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  • 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

  • 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
  • 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. n., Spiegel, J. Y., Craig, J. n., Claire, G. K., Frank, M. J., Muffly, L. n., Shiraz, P. n., Meyer, E. n., Arai, S. n., Brown, J. W., Johnston, L. n., Lowsky, R. n., Negrin, R. S., Rezvani, A. R., Weng, W. K., Latchford, T. n., Sahaf, B. n., Mackall, C. L., Miklos, D. B., Sidana, S. n. 2021; 5 (1): 143?55

    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 ?L 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

  • Outcomes of Patients with Large B-cell Lymphoma Progressing after Axicabtagene Ciloleucel. Blood Spiegel, J. Y., Dahiya, S., Jain, M. D., Tamaresis, J. S., Nastoupil, L., Jacobs, M. T., Ghobadi, A., Lin, Y., Lunning, M., Lekakis, L. J., Reagan, P., Oluwole, O. O., McGuirk, J. P., Deol, A., Goy, A., Vu, K., Andreadis, C., Munoz, J., Bennani, N. N., Vose, J., Dorritie, K. A., Neelapu, S. S., Locke, F. L., Rapoport, A. P., Hill, B., Miklos, D. B. 2020

    View details for DOI 10.1182/blood.2020006245

    View details for PubMedID 33156925

  • Molecular Imaging of Chimeric Antigen Receptor T Cells by ICOS-ImmunoPET. Clinical cancer research : an official journal of the American Association for Cancer Research Simonetta, F., Alam, I. S., Lohmeyer, J. K., Sahaf, B., Good, Z., Chen, W., Xiao, Z., Hirai, T., Scheller, L., Engels, P., Vermesh, O., Robinson, E., Haywood, T., Sathirachinda, A., Baker, J., Malipatlolla, M. B., Schultz, L. M., Spiegel, J. Y., Lee, J. T., Miklos, D. B., Mackall, C. L., Gambhir, S. S., Negrin, R. 2020

    Abstract

    PURPOSE: Immunomonitoring of chimeric antigen receptor (CAR) T cells relies primarily on their quantification in the peripheral blood, which inadequately quantifies their biodistribution and activation status in the tissues. Non-invasive molecular imaging of CAR T cells by positron emission tomography (PET) is a promising approach with the ability to provide spatial, temporal and functional information. Reported strategies rely on the incorporation of reporter transgenes or ex vivo biolabeling, significantly limiting the application of CAR T cell molecular imaging. In the present study, we assessed the ability of antibody-based PET (immunoPET) to non-invasively visualize CAR T cells.EXPERIMENTAL DESIGN: After analyzing human CAR T cells in vitro and ex vivo from patient samples to identify candidate targets for immunoPET, we employed a syngeneic, orthotopic murine tumor model of lymphoma to assess the feasibility of in vivo tracking of CAR T cells by immunoPET using the 89Zr-DFO-anti-ICOS tracer we previously reported.RESULTS: Analysis of human CD19-CAR T cells during activation identified the Inducible T-cell COStimulator (ICOS) as a potential target for immunoPET. In a preclinical tumor model, 89Zr-DFO-ICOS mAb PET-CT imaging detected significantly higher signal in specific bone marrow-containing skeletal sites of CAR T cell treated mice compared with controls. Importantly, administration of ICOS-targeting antibodies at tracer doses did not interfere with CAR T cell persistence and function.CONCLUSIONS: This study highlights the potential of ICOS-immunoPET imaging for monitoring of CAR T cell therapy, a strategy readily applicable to both commercially available and investigational CAR T cells.

    View details for DOI 10.1158/1078-0432.CCR-20-2770

    View details for PubMedID 33087332

  • Standard-of-Care Axicabtagene Ciloleucel for Relapsed or Refractory Large B-Cell Lymphoma: Results From the US Lymphoma CAR T Consortium. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Nastoupil, L. J., Jain, M. D., Feng, L., Spiegel, J. Y., Ghobadi, A., Lin, Y., Dahiya, S., Lunning, M., Lekakis, L., Reagan, P., Oluwole, O., McGuirk, J., Deol, A., Sehgal, A. R., Goy, A., Hill, B. T., Vu, K., Andreadis, C., Munoz, J., Westin, J., Chavez, J. C., Cashen, A., Bennani, N. N., Rapoport, A. P., Vose, J. M., Miklos, D. B., Neelapu, S. S., Locke, F. L. 2020: JCO1902104

    Abstract

    PURPOSE: Axicabtagene ciloleucel (axi-cel) is an autologous CD19-directed chimeric antigen receptor (CAR) T-cell therapy approved for relapsed/refractory large B-cell lymphoma (LBCL) on the basis of the single-arm phase II ZUMA-1 trial, which showed best overall and complete response rates in infused patients of 83% and 58%, respectively. We report clinical outcomes with axi-cel in the standard-of-care (SOC) setting for the approved indication.PATIENTS AND METHODS: Data were collected retrospectively from all patients with relapsed/refractory LBCL who underwent leukapheresis as of September 30, 2018, at 17 US institutions with the intent to receive SOC axi-cel. Toxicities were graded and managed according to each institution's guidelines. Responses were assessed as per Lugano 2014 classification.RESULTS: Of 298 patients who underwent leukapheresis, 275 (92%) received axi-cel therapy. Compared with the registrational ZUMA-1 trial, 129 patients (43%) in this SOC study would not have met ZUMA-1 eligibility criteria because of comorbidities at the time of leukapheresis. Among the axi-cel-treated patients, grade ? 3 cytokine release syndrome and neurotoxicity occurred in 7% and 31%, respectively. Nonrelapse mortality was 4.4%. Best overall and complete response rates in infused patients were 82% (95% CI, 77% to 86%) and 64% (95% CI, 58% to 69%), respectively. At a median follow-up of 12.9 months from the time of CAR T-cell infusion, median progression-free survival was 8.3 months (95% CI, 6.0 to15.1 months), and median overall survival was not reached. Patients with poor Eastern Cooperative Oncology Group performance status of 2-4 and elevated lactate dehydrogenase had shorter progression-free and overall survival on univariable and multivariable analysis.CONCLUSION: The safety and efficacy of axi-cel in the SOC setting in patients with relapsed/refractory LBCL was comparable to the registrational ZUMA-1 trial.

    View details for DOI 10.1200/JCO.19.02104

    View details for PubMedID 32401634

  • 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 1106 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/L), 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

  • Molecular Imaging of Chimeric Antigen Receptor T Cells by ICOS-ImmunoPET Clinical cancer research: an official journal of the American Association for Cancer Research Alam*, I. S., Simonetta*, F. 2020: 1058?68

    Abstract

    Immunomonitoring of chimeric antigen receptor (CAR) T cells relies primarily on their quantification in the peripheral blood, which inadequately quantifies their biodistribution and activation status in the tissues. Noninvasive molecular imaging of CAR T cells by PET is a promising approach with the ability to provide spatial, temporal, and functional information. Reported strategies rely on the incorporation of reporter transgenes or ex vivo biolabeling, significantly limiting the application of CAR T-cell molecular imaging. In this study, we assessed the ability of antibody-based PET (immunoPET) to noninvasively visualize CAR T cells.After analyzing human CAR T cells in vitro and ex vivo from patient samples to identify candidate targets for immunoPET, we employed a syngeneic, orthotopic murine tumor model of lymphoma to assess the feasibility of in vivo tracking of CAR T cells by immunoPET using the 89Zr-DFO-anti-ICOS tracer, which we have previously reported.Analysis of human CD19-CAR T cells during activation identified the Inducible T-cell COStimulator (ICOS) as a potential target for immunoPET. In a preclinical tumor model, 89Zr-DFO-ICOS mAb PET-CT imaging detected significantly higher signal in specific bone marrow-containing skeletal sites of CAR T-cell-treated mice compared with controls. Importantly, administration of ICOS-targeting antibodies at tracer doses did not interfere with CAR T-cell persistence and function.This study highlights the potential of ICOS-immunoPET imaging for monitoring of CAR T-cell therapy, a strategy readily applicable to both commercially available and investigational CAR T cells.See related commentary by Volpe et al., p. 911.

    View details for DOI 10.1158/1078-0432.CCR-20-2770

    View details for PubMedCentralID PMC7887027

  • Phase I Trial Using CD19/CD22 Bispecific CAR T Cells in Pediatric and Adult Acute Lymphoblastic Leukemia (ALL) Schultz, L. M., Muffly, L. S., Spiegel, J. Y., Ramakrishna, S., Hossain, N., Baggott, C., Sahaf, B., Patel, S., Craig, J., Yoon, J., Kadapakkam, M., Majzner, R. G., Frank, M. J., Erickson, C., Marcy, A., Fujimoto, M., Bhatia, N., Meyer, E. H., Kong, K. A., Egeler, E., Mavroukakis, S., Qin, H., Fry, T. J., Feldman, S. A., Miklos, D. B., Mackall, C. L., Davis, K. L. AMER SOC HEMATOLOGY. 2019
  • Characteristics and Outcomes of Patients Receiving Bridging Therapy While Awaiting Manufacture of Standard of Care Axicabtagene Ciloleucel CD19 Chimeric Antigen Receptor (CAR) T-Cell Therapy for Relapsed/Refractory Large B-Cell Lymphoma: Results from the US Lymphoma CAR-T Consortium Jain, M. D., Jacobs, M. T., Nastoupil, L. J., Spiegel, J. Y., Feng, G., Lin, Y., Lunning, M. A., Dahiya, S., Lekakis, L. J., Reagan, P. M., Oluwole, O. O., McGuirk, J. P., Deol, A., Goy, A., Hill, B. T., Munoz, J., Chavez, J., Rapoport, A. P., Vose, J. M., Miklos, D. B., Neelapu, S. S., Bennani, N., Andreadis, C., Sehgal, A. R., Ghobadi, A., Locke, F. L. AMER SOC HEMATOLOGY. 2019
  • Identification of Two CAR T-Cell Populations Associated with Complete Response or Progressive Disease in Adult Lymphoma Patients Treated with Axi-Cel Good, Z., Spiegel, J. Y., Sahaf, B., Malipatlolla, M. B., Frank, M. J., Baird, J., Muffly, L. S., Claire, G. K., Craig, J., Kong, K. A., Bendall, S., Miklos, D. B., Mackall, C. L. AMER SOC HEMATOLOGY. 2019
  • Detectable Circulating Tumor DNA 28 Days after the CD19 CAR T-Cell Therapy, Axicabtagene Ciloleucel, Is Associated with Poor Outcomes in Patients with Diffuse Large B-Cell Lymphoma Frank, M. J., Hossain, N., Bukhari, A., Dean, E., Spiegel, J. Y., Claire, G. K., Kirsch, I. M., Jacob, A. P., Mullins, C. D., Lee, L., Kong, K. A., Craig, J., Mackall, C. L., Rapoport, A. P., Dahiya, S., Locke, F. L., Miklos, D. B. AMER SOC HEMATOLOGY. 2019
  • Outcomes Following Failure of JAK 1/2 Inhibitor Therapy in Patients with Myelofibrosis is Dependent on the Pattern of Failure McNamara, C., Spiegel, J., Xu, W., Kennedy, J., Arruda, A., Yu, M., Claudio, J., Malik, S., Siddiq, N., Cheung, V., Tierens, A., Maze, D., Sibai, H., Gupta, V. CIG MEDIA GROUP, LP. 2019: S351?S352
  • 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
  • Utilization of value stream mapping to improve chimeric antigen receptor (CAR) T-cell patient experience at an academic medical center (AMC). Porter, J., Kong, K. A., Latchford, T., Bergman, D., Doran, S., Fajardo, N., Goldstein, G., Rodin, M., Smith, A., Spiegel, J. Y., Miklos, D. AMER SOC CLINICAL ONCOLOGY. 2019
  • Outcomes in large B-cell lymphoma progressing after axicabtagene ciloleucel (Axi-cel): Results from the US Lymphoma CAR-T Consortium. Spiegel, J. Y., Dahiya, S., Jain, M. D., Nastoupil, L. J., Ghobadi, A., Lin, Y., Lunning, M., Reagan, P., McGuirk, J., Deol, A., Munoz, J., Locke, F., Neelapu, S., Tamaresis, J. S., Rapoport, A., Miklos, D., Hill, B. AMER SOC CLINICAL ONCOLOGY. 2019
  • Circulating DNA for Molecular Response Prediction, Characterization of Resistance Mechanisms and Quantification of CAR T-Cells during Axicabtagene Ciloleucel Therapy American Society of Hematology Sworder, B., Kurtz, D. M., Macaulay, C., Frank, M. J., Alig, S., Garofalo, A., Sahaf, B., Esfahani, M. S., Spiegel, J. Y., Oak, J., Beygi, S., Jin, M. C., Chabon, J. J., Khodadoust, M. S., Majzner, R. G., Mackall, C. L., Diehn, M., Miklos, D. B., Alizadeh, A. A. 2019
  • 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
  • Target Antigen Downregulation and Other Mechanisms of Failure after Axicabtagene Ciloleucel (CAR19) Therapy Oak, J., Spiegel, J. Y., Sahaf, B., Natkunam, Y., Long, S. R., Hossain, N., Mackall, C. L., Kong, K. A., Miklos, D. B. AMER SOC HEMATOLOGY. 2018
  • 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
  • Axicabtagene Ciloleucel (Axi-cel) CD19 Chimeric Antigen Receptor (CAR) T-Cell Therapy for Relapsed/Refractory Large B-Cell Lymphoma: Real World Experience Nastoupil, L. J., Jain, M. D., Spiegel, J. Y., Ghobadi, A., Lin, Y., Dahiya, S., Lunning, M. A., Lekakis, L. J., Reagan, P. M., Oluwole, O. O., McGuirk, J. P., Deol, A., Sehgal, A. R., Goy, A., Hill, B. T., Andreadis, C., Munoz, J., Westin, J. R., Chavez, J. C., Cashen, A. F., Bennani, N. N., Rapoport, A. P., Vose, J. M., Miklos, D. B., Neelapu, S. S., Locke, F. L. AMER SOC HEMATOLOGY. 2018

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