  View details for DOI 10.1182/blood-2023-186828

  View details for Web of Science ID 001159740305129

• Long-Term Efficacy and Immune Reconstitution with Bendamustine As a Lymphodepleting Agent for Axicabtagene Ciloleucel (Axi-Cel) in Patients with Refractory or Relapsed Large B-Cell Lymphoma (LBCL) Bharadwaj, S., Lau, E., Goyal, A., Hamilton, M. P., Srinagesh, H., Jensen, A., Syal, S., Mallampet, J., Latchford, T., Sahaf, B., Weng, W., Smith, M., Maecker, H. T., Frank, M. J., Miklos, D. B., Dahiya, S. AMER SOC HEMATOLOGY. 2023

  View details for DOI 10.1182/blood-2023-188166

  View details for Web of Science ID 001159900800079

• Comparative Effectiveness of Axicabtagene Ciloleucel Vs Historical Standard-of-Care in Patients with Relapsed or Refractory Follicular Lymphoma: An Analysis of CIBMTR and SCHOLAR-5 Data Kambhampati, S., Wang, H., Yan, J., Herrera, A. F., Frank, M. J., Popplewell, L. L., Ahmed, N., Lin, Y., Locke, F. L., Ghione, P., Gribben, J. G., Best, T., Fu, C., Beygi, S., Ray, M. D., Bian, J., Hu, Z., Sun, F., Pasquini, M., Jacobson, C. A. AMER SOC HEMATOLOGY. 2023

  View details for DOI 10.1182/blood-2023-178629

  View details for Web of Science ID 001159306708094

• Second-Line Chimeric Antigen Receptor T Cell Therapy (CAR-T) As Standard of Care for Relapsed-Refractory Large B-Cell Lymphoma (LBCL) Dahiya, S., Spiegel, J. Y., Lee, D., Mohammed, T., Lutfi, F., Goyal, A., Hana, C., Chavez, J. C., Ionescu, F., Frank, M. J., Bharadwaj, S., Sandoval-Sus, J., Beitinjaneh, A. M., Lekakis, L. J., McGuirk, J. P., Locke, F. L., Miklos, D. B., Jain, M. D. AMER SOC HEMATOLOGY. 2023

  View details for DOI 10.1182/blood-2023-188918

  View details for Web of Science ID 001159900800077

• CD22 CAR T Cell-Related IEC-HS Is Associated with an IFN-. Cytokine Signature Srinagesh, H., Baird, J. H., Agarwal, N., Su, Y., Kramer, A., Reschke, A., Jeyakumar, N., Bharadwaj, S., Schultz, L., Ramakrishna, S., Davis, K. L., Sahaf, B., Feldman, S., Mackall, C. L., Miklos, D. B., Muffly, L. S., Frank, M. J. AMER SOC HEMATOLOGY. 2023

  View details for DOI 10.1182/blood-2023-178283

  View details for Web of Science ID 001159900800040

• Manufacturing of a Subsequent Autologous CAR-T Product after Prior CAR-T Is Safe and Feasible Su, Y., Kramer, A., Hamilton, M. P., Agarwal, N., Feldman, S., Sahaf, B., Kuo, A., Mackall, C. L., Muffly, L. S., Miklos, D. B., Frank, M. J. AMER SOC HEMATOLOGY. 2023

  View details for DOI 10.1182/blood-2023-185413

  View details for Web of Science ID 001159306704061

• Transcriptional Profiling Associated with CD22 CAR T Cell Clinical Response in LBCL Kramer, A., Hamilton, M. P., Prabhu, S., Desai, M., Kuo, A., Ehlinger, Z., Agarwal, N., Su, Y., Gkitsas, N., Fowler, C., Keerthi, V., Retherford, A., Klysz, D., Tunuguntla, R., Feldman, S., Sahaf, B., Baird, J. H., Muffly, L. S., Mackall, C. L., Miklos, D. B., Good, Z., Frank, M. J. AMER SOC HEMATOLOGY. 2023

  View details for DOI 10.1182/blood-2023-187615

  View details for Web of Science ID 001159306708064

• Post-CAR-T Minimal Residual Disease (MRD) Monitoring in Mantle Cell Lymphoma Enables Early Relapse Detection Ananth, S., Su, Y., Hamilton, M. P., Agarwal, N., Weng, W., Dahiya, S., Bharadwaj, S., Mallampet, J., Smith, M., Kong, K., Twoy, A., Miklos, D. B., Frank, M. J. AMER SOC HEMATOLOGY. 2023

  View details for DOI 10.1182/blood-2023-188338

  View details for Web of Science ID 001159306706144

• Analysis of PET-CT Derived Radiomic Biomarkers with Efficacy, Safety, and Expansion of Axicabtagene Ciloleucel (Axi-Cel) in Patients with Relapsed or Refractory Large B-Cell Lymphoma (LBCL) Bharadwaj, S., Lau, E., Hashmi, A., Hamilton, M. P., Jensen, A., Goyal, A., Marar, M., Lee, C., Ananth, S., Sahaf, B., Mallampet, J., Ehlinger, Z., Syal, S., Patil, S., Guo, H., Smith, M., Weng, W., Frank, M. J., Binkley, M. S., Miklos, D. B., Dahiya, S. AMER SOC HEMATOLOGY. 2023

  View details for DOI 10.1182/blood-2023-187617

  View details for Web of Science ID 001159306708098

• Phase 1 Trial Results for Patients with Advanced Hematologic Malignancies Undergoing Reduced Intensity Allogeneic HCT with Orca-T Donor Cell Therapy Product and Single Agent Tacrolimus Villar-Prados, A., Meyer, E. H., Sutherland, K., Negrin, R. S., Arai, S., Frank, M. J., Johnston, L., Lowsky, R., Miklos, D. B., Muffly, L. S., Dahiya, S., Rezvani, A. R., Sidana, S., Shiraz, P., Shizuru, J., Weng, W., Smith, M., Bharadwaj, S., Tamaresis, J., Pavlova, A., McClellan, S. AMER SOC HEMATOLOGY. 2023

  View details for DOI 10.1182/blood-2023-188162

  View details for Web of Science ID 001159740304171

• Bendamustine vs. fludarabine/cyclophosphamide lymphodepletion prior to BCMA CAR-T cell therapy in multiple myeloma. Blood cancer journal Sidana, S., Hosoya, H., Jensen, A., Liu, L., Goyal, A., Hovanky, V., Sahaf, B., Bharadwaj, S., Latchford, T., Arai, S., Leahy, S., Mei, M., Budde, L. E., Muffly, L. S., Frank, M. J., Dahiya, S., Htut, M., Miklos, D., Janakiram, M. 2023; 13 (1): 158

  View details for DOI 10.1038/s41408-023-00929-0

  View details for PubMedID 37833271

  View details for PubMedCentralID PMC10576036

• Detection of Aberrant CD58 Expression in a Wide Spectrum of Lymphoma Subtypes: Implications for Treatment Resistance. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc Younes, S., Zhao, S., Bharadwaj, S., Mosquera, A. P., Libert, D., Johnsrud, A., Majzner, R. G., Miklos, D. B., Frank, M. J., Natkunam, Y. 2023: 100256

  Abstract

  CD58 or lymphocyte function-associated antigen-3, is a ligand for CD2 receptors on T- and NK-cells and is required for their activation and target cell killing. We recently showed a trend towards higher frequency of CD58 aberrations in patients with diffuse large B-cell lymphoma (DLBCL) who progressed on CAR-T cell treatment compared to those who responded. Given that CD58 status may be an important measure of T-cell mediated therapy failure, we developed CD58 immunohistochemical assay and evaluated CD58 status in 748 lymphomas. Our results show that CD58 protein expression is downregulated in a significant proportion of all subtypes of B- T- and NK-cell lymphomas. CD58 loss is significantly related to poor prognostic indicators in DLBCL and to ALK and DUSP22 rearrangements in anaplastic large cell lymphoma. However, it is not associated with overall or progression free survival in any of the lymphoma subtypes. As eligibility for CAR-T therapy is being extended to a broader spectrum of lymphomas, mechanisms of resistance, such as target downregulation and CD58 loss, may limit therapeutic success. CD58 status is therefore an important biomarker in lymphoma patients who may benefit from next generation T-cell mediated therapies or other novel approaches that mitigate immune escape.

  View details for DOI 10.1016/j.modpat.2023.100256

  View details for PubMedID 37391168

• Real-world outcomes of brexucabtagene autoleucel (brexu-cel) for relapsed or refractory (R/R) mantle cell lymphoma (MCL): A CIBMTR subgroup analysis by prior treatment. Kambhampati, S., Ahmed, N., Hamadani, M., Grover, N., Shadman, M., Locke, F. L., Gerson, J. M., Frank, M., Budde, L., Wang, M., Hu, Z., Nunes, A., Dalton, D., Kloos, I., Lee, D., Xu, H., Pasquini, M. C., Herrera, A. LIPPINCOTT WILLIAMS & WILKINS. 2023

  View details for Web of Science ID 001053772003451

• Real-world early outcomes of axicabtagene ciloleucel for relapsed or refractory (R/R) follicular lymphoma (FL). Jacobson, C., Hemmer, M. T., Hu, Z., Frank, M., Popplewell, L., Ahmed, N., Lin, Y., Best, T., Beygi, S., Miao, H. H., Fu, C., Sun, F., Xu, H., Pasquini, M. C. LIPPINCOTT WILLIAMS & WILKINS. 2023

  View details for Web of Science ID 001053772003453

• Circulating Tumor DNA Adds Specificity to PET following Axicabtagene Ciloleucel in Large B-cell Lymphoma. Blood advances Dean, E. A., Kimmel, G. J., Frank, M. J., Bukhari, A., Hossain, N. M., Jain, M. D., Dahiya, S., Miklos, D. B., Altrock, P. M., Locke, F. L. 2023

  Abstract

  We examined the meaning of metabolically active lesions on 1 month restaging nuclear imaging of patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL) receiving axicabtagene ciloleucel (axi-cel) by assessing the relationship between total metabolic tumor volume (MTV) on positron emission tomography (PET) scans and circulating tumor DNA (ctDNA) in the plasma. In this prospective multicenter sample collection study, MTV was retrospectively calculated via commercial software at baseline, 1 and 3 months post chimeric antigen receptor (CAR) T-cell therapy; ctDNA was available pre and post axi-cel. Spearman correlation coefficient (rs) was used to study the relationship between the variables and a mathematical model was constructed to describe tumor dynamics 1 month post CAR T-cell therapy. The median time between baseline scan and axi-cel infusion was 33 (range, 1-137) days for all 57 patients. For 41 of the patients with imaging within 33 days of axi-cel or imaging before that time but no bridging therapy, the correlation at baseline became stronger (rs 0.61, P< 0.0001) compared to all patients (rs 0.38, P= 0.004). Excluding patients in complete remission with no measurable residual disease, ctDNA and MTV at 1 month did not correlate (rs 0.28, P= 0.11), but did correlate at 3 months (rs 0.79, P= 0.0007). Modeling of tumor dynamics, which incorporated ctDNA and inflammation as part of MTV, recapitulated outcomes of patients with positive radiologic 1-month scans. Our results suggested that non-progressing hypermetabolic lesions on 1 month PET represent ongoing treatment response and their composition may be elucidated by concurrent ctDNA.

  View details for DOI 10.1182/bloodadvances.2022009426

  View details for PubMedID 37126659

• Improved outcomes for relapsed/refractory Hodgkin lymphoma after autologous transplantation in the era of novel agents. Blood Spinner, M. A., Sica, R. A., Tamaresis, J. S., Lu, Y., Chang, C., Lowsky, R., Frank, M. J., Johnston, L. J., Miklos, D. B., Muffly, L., Negrin, R. S., Rezvani, A. R., Shiraz, P., Shizuru, J. A., Weng, W. K., Binkley, M. S., Hoppe, R. T., Advani, R. H., Arai, S. 2023

  Abstract

  The treatment landscape of relapsed/refractory (R/R) classic Hodgkin lymphoma (cHL) has evolved significantly over the past decade following the approval of brentuximab vedotin (BV) and the programmed death-1 (PD-1) inhibitors. We evaluated how outcomes and practice patterns have changed for R/R cHL patients who underwent autologous hematopoietic cell transplantation (AHCT) at our institution from 2011-2020 (N=183) compared to 2001-2010 (N=159) and evaluated prognostic factors for progression-free survival (PFS) and overall survival (OS) in both eras. OS was superior in the modern era (4-year estimates 89.1% vs 79.0%, HR 0.53, 95% CI 0.33-0.85, p=0.011) with a trend towards lower non-relapse mortality beyond 2 years post-transplant. Among patients who progressed after AHCT, 4-year post-progression survival increased from 43.3% to 71.4% in the modern era, reflecting increasing use of BV and the PD-1 inhibitors. In multivariable analysis for patients transplanted in the modern era, age ³45 years, primary refractory disease, and lack of complete remission pre-AHCT were associated with inferior PFS, while receipt of a PD-1 inhibitor-based regimen pre-AHCT was associated with superior PFS (HR 0.21, 95% CI 0.05-0.80, p=0.030). Extranodal disease at relapse was associated with inferior OS (HR 3.12, 95% CI 1.25-7.77, p=0.014). Our study demonstrates improved survival for R/R cHL after AHCT in the modern era attributed to more effective salvage regimens allowing for better disease control pre-AHCT and improved outcomes for patients who progressed after AHCT. Excellent outcomes were observed with PD-1 inhibitor-based salvage regimens pre-AHCT and support a randomized trial evaluating immunotherapy in the second line setting.

  View details for DOI 10.1182/blood.2022018827

  View details for PubMedID 36857637

• Brexucabtagene Autoleucel for Relapsed or Refractory Mantle Cell Lymphoma in Standard-of-Care Practice: Results From the US Lymphoma CAR T Consortium. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Wang, Y., Jain, P., Locke, F. L., Maurer, M. J., Frank, M. J., Munoz, J. L., Dahiya, S., Beitinjaneh, A. M., Jacobs, M. T., Mcguirk, J. P., Vose, J. M., Goy, A., Andreadis, C., Hill, B. T., Dorritie, K. A., Oluwole, O. O., Deol, A., Paludo, J., Shah, B., Wang, T., Banerjee, R., Miklos, D. B., Rapoport, A. P., Lekakis, L., Ghobadi, A., Neelapu, S. S., Lin, Y., Wang, M. L., Jain, M. D. 2023: JCO2201797

  Abstract

  Brexucabtagene autoleucel (brexu-cel) is an autologous CD19-directed chimeric antigen receptor (CAR) T-cell therapy approved for relapsed/refractory mantle cell lymphoma (MCL). This therapy was approved on the basis of the single-arm phase II ZUMA-2 trial, which showed best overall and complete response rates of 91% and 68%, respectively. We report clinical outcomes with brexu-cel in the standard-of-care setting for the approved indication.Patients who underwent leukapheresis between August 1, 2020 and December 31, 2021, at 16 US institutions, with an intent to manufacture commercial brexu-cel for relapsed/refractory MCL, were included. Patient data were collected for analyses of responses, outcomes, and toxicities as per standard guidelines.Of 189 patients who underwent leukapheresis, 168 (89%) received brexu-cel infusion. Of leukapheresed patients, 79% would not have met ZUMA-2 eligibility criteria. Best overall and complete response rates were 90% and 82%, respectively. At a median follow-up of 14.3 months after infusion, the estimates for 6- and 12-month progression-free survival (PFS) were 69% (95% CI, 61 to 75) and 59% (95% CI, 51 to 66), respectively. The nonrelapse mortality was 9.1% at 1 year, primarily because of infections. Grade 3 or higher cytokine release syndrome and neurotoxicity occurred in 8% and 32%, respectively. In univariable analysis, high-risk simplified MCL international prognostic index, high Ki-67, TP53 aberration, complex karyotype, and blastoid/pleomorphic variant were associated with shorter PFS after brexu-cel infusion. Patients with recent bendamustine exposure (within 24 months before leukapheresis) had shorter PFS and overall survival after leukapheresis in intention-to-treat univariable analysis.In the standard-of-care setting, the efficacy and toxicity of brexu-cel were consistent with those reported in the ZUMA-2 trial. Tumor-intrinsic features of MCL, and possibly recent bendamustine exposure, may be associated with inferior efficacy outcomes.

  View details for DOI 10.1200/JCO.22.01797

  View details for PubMedID 36753699

• Multifocal demyelinating leukoencephalopathy and oligodendroglial lineage cell loss with immune effector cell-associated neurotoxicity syndrome (ICANS) following CD19 CAR T-cell therapy for mantle cell lymphoma. Journal of neuropathology and experimental neurology Nie, E. H., Ahmadian, S. S., Bharadwaj, S. N., Acosta-Alvarez, L., Threlkeld, Z. D., Frank, M. J., Miklos, D. B., Monje, M., Scott, B. J., Vogel, H. 2023

  Abstract

  Immune effector cell-associated neurotoxicity syndrome (ICANS) is a prevalent condition seen after treatment with chimeric antigen receptor T-cell (CAR T) therapy and other cancer cell therapies. The underlying pathophysiology and neuropathology of the clinical syndrome are incompletely understood due to the limited availability of brain tissue evaluation from patient cases, and a lack of high-fidelity preclinical animal models for translational research. Here, we present the cellular and tissue neuropathologic analysis of a patient who experienced grade 4 ICANS after treatment with anti-CD19 CAR T therapy for mantle cell lymphoma. Our pathologic evaluation reveals a pattern of multifocal demyelinating leukoencephalopathy associated with a clinical course of severe ICANS. A focused analysis of glial subtypes further suggests region-specific oligodendrocyte lineage cell loss as a potential cellular and pathophysiologic correlate in severe ICANS. We propose a framework for the continuum of neuropathologic changes thus far reported across ICANS cases. Future elucidation of the mechanistic processes underlying ICANS will be critical in minimizing neurotoxicity following CAR T-cell and related immunotherapy treatments across oncologic and autoimmune diseases.

  View details for DOI 10.1093/jnen/nlac121

  View details for PubMedID 36592076

• 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

• Belumosudil Combination Therapy in Refractory Chronic Graft-Versus-Host Disease Chin, M., Shizuru, J. A., Muffly, L., Shiraz, P., Johnston, L. J., Lowsky, R., Rezvani, A. R., Frank, M. J., Bharadwaj, S., Weng, W., Negrin, R. S., Miklos, D. B., Arai, S. AMER SOC HEMATOLOGY. 2022: 4788-4789

  View details for DOI 10.1182/blood-2022-165547

  View details for Web of Science ID 000893223204356

• Outcomes for Acute Myeloid Leukemia Relapse after Allogeneic Hematopoietic Cell Transplantation Remain Poor in the Modern Era Philip, S., Lowsky, R., Johnston, L. J., Arai, S., Meyer, E. H., Negrin, R. S., Rezvani, A. R., Shiraz, P., Shizuru, J. A., Sidana, S., Weng, W., Bharadwaj, S., Frank, M. J., Miklos, D. B., Smith, M., Muffly, L., Agrawal, V. AMER SOC HEMATOLOGY. 2022: 4825-4827

  View details for DOI 10.1182/blood-2022-168546

  View details for Web of Science ID 000893223204372

• Clonal Hematopoiesis Driven By Recurrent Somatic Mutations but Not with Recurrent Copy Number Alterations Is Associated with Inferior Outcomes in DLBCL after Induction Chemotherapy, but Not CAR19 Therapy Boegeholz, J., Alig, S. K., Sworder, B., Schroers-Martin, J., Macaulay, C., Craig, A. M., Duehrsen, U., Huettmann, A., Westin, J., Cherng, H. J., Miklos, D. B., Frank, M. J., Diehn, M., Kurtz, D. M., Alizadeh, A. A. AMER SOC HEMATOLOGY. 2022: 8609-8610

  View details for DOI 10.1182/blood-2022-170087

  View details for Web of Science ID 000893230301297

• Long-Term Cognitive and Neuropsychiatric Outcomes in Adults Who Have Received Chimeric Antigen Receptor T-Cell (CAR-T) Therapy for Aggressive Lymphoma at Stanford - a Pilot Feasibility Study Scott, B. J., Murray, T., Deutsch, G. K., Lahijani, S., Frank, M. J., Monje, M. AMER SOC HEMATOLOGY. 2022: 5201-5202

  View details for DOI 10.1182/blood-2022-168229

  View details for Web of Science ID 000893223205100

• 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

• Higher Rates of Severe Infection and Persistent Cytopenias in Long-Term CAR19 Responders Than after Autologous HCT: A Single Institution Study of 139 Subjects Hamilton, M. P., Liu-Fei, F. C., Alig, S. K., Tamaresis, J., Esfahani, M., Good, Z., Sworder, B., Schroers-Martin, J., Liu, C., Severinsen, F., Hanson, P. J., Lu, Y., Lowsky, R., Negrin, R. S., Meyer, E. H., Smith, M., Bharadwaj, S., Shizuru, J. A., Sidana, S., Shiraz, P., Rezvani, A. R., Johnston, L. J., Weng, W., Arai, S., Muffly, L., Dahiya, S., Diehn, M., Kurtz, D. M., Sahaf, B., Mackall, C. L., Frank, M. J., Miklos, D. B., Alizadeh, A. A. AMER SOC HEMATOLOGY. 2022: 7545-7547

  View details for DOI 10.1182/blood-2022-165600

  View details for Web of Science ID 000893230300247

• The Development of Carhlh after Axicabtagene Ciloleucel Is Associated with Poor Outcomes Philip, S., Srinagesh, H. K., Hamilton, M. P., Gentille, C., Mina, A., Arai, S., Johnston, L. J., Lowsky, R., Meyer, E. H., Negrin, R. S., Rezvani, A. R., Shiraz, P., Shizuru, J. A., Sidana, S., Weng, W., Bharadwaj, S., Dahiya, S., Muffly, L., Smith, M., Miklos, D. B., Frank, M. J. AMER SOC HEMATOLOGY. 2022: 12775-12777

  View details for DOI 10.1182/blood-2022-170877

  View details for Web of Science ID 000893230305401

• Analysis of Bendamustine Lymphodepletion, CD19 CART Expansion, Safety and Efficacy in Patients with Rel/Ref NonHodgkin Lymphoma Bharadwaj, S., Hamilton, M. P., Sahaf, B., Tamaresis, J., Patil, S., Hanson, P. J., Latchford, T., Arai, S., Johnston, L. J., Lowsky, R., Negrin, R. S., Rezvani, A. R., Shizuru, J. A., Meyer, E. H., Shiraz, P., Sidana, S., Smith, M., Weng, W., Muffly, L., Mackall, C. L., Frank, M. J., Miklos, D. B., Dahiya, S. AMER SOC HEMATOLOGY. 2022: 10371-10373

  View details for DOI 10.1182/blood-2022-170759

  View details for Web of Science ID 000893230303169

• Long-Term Follow-up of CD19/22 CAR Therapy in Children and Young Adults with B-ALL Reveals Efficacy, Tolerability and High Survival Rates When Coupled with Hematopoietic Stem Cell Transplantation Schultz, L. M., Ramakrishna, S., Baskar, R., Richards, R. M., Moon, J., Baggott, C., Fujimoto, M., Kunicki, M., Li, A., Jariwala, S., Erickson, C., Jacobs, A., Yamabe, K., Barsan, V., Majzner, R. G., Egeler, E. L., Mavroukakis, S., Ehlinger, Z., Reynolds, W. D., Sahaf, B., Muffly, L., Frank, M. J., Gramstrup, A., Chinnasamy, H., Patel, S., Miklos, D. B., Feldman, S. A., Mackall, C. L., Davis, K. L. AMER SOC HEMATOLOGY. 2022: 10300-10302

  View details for DOI 10.1182/blood-2022-167789

  View details for Web of Science ID 000893230303140

• 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

• CD22 CAR T Cells Demonstrate Favorable Safety Profile and High Response Rates in Pediatric and Adult B-ALL: Results of a Phase 1b Study Jeyakumar, N., Ramakrishna, S., Frank, M. J., Sahaf, B., Feldman, S. A., Miklos, D. B., Mackall, C. L., Davis, K. L., Muffly, L., Schultz, L. M. AMER SOC HEMATOLOGY. 2022: 2374-2375

  View details for DOI 10.1182/blood-2022-164456

  View details for Web of Science ID 000893223202157

• A Phase 1 Study of ADI-001: Anti-CD20 CAR-Engineered Allogeneic Gamma Delta1 (gamma delta) T Cells in Adults with B-Cell Malignancies Neelapu, S. S., Stevens, D. A., Hamadani, M., Frank, M. J., Holmes, H., Jacobovits, A., Hinkle, J., Kennedy-Wilde, J., Maller, O., Weinstein, B., Galimi, F., Lai, R. K., Miklos, D. B. AMER SOC HEMATOLOGY. 2022: 4617-4619

  View details for DOI 10.1182/blood-2022-157400

  View details for Web of Science ID 000893223204283

• Post-infusion CAR T-Reg cells identify patients resistant to CD19-CAR therapy NATURE MEDICINE Good, Z., Spiegel, J. Y., Sahaf, B., Malipatlolla, M. B., Ehlinger, Z. J., Kurra, S., Desai, M. H., Reynolds, W. D., Lin, A., Vandris, P., Wu, F., Prabhu, S., Hamilton, M. P., Tamaresis, J. S., Hanson, P. J., Patel, S., Feldman, S. A., Frank, M. J., Baird, J. H., Muffly, L., Claire, G. K., Craig, J., Kong, K. A., Wagh, D., Coller, J., Bendall, S. C., Tibshirani, R. J., Plevritis, S. K., Miklos, D. B., Mackall, C. L. 2022

  Abstract

  Approximately 60% of patients with large B cell lymphoma treated with chimeric antigen receptor (CAR) T cell therapies targeting CD19 experience disease progression, and neurotoxicity remains a challenge. Biomarkers associated with resistance and toxicity are limited. In this study, single-cell proteomic profiling of circulating CAR T cells in 32 patients treated with CD19-CAR identified that CD4+Helios+ CAR T cells on day 7 after infusion are associated with progressive disease and less severe neurotoxicity. Deep profiling demonstrated that this population is non-clonal and manifests hallmark features of T regulatory (TReg) cells. Validation cohort analysis upheld the link between higher CAR TReg cells with clinical progression and less severe neurotoxicity. A model combining expansion of this subset with lactate dehydrogenase levels, as a surrogate for tumor burden, was superior for predicting durable clinical response compared to models relying on each feature alone. These data credential CAR TReg cell expansion as a novel biomarker of response and toxicity after CAR T cell therapy and raise the prospect that this subset may regulate CAR T cell responses in humans.

  View details for DOI 10.1038/s41591-022-01960-7

  View details for Web of Science ID 000852940800007

  View details for PubMedID 36097223

• Assessment of Pretreatment and Posttreatment Evolution of Neurofilament Light Chain Levels in Patients Who Develop Immune Effector Cell-Associated Neurotoxicity Syndrome. JAMA oncology Butt, O. H., Zhou, A. Y., Caimi, P. F., Luckett, P. H., Wisch, J. K., Derenoncourt, P., Lee, K., Wu, G. F., de Lima, M. J., Campian, J. L., Frank, M. J., DiPersio, J. F., Ghobadi, A., Ances, B. M. 2022

  Abstract

  Importance: Determining whether neurofilament light chain (NfL) elevations in patients who develop immune effector cell-associated neurotoxicity syndrome (ICANS) occur before or after infusion of cellular product is important to identify high-risk patients and inform whether neuroaxonal injury is latent or a consequence of treatment.Objective: To quantify serial NfL levels in patients undergoing cellular therapy.Design, Setting, and Participants: This retrospective 2-center study examined plasma NfL levels in 30 patients with detailed medical and treatment history, including all major pretreatment and posttreatment risk factors. Exclusion criteria included dementia and severe, symptomatic central nervous system (CNS) involvement.Main Outcomes and Measures: Patients' NfL levels were measured at 7 time points: baseline (prelymphodepletion), during lymphodepletion, postinfusion day (D) 1, D3, D7, D14, and D30. Prediction accuracy for the development of ICANS was next modeled using receiver operating characteristic (ROC) classification. Finally, univariate and multivariate modeling examined the association between NfL levels, ICANS, and potential risk factors including demographic (age, sex), oncologic (tumor burden, history of CNS involvement), neurologic (history of nononcologic CNS disease or neuropathy), and neurotoxic exposure histories (vincristine, cytarabine, methotrexate, or CNS radiotherapy).Results: A total of 30 patients (median [range] age, 64 [22-80] years; 12 women [40%] and 18 men [60%]) were included. Individuals who developed ICANS had elevations in NfL prior to lymphodepletion and chimeric antigen receptor T-cell infusion compared with those who did not develop ICANS (no ICANS: 29.4 pg/mL, vs any ICANS: 87.6 pg/mL; P<.001). Baseline NfL levels further predicted ICANS development with high accuracy (area under the ROC curve, 0.96), sensitivity (0.91), and specificity (0.95). Levels of NfL remained elevated across all time points, up to 30 days postinfusion. Baseline NfL levels correlated with ICANS severity but not demographic factors, oncologic history, nononcologic neurologic history, or history of exposure to neurotoxic therapies.Conclusions and Relevance: In a subset of patients in this cross-sectional study, the risk of developing ICANS was associated with preexisting neuroaxonal injury that was quantifiable with plasma NfL level. This latent neuroaxonal injury was present prior to drug administration but was not associated with historic neurotoxic therapies or nononcologic neurologic disease. Preinfusion NfL may further permit early screening and identification of patients most at risk for ICANS. Additional studies are needed to determine NfL's utility as a predictive biomarker for early (preemptive or prophylactic) intervention and to delineate the origin of this underlying neural injury.

  View details for DOI 10.1001/jamaoncol.2022.3738

  View details for PubMedID 36048456

• CAR T-cell therapy for mantle cell lymphoma with central nervous system relapse. Blood advances Vu, K., Frank, M. J. 2022

  View details for DOI 10.1182/bloodadvances.2022008031

  View details for PubMedID 35895518

• Reverse fate mapping of CD19-targeted CAR T cells in patients with large B-cell lymphoma Good, Z., Hamilton, M. P., Spiegel, J. Y., Kurra, S., Desai, M., Prabhu, S., Yang, E., Ozawa, M. G., Hanson, P. J., Wu, F., Frank, M. J., Baird, J. H., Muffly, L., Claire, G. K., Craig, J., Kong, K. A., Wagh, D., Coller, J., Plevritis, S. K., Sahaf, B., Miklos, D. B., Mackall, C. L. AMER ASSOC CANCER RESEARCH. 2022

  View details for Web of Science ID 000892509507391

• Brexucabtagene autoleucel for relapsed/refractory mantle cell lymphoma: Real-world experience from the United States lymphoma CAR T consortium. Jain, P., Wang, Y., Locke, F. L., Munoz, J., Beitinjaneh, A., Frank, M., Dahiya, S., Jacobs, M. T., Hill, B. T., Lekakis, L. J., Miklos, D., Ghobadi, A., Neelapu, S., Lin, Y., Wang, M., Jain, M. D., Maurer, M. J., US Lymphoma CAR T cell Consortium LIPPINCOTT WILLIAMS & WILKINS. 2022

  View details for Web of Science ID 000863680304110

• Multifocal demyelinating leukoencephalopathy and oligodendroglial lineage cell loss with CD19 CAR T-cell lymphoma therapy Nie, E., Ahmadian, S., Bharadwaj, S., Acosta-Alvarez, L., Threlkeld, Z., Frank, M., Miklos, D., Born, D., Scott, B., Monje, M., Vogel, H. OXFORD UNIV PRESS INC. 2022: 464

  View details for Web of Science ID 000798368400099

• Allogeneic Hematopoietic Cell Transplantation for Adult Acute Lymphoblastic Leukemia in the Modern Era. Transplantation and cellular therapy Liang, E. C., Craig, J., Torelli, S., Cunanan, K., Iglesias, M., Arai, S., Frank, M. J., Johnston, L., Lowsky, R., Meyer, E. H., Miklos, D. B., Negrin, R., Rezvani, A., Shiraz, P., Shizuru, J., Sidana, S., Weng, W. K., Bharadwaj, S., Muffly, L. 2022

  Abstract

  Allogeneic hematopoietic cell transplantation (HCT) remains an important treatment for adults with acute lymphoblastic leukemia (ALL). We hypothesized that advances in ALL and transplantation have resulted in improved HCT outcomes in recent years.To evaluate the characteristics and outcomes of adult ALL patients undergoing allogeneic HCT over the last decade.Patients with ALL aged ≥18 years old who underwent allogeneic HCT at Stanford University between 2008 and 2019 were included in this study. Patients were divided into two Eras based on year of HCT: 2008-2013 (Earlier Era) and 2014-2019 (Later Era).A total of 285 patients were included: 119 patients underwent HCT in the Earlier Era and 166 in the Later Era. Patients transplanted in the Later Era were more likely to be Hispanic (38% vs. 21%) and to have HCT-Comorbidity Index of ≥ 3 (31% vs. 18%). Donor source for HCT also differed with an increase in the use of HLA-mismatched donor sources (38% vs. 24%), notably umbilical cord blood (UCB) in the Later Era (16% vs. 0%). Patients in the Later Era were less likely to undergo transplant with active disease (4% vs.16%); pre-HCT rates of measurable residual disease (MRD) were similar across the Eras (38% vs. 40%). In unadjusted analyses, overall survival (OS) improved across Eras, with 2-year estimates for the Later and Earlier Eras of 73% (95% CI, 66%-80%) vs. 55% (95% CI, 46%-64%), respectively. Multivariable analysis confirmed the association between Later Era and OS (HR = 0.52, 95% CI, 0.34-0.78). Finally, among patients relapsing after HCT (25% in Later Era and 33% in Earlier Era), the utilization of novel immunotherapies increased in the Later Era (44% vs. 3%), as did the median OS following post-HCT relapse (16 months vs. 8 months, p < 0.001).OS following HCT for adult ALL has improved in recent years. This is due, in part, to a significant improvement in the ability to effectively salvage adults with ALL relapsing after HCT.

  View details for DOI 10.1016/j.jtct.2022.05.010

  View details for PubMedID 35584783

• Inferring gene expression from cell-free DNA fragmentation profiles. Nature biotechnology Esfahani, M. S., Hamilton, E. G., Mehrmohamadi, M., Nabet, B. Y., Alig, S. K., King, D. A., Steen, C. B., Macaulay, C. W., Schultz, A., Nesselbush, M. C., Soo, J., Schroers-Martin, J. G., Chen, B., Binkley, M. S., Stehr, H., Chabon, J. J., Sworder, B. J., Hui, A. B., Frank, M. J., Moding, E. J., Liu, C. L., Newman, A. M., Isbell, J. M., Rudin, C. M., Li, B. T., Kurtz, D. M., Diehn, M., Alizadeh, A. A. 2022

  Abstract

  Profiling of circulating tumor DNA (ctDNA) in the bloodstream shows promise for noninvasive cancer detection. Chromatin fragmentation features have previously been explored to infer gene expression profiles from cell-free DNA (cfDNA), but current fragmentomic methods require high concentrations of tumor-derived DNA and provide limited resolution. Here we describe promoter fragmentation entropy as an epigenomic cfDNA feature that predicts RNA expression levels at individual genes. We developed 'epigenetic expression inference from cell-free DNA-sequencing' (EPIC-seq), a method that uses targeted sequencing of promoters of genes of interest. Profiling 329 blood samples from 201 patients with cancer and 87 healthy adults, we demonstrate classification of subtypes of lung carcinoma and diffuse large B cell lymphoma. Applying EPIC-seq to serial blood samples from patients treated with PD-(L)1 immune-checkpoint inhibitors, we show that gene expression profiles inferred by EPIC-seq are correlated with clinical response. Our results indicate that EPIC-seq could enable noninvasive, high-throughput tissue-of-origin characterization with diagnostic, prognostic and therapeutic potential.

  View details for DOI 10.1038/s41587-022-01222-4

  View details for PubMedID 35361996

• Detection of Aberrant CD58 Expression in a Wide Spectrum of Hodgkin and Non-Hodgkin Lymphomas: Implications for CAR T Cell Resistance Younes, S., Libert, D., Zhao, S., Johnsrud, A., Bharadwaj, S., Majzner, R., Frank, M., Miklos, D., Natkunam, Y. SPRINGERNATURE. 2022: 1046-1048

  View details for Web of Science ID 000770360202309

• Detection of Aberrant CD58 Expression in a Wide Spectrum of Hodgkin and Non-Hodgkin Lymphomas: Implications for CAR T Cell Resistance Younes, S., Libert, D., Zhao, S., Johnsrud, A., Bharadwaj, S., Majzner, R., Frank, M., Miklos, D., Natkunam, Y. SPRINGERNATURE. 2022: 1046-1048

  View details for Web of Science ID 000770361802309

• Real-world Experience of Cryopreserved Allogeneic Hematopoietic Grafts in the COVID-19 Pandemic: A Single Center Report. Transplantation and cellular therapy Bankova, A. K., Caveney, J., Yao, B., Ramos, T. L., Bogeholz, J., Heydari, K., Diaz, N., Jackson, M. L., Lowsky, R., Brown, J. W., Johnston, L., Rezvani, A. R., Frank, M. J., Muffly, L., Weng, W., Sidana, S., Negrin, R. S., Miklos, D. B., Shiraz, P., Meyer, E. H., Shizuru, J. A., Arai, S. 1800

  Abstract

  BACKGROUND: As a result of the COVID-19 widespread pandemic, cryopreservation of allogeneic donor apheresis products was implemented to mitigate the challenges of donor availability and product transport. Although logistically beneficial, the impact of cryopreservation on clinical outcomes and graft composition remains unclear.OBJECTIVES: To compare the outcomes and graft composition with cryopreserved versus fresh allografts in the setting of allogeneic hematopoietic cell transplantation (allo-HCT).STUDY DESIGN: We retrospectively analyzed the clinical outcomes of 30 consecutive patients who received cryopreserved allografts between March and August 2020 as compared to 60 consecutive patients who received fresh allografts prior to the COVID-19 pandemic. Primary endpoints were hematopoietic engraftment, graft failure (GF) and secondary outcomes were overall survival (OS), relapse free survival (RFS) and non-relapse mortality (NRM). In addition, extended immunophenotype analysis was performed on cryopreserved versus prospectively collected fresh apheresis samples.RESULTS: Compared to fresh allografts, both neutrophil and platelet recovery were delayed in recipients of cryopreserved reduced intensity conditioning (RIC) allo-HCT with median times to engraftment of 24 days vs 18 days (P = .01) and 27 days vs 18 days (P = .069), respectively. We observed primary GF in 4 of 30 patients in the cryopreserved cohort (13.3%) vs only one of 60 patients (1.7 %) in the fresh cohort (P = .03). Cryopreserved RIC allo-HCT was associated with significantly lower median total, myeloid and T-cell donor chimerism at 1 month. OS and RFS were inferior for cryograft recipients with hazard ratio [HR (95%Cl)]: 2.16 (1.00, 4.67) and 1.90 (0.95, 3.79), respectively. Using an extended immunophenotype analysis we compared 14 samples from the cryopreserved cohort to 6 prospectively collected fresh apheresis donor samples. These analyses showed both decrease in total cell viability and significantly reduced absolute numbers of NK cells (CD3-CD56+) in the cryopreserved apheresis samples.CONCLUSION: In this single institution study we note delayed engraftment and a trend toward clinical inferiority of cryopreserved vs fresh allografts. Further evaluation of the use of cryopreserved allografts and their impact on clinical and laboratory outcomes is warranted.

  View details for DOI 10.1016/j.jtct.2022.01.010

  View details for PubMedID 35042013

• Mgta-145+Plerixafor Provides GCSFFree Rapid and Reliable Hematopoietic Stem Cell Mobilization for Autologous Stem Cell Transplant in Patients with Multiple Myeloma: A Phase 2 Study Sidana, S., Bankova, A. K., Hosoya, H., Kumar, S., Tamaresis, J., Le, A., Muffly, L., Johnston, L. J., Arai, S., Lowsky, R., Meyer, E. H., Rezvani, A. R., Weng, W., Frank, M. J., Shiraz, P., Girgenti, D., Goncalves, K. A., Schmelmer, V., Davis, J. C., Lu, Y., Shizuru, J. A., Miklos, D. B. AMER SOC HEMATOLOGY. 2021

  View details for DOI 10.1182/blood-2021-149306

  View details for Web of Science ID 000736413908010

• ALPHA Study: ALLO-501 Produced Deep and Durable Responses in Patients with Relapsed/Refractory Non-Hodgkin's Lymphoma Comparable to Autologous CAR T Neelapu, S. S., Nath, R., Munoz, J., Tees, M., Miklos, D. B., Frank, M. J., Malik, S. A., Stevens, D., Shin, C., Balakumaran, A., Loomis-Navale, L., Goyal, L., Nguyen, A., Locke, F. L. AMER SOC HEMATOLOGY. 2021

  View details for DOI 10.1182/blood-2021-146038

  View details for Web of Science ID 000736413908003

• ALPHA2 Study: ALLO-501A Allogeneic CAR T in LBCL, Updated Results Continue to Show Encouraging Safety and Efficacy with Consolidation Dosing Lekakis, L. J., Locke, F. L., Tees, M., Neelapu, S. S., Malik, S. A., Hamadani, M., Frank, M. J., Popplewell, L. L., Abramson, J. S., Vos, S., Munoz, J., Shi, C., Balakumaran, A., Loomis-Navale, L., Goyal, L., Zhou, X., Miklos, D. B. AMER SOC HEMATOLOGY. 2021

  View details for DOI 10.1182/blood-2021-146045

  View details for Web of Science ID 000736398802189

• Brexucabtagene Autoleucel for Relapsed/Refractory Mantle Cell Lymphoma: Real World Experience from the US Lymphoma CAR T Consortium Wang, Y., Jain, P., Locke, F. L., Munoz, J., Maurer, M. J., Beitinjaneh, A., Frank, M. J., Dahiya, S., McGuirk, J. P., Jacobs, M. T., Goy, A. H., Vose, J. M., Hill, B. T., Oluwole, O. O., Deol, A., Shah, B. D., Paludo, J., Wang, T., Lekakis, L. J., Miklos, D. B., Rapoport, A. P., Ghobadi, A., Neelapu, S. S., Lin, Y., Wang, M., Jain, M. D. AMER SOC HEMATOLOGY. 2021

  View details for DOI 10.1182/blood-2021-147563

  View details for Web of Science ID 000736398803044

• Worsening Financial Toxicity Among Patients Receiving Chimeric Antigen Receptor t-Cell (CAR-T) Therapy: A Mixed Methods Longitudinal Study Cusatis, R., Tan, I., Piehowski, C., Akinola, I., Crawford, E., Craig, J., Thiengmany, A., Frank, M. J., Miklos, D. B., Shah, N. N., D'Souza, A., Knight, J. M., Muffly, L., Flynn, K. E., Sidana, S. AMER SOC HEMATOLOGY. 2021

  View details for DOI 10.1182/blood-2021-146032

  View details for Web of Science ID 000736398802108

• Do PROs Tell the Whole Story? Differential Outcomes Based on PatientReported Outcomes (PROs) Versus Performance-Based Metrics (PBM) on Cognition for Patients Receiving Chimeric Antigen Receptor (CAR)-T Cell Therapy Tan, I., Cusatis, R., Crawford, E., Thiengmany, A., Piehowski, C., Akinola, I., Craig, J., Lahijani, S., Frank, M. J., Shah, N. N., D'Souza, A., Miklos, D. B., Muffly, L., Flynn, K. E., Sidana, S. AMER SOC HEMATOLOGY. 2021

  View details for DOI 10.1182/blood-2021-145746

  View details for Web of Science ID 000736413904116

• 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

• Incidence and risk factors associated with bleeding and thrombosis following chimeric antigen receptor T-cell therapy BLOOD ADVANCES Johnsrud, A., Craig, J., Baird, J., Spiegel, J., Muffly, L., Zehnder, J., Tamaresis, J., Negrin, R., Johnston, L., Arai, S., Shizuru, J., Lowsky, R., Meyer, E., Weng, W., Shiraz, P., Rezvani, A., Latchford, T., Mackall, C., Miklos, D., Frank, M., Sidana, S. 2021; 5 (21): 4465-4475

  View details for DOI 10.1182/bloodadvances.2021004716.

  View details for Web of Science ID 000718993700016

• Concordance of peripheral blood and bone marrow measurable residual disease in adult acute lymphoblastic leukemia. Blood advances Muffly, L., Sundaram, V., Chen, C., Yurkiewicz, I., Kuo, E., Burnash, S., Spiegel, J. Y., Arai, S., Frank, M. J., Johnston, L. J., Lowsky, R., Meyer, E. H., Negrin, R. S., Rezvani, A. R., Sidana, S., Shiraz, P., Shizuru, J. A., Weng, W., Liedtke, M., Vempaty, H. T., Miklos, D. B. 2021; 5 (16): 3147-3151

  Abstract

  Monitoring of measurable residual disease (MRD) is essential to the management of acute lymphoblastic leukemia (ALL) and is typically performed through repeated bone marrow (BM) assessments. Using a next-generation sequencing (NGS) MRD platform, we performed a prospective observational study evaluating the correlation between peripheral blood (PB) and BM MRD in adults with ALL receiving cellular therapies (hematopoietic cell transplantation [HCT] and chimeric antigen receptor T-cell [CAR-T] therapies). Among the study cohort (N = 69 patients; 126 paired PB/BM samples), we found strong correlation between PB and BM MRD (r = 0.87; P < .001), with a sensitivity and specificity of MRD detection in the PB of 87% and 90%, respectively, relative to MRD in the BM. MRD became detectable in the PB in 100% of patients who subsequently relapsed following HCT, with median time from MRD+ to clinical relapse of 90 days, and in 85% of patients who relapsed following CAR T, with median time from MRD+ to clinical relapse of 60 days. In adult patients with ALL undergoing cellular therapies, we demonstrate strong concordance between NGS-based MRD detected in the PB and BM. Monitoring of ALL MRD in the PB appears to be an adequate alternative to frequent invasive BM evaluations in this clinical setting.

  View details for DOI 10.1182/bloodadvances.2021004234

  View details for PubMedID 34424318

• CAR T cells with dual targeting of CD19 and CD22 in adult patients with recurrent or refractory B cell malignancies: a phase 1 trial. Nature medicine Spiegel, J. Y., Patel, S., Muffly, L., Hossain, N. M., Oak, J., Baird, J. H., Frank, M. J., Shiraz, P., Sahaf, B., Craig, J., Iglesias, M., Younes, S., Natkunam, Y., Ozawa, M. G., Yang, E., Tamaresis, J., Chinnasamy, H., Ehlinger, Z., Reynolds, W., Lynn, R., Rotiroti, M. C., Gkitsas, N., Arai, S., Johnston, L., Lowsky, R., Majzner, R. G., Meyer, E., Negrin, R. S., Rezvani, A. R., Sidana, S., Shizuru, J., Weng, W., Mullins, C., Jacob, A., Kirsch, I., Bazzano, M., Zhou, J., Mackay, S., Bornheimer, S. J., Schultz, L., Ramakrishna, S., Davis, K. L., Kong, K. A., Shah, N. N., Qin, H., Fry, T., Feldman, S., Mackall, C. L., Miklos, D. B. 2021

  Abstract

  Despite impressive progress, more than 50% of patients treated with CD19-targeting chimeric antigen receptor T cells (CAR19) experience progressive disease. Ten of 16 patients with large B cell lymphoma (LBCL) with progressive disease after CAR19 treatment had absent or low CD19. Lower surface CD19 density pretreatment was associated with progressive disease. To prevent relapse with CD19- or CD19lo disease, we tested a bispecific CAR targeting CD19 and/or CD22 (CD19-22.BB.z-CAR) in a phase I clinical trial ( NCT03233854 ) of adults with relapsed/refractory B cell acute lymphoblastic leukemia (B-ALL) and LBCL. The primary end points were manufacturing feasibility and safety with a secondary efficacy end point. Primary end points were met; 97% of products met protocol-specified dose and no dose-limiting toxicities occurred during dose escalation. In B-ALL (n=17), 100% of patients responded with 88% minimal residual disease-negative complete remission (CR); in LBCL (n=21), 62% of patients responded with 29% CR. Relapses were CD19-/lo in 50% (5 out of 10) of patients with B-ALL and 29% (4 out of 14) of patients with LBCL but were not associated with CD22-/lo disease. CD19/22-CAR products demonstrated reduced cytokine production when stimulated with CD22 versus CD19. Our results further implicate antigen loss as a major cause of CAR T cell resistance, highlight the challenge of engineering multi-specific CAR T cells with equivalent potency across targets and identify cytokine production as an important quality indicator for CAR T cell potency.

  View details for DOI 10.1038/s41591-021-01436-0

  View details for PubMedID 34312556

• Outcomes after delayed and second autologous stem cell transplant in patients with relapsed multiple myeloma. Bone marrow transplantation Lemieux, C., Muffly, L. S., Iberri, D. J., Craig, J. K., Johnston, L. J., Lowsky, R., Shiraz, P., Rezvani, A. R., Frank, M. J., Weng, W., Meyer, E., Shizuru, J. A., Arai, S., Liedtke, M., Negrin, R. S., Miklos, D. B., Sidana, S. 2021

  Abstract

  We evaluated the outcomes of 168 patients undergoing delayed or second autologous stem cell transplant (ASCT) for relapsed multiple myeloma (MM) from 2010 to 2019. Overall, 21% (n=35) patients had received a prior transplant and 69% (n=116) underwent transplant at first relapse. Overall, 27% patients had high-risk cytogenetics and 15% had ISS stage III disease. Stem cell collection was performed after relapse in 72% and 35% of patients received maintenance therapy. Median PFS from salvage treatment and transplant were 28 and 19 months, respectively. Median OS from salvage treatment and transplant was 69 and 55 months. Multivariate analysis revealed that ASCT in first relapse was associated with superior PFS (HR 0.63, p=0.03) and OS (HR 0.59, p=0.04) compared to later lines of therapy. In addition, PFS of ≥36 months with prior therapy was associated with improved PFS (HR 0.62, p=0.04) and OS (HR 0.41, p=0.01). Ninety-five patients underwent delayed transplant at first relapse, median PFS and OS from start of therapy was 30 and 69 months, and median OS from diagnosis was 106 months. These data may serve as a guide when counseling patients undergoing ASCT for relapsed MM and provide a benchmark in designing clinical trials of transplantation/comparative treatments for relapsed MM.

  View details for DOI 10.1038/s41409-021-01371-1

  View details for PubMedID 34163014

• Inferior Clinical Outcomes in Recipients of Cryopreserved Grafts Following Reduced Intensity Allogeneic Hematopoietic Cell Transplantation: A Single Center Report Bankova, A., Caveney, J., Ramos, T., Bogeholz, J., Heydari, K., Diaz, N., Jackson, M., Lowsky, R., Brown, J., Johnston, L., Rezvani, A., Frank, M., Muffly, L., Weng, W., Sidana, S., Negrin, R., Miklos, D., Shiraz, P., Meyer, E., Shizuru, J., Arai, S. SPRINGERNATURE. 2021: 181

  View details for Web of Science ID 000668928500152

• Phase 2 study of MGTA-145+plerixafor for rapid and reliable hematopoietic stem cell (HSC) mobilization for autologous transplant in multiple myeloma. Sidana, S., Bankova, A., Hosoya, H., Muffly, L. S., Kumar, S., Johnston, L. J., Lowsky, R., Meyer, E., Rezvani, A., Weng, W., Arai, S., Frank, M., Shiraz, P., Howell, H., Goncalves, K. A., Schmelmer, V., Davis, J., Shizuru, J., Miklos, D. LIPPINCOTT WILLIAMS & WILKINS. 2021

  View details for DOI 10.1200/JCO.2021.39.15_suppl.8023

  View details for Web of Science ID 000708120604186

• Stem Cell Mobilization in Multiple Myeloma: Comparing Safety and Efficacy of Cyclophosphamide +/- Plerixafor vs. G-CSF +/- Plerixafor in the Lenalidomide Era. Transplantation and cellular therapy Johnsrud, A., Ladha, A., Muffly, L., Shiraz, P., Goldstein, G., Osgood, V., Shizuru, J. A., Johnston, L., Arai, S., Weng, W., Lowsky, R., Rezvani, A. R., Meyer, E. H., Frank, M. J., Negrin, R. S., Miklos, D. B., Sidana, S. 2021

  Abstract

  Growth factor and chemotherapy-based stem cell mobilization strategies are commonly used for patients with multiple myeloma. We retrospectively compared 398 patients mobilized between 2017-2020 using either cyclophosphamide (4g/m2) plus granulocyte colony stimulating factor (GCSF) or G-CSF alone, with on demand plerixafor (PXF) in both groups. While total CD34+yield was higher after chemo-mobilization compared to GCSF+/-PXF (median 13.6 vs. 4.4 * 106/kg,P< .01), achievement of≥2 * 106CD34+ cells (95% vs 93.7%,P= .61), and rates of mobilization failure (5% vs. 6.3%,P= .61) were similar. Fewer patients required PXF with chemo-mobilization (12.3% vs 49.5%,P< .01), and apheresis sessions were fewer (median: 1, range 1-4 vs. 2, range 1-5). Complications were higher after chemo-mobilization (30% vs. 7.4%,P< .01), including neutropenic fever, ED visits, and hospitalizations. Prior lenalidomide≤6 cycles did not impair cell yield in either group.Median cost of mobilization was 17.4% lower in the GCSF +/- PXF group (P= .01).Differences in time to engraftment were not clinically significant. Given similar rates mobilization success, engraftment time, and less toxicity and lower costs compared to chemo-mobilization, G-CSF with on-demand PXF may be preferable in myeloma patients with adequate disease control and limited lenalidomide exposure.

  View details for DOI 10.1016/j.jtct.2021.04.016

  View details for PubMedID 33915323

• Use of Backup Stem Cells for Stem Cell Boost and Second Transplant in Patients with Multiple Myeloma Undergoing Autologous Stem Cell Transplantation. Transplantation and cellular therapy Liang, E. C., Muffly, L. S., Shiraz, P., Shizuru, J. A., Johnston, L., Arai, S., Frank, M. J., Weng, W., Lowsky, R., Rezvani, A., Meyer, E. H., Negrin, R., Miklos, D. B., Sidana, S. 2021

  Abstract

  Autologous hematopoietic stem cell transplantation (ASCT) is a standard treatment for multiple myeloma (MM). Consensus guidelines recommend collecting sufficient stem cells in case there is a need for stem cell boost for delayed/poor engraftment or for future second ASCT. However, collecting and storing backup stem cells in all patients requires significant resources and cost, and the rates of backup stem cell utilization are not well studied. We sought to examine the utilization of backup stem cells (BSCs) in patients with MM undergoing ASCT. Patients with MM aged ≥18 years old who underwent first ASCT at our institution from January 2010 through December 2015 and collected sufficient stem cells for at least 2 transplants were included in this single-center retrospective study. This timeframe was selected to allow for adequate follow-up. A total of 393 patients were included. The median age was 58 years (range, 25-73). After a median follow-up of 6 years, the median progression-free survival (PFS) of the cohort was 3 years. Sixty-one percent (n=240) of patients progressed or relapsed. Chemotherapy-based mobilization was used in almost all patients (98%). The median total CD34+ cells collected was 18.2*106/kg (range, 3.4-112.4). A median of 5.7*106 CD34+ cells/kg (range, 1.8-41.9) was infused during the first ASCT, and a median of 10.1*106 CD34+ cells/kg (range, 1.5-104.5) was cryopreserved for future use. Of the patients, 6.9% (n=27) used backup stem cells, with 2.3% (n=10) using them for stem cell boost, 4.6% (n=18) for a second salvage ASCT, including 1 patient for both stem cell boost and second ASCT. Rates of backup stem cell use among patients aged <60, 60-69, and ≥70 years were 7.8%, 5.7%, and 5.9%, respectively. There was a trend toward higher rates of backup stem cell use for second ASCT in patients who were younger, had suboptimal disease control at time of first ASCT, and longer PFS. The median dose of stem cell boost given was 5.6*106 CD34+ cells/kg (range, 1.9-20). The median time from stem cell boost to neutrophil, hemoglobin, and platelet engraftment was 4 (range, 2-11), 15 (range, 4-34), and 12 (range, 0-34) days, respectively. Lower CD34+ dose and older age at time of ASCT predicted need for stem cell boost. With new salvage therapies for relapsed MM, the rates of second ASCT are very low. The low rates of use suggest that institutional policies regarding universal BSC collection and long-term storage should be reassessed and individualized. However, need for stem cell boost in 2.3% of patients may present a challenge to that.

  View details for DOI 10.1016/j.jtct.2021.02.026

  View details for PubMedID 33775587

• Immune reconstitution and infectious complications following axicabtagene ciloleucel therapy for large B-cell lymphoma. Blood advances Baird, J. H., Epstein, D. J., Tamaresis, J. S., Ehlinger, Z., Spiegel, J. Y., Craig, J., Claire, G. K., Frank, M. J., Muffly, L., Shiraz, P., Meyer, E., Arai, S., Brown, J. W., Johnston, L., Lowsky, R., Negrin, R. S., Rezvani, A. R., Weng, W. K., Latchford, T., Sahaf, B., Mackall, C. L., Miklos, D. B., Sidana, S. 2021; 5 (1): 143-155

  Abstract

  Chimeric antigen receptor (CAR) T-cell therapy targeting CD19 has significantly improved outcomes in the treatment of refractory or relapsed large B-cell lymphoma (LBCL). We evaluated the long-term course of hematologic recovery, immune reconstitution, and infectious complications in 41 patients with LBCL treated with axicabtagene ciloleucel (axi-cel) at a single center. Grade 3+ cytopenias occurred in 97.6% of patients within the first 28 days postinfusion, with most resolved by 6 months. Overall, 63.4% of patients received a red blood cell transfusion, 34.1% of patients received a platelet transfusion, 36.6% of patients received IV immunoglobulin, and 51.2% of patients received growth factor (granulocyte colony-stimulating factor) injections beyond the first 28 days postinfusion. Only 40% of patients had recovered detectable CD19+ B cells by 1 year, and 50% of patients had a CD4+ T-cell count <200 cells per μL by 18 months postinfusion. Patients with durable responses to axi-cel had significantly longer durations of B-cell aplasia, and this duration correlated strongly with the recovery of CD4+ T-cell counts. There were significantly more infections within the first 28 days compared with any other period of follow-up, with the majority being mild-moderate in severity. Receipt of corticosteroids was the only factor that predicted risk of infection in a multivariate analysis (hazard ratio, 3.69; 95% confidence interval, 1.18-16.5). Opportunistic infections due to Pneumocystis jirovecii and varicella-zoster virus occurred up to 18 months postinfusion in patients who prematurely discontinued prophylaxis. These results support the use of comprehensive supportive care, including long-term monitoring and antimicrobial prophylaxis, beyond 12 months after axi-cel treatment.

  View details for DOI 10.1182/bloodadvances.2020002732

  View details for PubMedID 33570626

• Immune reconstitution and infectious complications following axicabtagene ciloleucel therapy for large B-cell lymphoma BLOOD ADVANCES Baird, J. H., Epstein, D. J., Tamaresis, J. S., Ehlinger, Z., Spiegel, J. Y., Craig, J., Claire, G. K., Frank, M. J., Muffly, L., Shiraz, P., Meyer, E., Arai, S., Brown, J., Johnston, L., Lowsky, R., Negrin, R. S., Rezvani, A. R., Weng, W., Latchford, T., Sahaf, B., Mackall, C. L., Miklos, D. B., Sidana, S. 2021; 5 (1): 143–55

  View details for DOI 10.1182/bloodadvances.2020002732

  View details for Web of Science ID 000607932700016

• Incidence and Risk Factors Associated with Bleeding and Thrombosis Following Chimeric Antigen Receptor T Cell Therapy. Blood advances Johnsrud, A. J., Craig, J., Baird, J. H., Spiegel, J. Y., Muffly, L., Zehnder, J. L., Tamaresis, J. S., Negrin, R. S., Johnston, L., Arai, S., Shizuru, J. A., Lowsky, R., Meyer, E., Weng, W. K., Shiraz, P., Rezvani, A. R., Latchford, T., Mackall, C. L., Miklos, D. B., Frank, M. J., Sidana, S. 2021

  Abstract

  Bleeding and thrombotic events are an emerging toxicity associated with chimeric antigen receptor (CAR) therapies. To determine their incidence, we retrospectively analyzed consecutive adult patients (n=127) with large B-cell lymphoma (LBCL) or B-cell acute lymphoblastic leukemia (B-ALL) treated between 2017-2020 with axicabtagene ciloleucel (axi-cel) (N=89) or a bispecific CD19/CD22 CAR (N=38). 12 (9.4%) and 8 (6.3%) patients developed bleeding and thrombosis within first 3 months, respectively. In the axi-cel subgroup, these occurred in 11.2% and 6.7%, respectively. Bleeding occurred between days 8-30 (median 17.5), and thrombosis between days 2-91 (median 29). Bleeding sites included genitourinary (N=6), soft tissue (N=2), intracranial (N=2), gastrointestinal (N=1), pulmonary (N=1), and were associated with features of consumptive coagulopathy. On univariate analysis, patients with bleeding were older (median 72 vs. 60 yrs, P<0.01), had lower baseline platelets (86 vs. 178 K/uL, P<0.01), lower platelet nadir after CAR-T (median 17.5 vs. 48 K/uL; P<0.01), lower fibrinogen nadir (median 122 vs. 340 ug/mL; P<0.01) and elevated LDH (P=0.01). ICANS grade ≥3 was associated with increased bleeding (50% vs. 15%; P=0.01), thrombosis (50% vs. 16%; P=0.04), PT prolongation, hypofibrinogenemia and elevated D-dimer. A paucity of events limited multivariate analysis, however low pre-treatment platelets were associated with bleeding in a multivariate logistic regression model. Patients with thrombocytopenia or severe ICANS are at increased risk of bleeding complications and should be closely monitored particularly within the first month after CAR therapy. Future studies in larger cohorts should assess risk factors for systemic coagulopathies in CAR-T therapy, including their association with neurotoxicity.

  View details for DOI 10.1182/bloodadvances.2021004716

  View details for PubMedID 34521106

• Serial FNA allows direct sampling of malignant and infiltrating immune cells in patients with B-cell lymphoma receiving immunotherapy. Cancer cytopathology Mooney, K. L., Czerwinski, D. K., Shree, T., Frank, M. J., Haebe, S., Martin, B. A., Testa, S., Levy, R., Long, S. R. 2021

  Abstract

  Fine-needle aspiration (FNA) is used to diagnose malignancies, recurrences, and metastases. The procedure is quick and well tolerated and can be facilitated by ultrasound guidance.This article describes the authors' experience in using serial FNA to harvest cellular material during 4 clinical trials of immunotherapy by in situ vaccination in patients with low-grade lymphoma.Two hundred ninety-six FNA samples were collected from 44 patients over a span of approximately 6 weeks for each patient. Samples were sufficient in quantity and quality to be analyzed by flow cytometry and/or single-cell messenger RNA sequencing. FNA samples yielded an average of 12 × 106 cells with a mean cellular viability of 86%. Material collected from the tumor lymph nodes differed significantly in the proportions and phenotypes of cellular populations in comparison with matched peripheral blood samples. A comparison of flow cytometry results obtained by FNA directly from the patient and by FNA performed ex vivo and a dissociation of the same lymph node after surgical excision confirmed that FNA sampling of the patient accurately represented the tumor and the microenvironment. An analysis of the FNA samples from immunotherapy-treated target lymph nodes versus nodes from nontreated tumor sites provided insight into the impact of specific immunotherapy regimens.This is the largest study describing the use of serial FNA sampling to harvest cellular material during immunotherapy clinical trials. The success of this technique opens the door for FNA sampling to expand significantly future investigations of the dynamic effects of investigational agents, be they immunotherapies or targeted therapies.

  View details for DOI 10.1002/cncy.22531

  View details for PubMedID 34780125

• Outcomes with Autologous or Allogeneic Stem Cell Transplantation in Patients with Plasma Cell Leukemia in the Era of Novel Agents. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation Lemieux, C., Johnston, L. J., Lowsky, R., Muffly, L. S., Craig, J. K., Shiraz, P., Rezvani, A., Frank, M. J., Weng, W., Meyer, E., Shizuru, J., Arai, S., Negrin, R., Miklos, D. B., Sidana, S. 2020

  Abstract

  Plasma cell leukemia (PCL) is a rare and very aggressive plasma cell disorder. The optimal treatment approach, including whether to pursue an autologous (autoSCT) or allogeneic (alloSCT) transplant is not clear as there is lack of clinical trial based evidence. This single center retrospective study describes the outcomes of 16 patients with PCL (N=14 primary PCL) who underwent either autoSCT (N=9) or alloSCT (N=7) for PCL in the era of novel agents, between 2007 and 2019. Median age of the cohort was 58 years. High-risk cytogenetics were seen in 50% of patients. All patients received a proteasome inhibitor (PI) and/or immunomodulatory drug (IMiD) based regimen before transplant. At transplant, 10 (62%) patients obtained at least a very good partial response. Response after autoSCT (3 month) was at least VGPR in 6 (67%, CR=5) patients. All patients undergoing alloSCT achieved CR at 3 months. Maintenance was used in 5 patients (56%) after autoSCT. Median PFS from transplant in the autoSCT vs. alloSCT group was 6 vs. 18 months, p=0.09, while median OS from transplant was 19 vs. 40 months (p=0.41), respectively. The median OS from diagnosis was 27 vs. 49 months, p=0.50, respectively. Of all the deaths, 10 (91%) patients died of relapsed disease. In conclusion, alloSCT was not observed to offer any significant survival advantage over autoSCT in PCL, which is comparable to other recent reports and relapse remains the primary cause of death.

  View details for DOI 10.1016/j.bbmt.2020.08.035

  View details for PubMedID 32961371

• Autologous stem cell transplantation versus no transplant in patients above 70 with multiple myeloma. Lemieux, C., Muffly, L. S., Iberri, D., Rezvani, A., Lowsky, R., Frank, M., Craig, J. K., Liedtke, M., Negrin, R., Weng, W., Meyer, E., Johnston, L. J., Shizuru, J., Shiraz, P., Arai, S., Miklos, D., Sidana, S. LIPPINCOTT WILLIAMS & WILKINS. 2020

  View details for Web of Science ID 000560368307442

• Impact of proteasome inhibitor vs. IMiD maintenance therapy on outcomes of patients with high-risk multiple myeloma (HRMM). Tam, E., Iberri, D., Liedtke, M., Muffly, L. S., Shiraz, P., Frank, M., Lowsky, R., Rezvani, A., Negrin, R., Meyer, E., Arai, S., Johnston, L. J., Shizuru, J., Weng, W., Miklos, D., Sidana, S. LIPPINCOTT WILLIAMS & WILKINS. 2020

  View details for Web of Science ID 000560368307484

• CD22-Directed CAR T-Cell Therapy Induces Complete Remissions in CD19-Directed CAR-Refractory Large B-Cell Lymphoma. Blood Baird, J. H., Frank, M. J., Craig, J. n., Patel, S. n., Spiegel, J. Y., Sahaf, B. n., Oak, J. S., Younes, S. n., Ozawa, M. n., Yang, E. n., Natkunam, Y. n., Tamaresis, J. S., Ehlinger, Z. n., Reynolds, W. D., Arai, S. n., Johnston, L. n., Lowsky, R. n., Meyer, E. n., Negrin, R. S., Rezvani, A. R., Shiraz, P. n., Sidana, S. n., Weng, W. K., Davis, K. L., Ramakrishna, S. n., Schultz, L. n., Mullins, C. D., Jacob, A. P., Kirsch, I. R., Feldman, S. A., Mackall, C. L., Miklos, D. B., Muffly, L. n. 2020

  Abstract

  The prognosis for patients with large B-cell lymphoma (LBCL) progressing after treatment with chimeric antigen receptor (CAR) T-cell therapy targeting CD19 (CAR19) is poor. We report on the first three consecutive patients with autologous CAR19-refractory LBCL treated with a single infusion of autologous 1×106 CAR+ T-cells/kg targeting CD22 (CAR22) as part of a phase I dose escalation study. CAR22 therapy was relatively well tolerated, without any observed non-hematologic adverse events higher than grade 2. Following infusion, all three patients achieved complete remission, with all responses ongoing at the time of last follow up (mean 7.8 months, range 6-9.3). Circulating CAR22 cells demonstrated robust expansion (peak range 85.4-350 cells/µL), and persisted beyond three months in all patients with continued radiographic responses and corresponding decreases in circulating tumor DNA (ctDNA) beyond six months post-infusion. Further accrual at a higher dose level in this phase 1 dose-escalation study is ongoing and will explore the role of this therapy in patients who have failed prior CAR T-cell therapies. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT04088890).

  View details for DOI 10.1182/blood.2020009432

  View details for PubMedID 33512414

• A novel antibody-cell conjugation method to enhance and characterize cytokine-induced killer cells. Cytotherapy Frank, M. J., Olsson, N. n., Huang, A. n., Tang, S. W., Negrin, R. S., Elias, J. E., Meyer, E. H. 2020; 22 (3): 135–43

  Abstract

  Cytokine-induced killer (CIK) cells are an ex vivo-expanded cellular therapy product with potent anti-tumor activity in a subset of patients with solid and hematologic malignancies. We hypothesize that directing CIK cells to a specific tumor antigen will enhance CIK cell anti-tumor cytotoxicity.We present a newly developed method for affixing antibodies directly to cell surface proteins. First, we evaluated the anti-tumor potential of CIK cells after affixing tumor-antigen targeting monoclonal antibodies. Second, we evaluated whether this antibody-conjugation method can profile the surface proteome of CIK cells.We demonstrated that affixing rituximab or daratumumab to CIK cells enhances cytotoxic killing of multiple lymphoma cell lines in vitro. These 'armed' CIK cells exhibited enhanced intracellular signaling after engaging tumor targets. Cell surface proteome profiling suggested mechanisms by which antibody-armed CIK cells concurrently activated multiple surface proteins, leading to enhanced cytolytic activity. Our surface proteome analysis indicated that CIK cells display enhanced protein signatures indicative of immune responses, cellular activation and leukocyte migration.Here, we characterize the cell surface proteome of CIK cells using a novel methodology that can be rapidly applied to other cell types. Our study also demonstrates that without genetic modification CIK cells can be rapidly armed with monoclonal antibodies, which endows them with high specificity to kill tumor targets.

  View details for DOI 10.1016/j.jcyt.2020.01.003

  View details for PubMedID 32171435

• Outcomes with autologous stem cell transplant vs. non-transplant therapy in patients 70 years and older with multiple myeloma. Bone marrow transplantation Lemieux, C. n., Muffly, L. S., Rezvani, A. n., Lowsky, R. n., Iberri, D. J., Craig, J. K., Frank, M. J., Johnston, L. J., Liedtke, M. n., Negrin, R. n., Weng, W. K., Meyer, E. n., Shizuru, J. n., Shiraz, P. n., Arai, S. n., Miklos, D. B., Sidana, S. n. 2020

  Abstract

  We evaluated 79 patients with multiple myeloma (MM) ≥70 years referred to our blood and marrow transplant clinic, within 1 year of diagnosis from 2010 to 2019, for consideration of autologous stem cell transplant (ASCT). Thirty-eight (48%) of 79 patients underwent ASCT. ASCT was not pursued in 41 (52%) patients due to: patient or physician preference in 80% (n = 33) or ineligibility in 20% (n = 8). Baseline characteristics of patients in the two groups were similar. Median PFS from treatment start amongst patients undergoing ASCT (n = 38) vs. not (n = 41) was 41 months vs. 33 months, p = 0.03. There was no difference in OS, with estimated 5-year OS of 73% vs. 83%, respectively (p = 0.86). Day +100 transplant-related mortality (TRM) was 0%. ASCT was an independent favorable prognostic factor for PFS in multivariate analysis, after accounting for HCT-CI score, performance status, hematologic response, and maintenance. Finally, patients ≥70 years undergoing ASCT had similar PFS compared to a contemporaneous institutional cohort of patients <70 years (n = 631) (median PFS from transplant: 36 vs. 47 months, p = 0.25). In this retrospective analysis, ASCT was associated with low TRM and better PFS in fit older adults with MM compared to non-transplant therapy, with comparable benefits as seen in younger patients.

  View details for DOI 10.1038/s41409-020-01026-7

  View details for PubMedID 32782351

• 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

• Monitoring ctDNA in r/r DLBCL patients following the CAR T-cell therapy axicabtagene ciloleucel: Day 28 landmark analysis. Frank, M., Hossain, N. M., Bukhari, A., Dean, E., Spiegel, J. Y., Claire, G. K., Kirsch, I., Jacob, A., Mullins, C. D., Lee, L., Kong, K. A., Craig, J. K., Mackall, C., Rapoport, A., Dahiya, S., Locke, F., Miklos, D. AMER SOC CLINICAL ONCOLOGY. 2019

  View details for Web of Science ID 000487345806314

• Serial Fine Needle Aspiration (FNA) Allows Direct Sampling of Low-grade Lymphoma Tumor Nodules and Subsequent Analysis of the Tumor and Its Microenvironment in Clinical Trial Patients Receiving Immunotherapy Mooney, K., Long, S., Martin, B., Frank, M., Czerwinski, D., Levy, R., Guo, X., Shree, T., Greenstein, R. NATURE PUBLISHING GROUP. 2019

  View details for Web of Science ID 000478081100412

• Serial Fine Needle Aspiration (FNA) Allows Direct Sampling of Low-grade Lymphoma Tumor Nodules and Subsequent Analysis of the Tumor and Its Microenvironment in Clinical Trial Patients Receiving Immunotherapy Mooney, K., Long, S., Martin, B., Frank, M., Czerwinski, D., Levy, R., Guo, X., Shree, T., Greenstein, R. NATURE PUBLISHING GROUP. 2019

  View details for Web of Science ID 000478915500394

• Elevated Axicabtagene Ciloleucel (CAR-19) Expansion By Immunophenotyping Is Associated with Toxicity in Diffuse Large B-Cell Lymphoma Spiegel, J. Y., Sahaf, B., Hossain, N., Frank, M. J., Claire, G., Abramian, M., Latchford, T., Villa, B., Cancilla, J., Oak, J., Natkunam, Y., Long, S. R., Arai, S., Johnston, L. J., Lowsky, R., Meyer, E. H., Muffly, L. S., Negrin, R. S., Rezvani, A. R., Shizuru, J. A., Weng, W., Kong, K. A., Mackall, C. L., Miklos, D. B. AMER SOC HEMATOLOGY. 2018

  View details for DOI 10.1182/blood-2018-99-113261

  View details for Web of Science ID 000454837601285

• Phase I Experience with a Bi-Specific CAR Targeting CD19 and CD22 in Adults with B-Cell Malignancies Hossain, N., Sahaf, B., Abramian, M., Spiegel, J. Y., Kong, K., Kim, S., Mavroukakis, S., Oak, J., Natkunam, Y., Meyer, E. H., Frank, M. J., Feldman, S. A., Long, S. R., Qin, H., Fry, T. J., Muffly, L. S., Mackall, C. L., Miklos, D. B. AMER SOC HEMATOLOGY. 2018

  View details for DOI 10.1182/blood-2018-99-110142

  View details for Web of Science ID 000454837601199

• In Situ Vaccination with a TLR 9 Agonist and Local Low Dose Radiation Induces Systemic Responses in Untreated Indolent Lymphoma. Cancer discovery Frank, M. J., Reagan, P. M., Bartlett, N. L., Gordon, L. I., Friedberg, J. W., Czerwinski, D. K., Long, S. R., Hoppe, R. T., Janssen, R. S., Candia, A. F., Coffman, R. L., Levy, R. 2018

  Abstract

  This multicenter phase 1/2 clinical trial evaluated intratumoral SD-101, a TLR9 agonist, and low-dose radiation in patients with untreated indolent lymphoma. 29 enrolled patients received 4 Gy of radiation followed by five weekly intratumoral injections of SD-101 at a single tumor site. No treatment-related grade 4 or serious adverse events occurred. Nearly all patients had tumor reduction at their treated site. More importantly, 24 patients had tumor reduction at their non-treated sites with 5 patients achieving a partial response and one achieving a complete response. Treatment-related increases of CD8+ and CD4+ effector T-cells and decreases of T Follicular Helper and T regulatory cells (Tregs) were observed in the tumor microenvironment. Low pre-treatment levels of CD4+ Tregs, proliferating CD8+ T-cells, and GranzymeB+ CD8+ T-cells were associated with favorable outcomes. Intratumoral SD-101 in combination with low-dose radiation is well tolerated and results in regression of both treated and untreated sites of disease.

  View details for PubMedID 30154192

• 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

• 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

• 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

• 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

• Epigenetic silencing of Stk39 in B-cell lymphoma inhibits apoptosis from genotoxic stress. The American journal of pathology Balatoni, C. E., Dawson, D. W., Suh, J., Sherman, M. H., Sanders, G., Hong, J. S., Frank, M. J., Malone, C. S., Said, J. W., Teitell, M. A. 2009; 175 (4): 1653-61

  Abstract

  B-cell lymphomas, the most frequent human immune system malignancies, often contain dysregulated TCL1 oncogene expression. TCL1 transgenic (TCL1-tg) mice develop a spectrum of B-cell malignancies, supporting an oncogenic role for TCL1 in B cells. Our prior global survey of DNA methylation patterns in TCL1-tg B-cell lymphomas identified many lymphoma-specific candidate hypermethylated genes, including Stk39. The Stk39 encoded protein, sterile 20-like-related proline-alanine-rich kinase (SPAK), regulates cell stress responses, and microarray studies identified reduced SPAK expression in metastatic prostate and treatment-resistant breast cancers, suggesting that its loss may have a role in cancer progression. Here we identified DNA hypermethylation and SPAK silencing in TCL1-tg B-cell lymphomas and SPAK silencing without DNA methylation in multiple subtypes of human B-cell lymphomas. SPAK knockdown by shRNA protected B cells from caspase-dependent apoptosis induced by DNA double-strand breaks but not apoptosis in response to osmotic or oxidative cell stressors. Caspase 3 activation by cleavage was impaired with SPAK repression in DNA damaged B cells. Interestingly, c-Jun NH(2)-terminal kinase is potentially activated by SPAK and pharmacological inhibition of c-Jun NH(2)-terminal kinase in SPAK-expressing B cells recapitulated the cell-protective phenotype of SPAK knockdown. Taken together, these data indicate that SPAK loss in B-cell lymphomas promotes increased cell survival with DNA damage and provides a potential mechanism for increased resistance to genotoxic stress in cancer.

  View details for DOI 10.2353/ajpath.2009.090091

  View details for PubMedID 19717643

  View details for PubMedCentralID PMC2751561

• Expression of sprouty2 inhibits B-cell proliferation and is epigenetically silenced in mouse and human B-cell lymphomas. Blood Frank, M. J., Dawson, D. W., Bensinger, S. J., Hong, J. S., Knosp, W. M., Xu, L., Balatoni, C. E., Allen, E. L., Shen, R. R., Bar-Sagi, D., Martin, G. R., Teitell, M. A. 2009; 113 (11): 2478-87

  Abstract

  B-cell lymphoma is the most common immune system malignancy. TCL1 transgenic mice (TCL1-tg), in which TCL1 is ectopically expressed in mature lymphocytes, develop multiple B- and T-cell leukemia and lymphoma subtypes, supporting an oncogenic role for TCL1 that probably involves AKT and MAPK-ERK signaling pathway augmentation. Additional, largely unknown genetic and epigenetic alterations cooperate with TCL1 during lymphoma progression. We examined DNA methylation patterns in TCL1-tg B-cell tumors to discover tumor-associated epigenetic changes, and identified hypermethylation of sprouty2 (Spry2). Sprouty proteins are context-dependent negative or positive regulators of MAPK-ERK pathway signaling, but their role(s) in B-cell physiology or pathology are unknown. Here we show that repression of Spry2 expression in TCL1-tg mouse and human B-cell lymphomas and cell lines is associated with dense DNA hypermethylation and was reversed by inhibition of DNA methylation. Spry2 expression was induced in normal splenic B cells by CD40/B-cell receptor costimulation and regulated a negative feedback loop that repressed MAPK-ERK signaling and decreased B-cell viability. Conversely, loss of Spry2 function hyperactivated MAPK-ERK signaling and caused increased B-cell proliferation. Combined, these results implicate epigenetic silencing of Spry2 expression in B lymphoma progression and suggest it as a companion lesion to ectopic TCL1 expression in enhancing MAPK-ERK pathway signaling.

  View details for DOI 10.1182/blood-2008-05-156943

  View details for PubMedID 19147787

  View details for PubMedCentralID PMC2656273

• High throughput cell nanomechanics with mechanical imaging interferometry NANOTECHNOLOGY Reed, J., Frank, M., Troke, J. J., Schmit, J., Han, S., Teitell, M. A., Gimzewski, J. K. 2008; 19 (23)

  Abstract

  The dynamic nanomechanical properties of a large number of cells (up to hundreds), measured in parallel with high throughput, are reported. Using NIH 3T3 and HEK 293T fibroblasts and actin depolymerizing drugs, we use a novel nanotechnology to quantify the local viscoelastic properties with applied forces of 20 pN-20 nN, a spatial resolution of <20 nm, and a mechanical dynamic range of several Pa up to ~200 kPa. Our approach utilizes imaging interferometry in combination with reflective, magnetic probes attached to cells. These results indicate that mechanical imaging interferometry is a sensitive and scalable technology for measuring the nanomechanical properties of large arrays of live cells in fluid.

  View details for DOI 10.1088/0957-4484/19/23/235101

  View details for Web of Science ID 000255662700001

  View details for PubMedID 20737027

  View details for PubMedCentralID PMC2925287