Safety and tolerability of conditioning chemotherapy followed by CD19-targeted CAR T cells for relapsed/refractory CLL
Mark B. Geyer, Isabelle Rivière, Brigitte Sénéchal, Xiuyan Wang, Yongzeng Wang, Terence J. Purdon, Meier Hsu, Sean M. Devlin, M. Lia Palomba, Elizabeth Halton, Yvette Bernal, Dayenne G. van Leeuwen, Michel Sadelain, Jae H. Park, Renier J. Brentjens
Mark B. Geyer, Isabelle Rivière, Brigitte Sénéchal, Xiuyan Wang, Yongzeng Wang, Terence J. Purdon, Meier Hsu, Sean M. Devlin, M. Lia Palomba, Elizabeth Halton, Yvette Bernal, Dayenne G. van Leeuwen, Michel Sadelain, Jae H. Park, Renier J. Brentjens
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Clinical Research and Public Health Clinical trials Immunology

Safety and tolerability of conditioning chemotherapy followed by CD19-targeted CAR T cells for relapsed/refractory CLL

Abstract

BACKGROUND Subgroups of patients with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL) exhibit suboptimal outcomes after standard therapies, including oral kinase inhibitors. We and others have previously reported on the safety and efficacy of autologous CD19-targeted CAR T cells for these patients. Here, we report safety and long-term follow-up of CAR T cell therapy with or without conditioning chemotherapy for patients with R/R CLL and indolent B cell non-Hodgkin lymphoma (B-NHL).METHODS We conducted a phase I clinical trial investigating CD19-targeted CAR T cells incorporating a CD28 costimulatory domain (19–28z). Seventeen of twenty patients received conditioning chemotherapy prior to CAR T cell infusion. Five patients with CLL received ibrutinib at the time of autologous T cell collection and/or CAR T cell administration.RESULTS This analysis included 16 patients with R/R CLL and 4 patients with R/R indolent B-NHL. Cytokine release syndrome (CRS) was observed in all 20 patients, but grade 3 and 4 CRS and neurological events were uncommon (10% for each). Ex vivo expansion of T cells and proportions of CAR T cells with the CD62L+CD127+ immunophenotype were significantly greater (P = 0.047; CD8 subset, P = 0.0061, CD4 subset) in patients on ibrutinib at leukapheresis. Three of twelve evaluable CLL patients receiving conditioning chemotherapy achieved complete response (CR) (2 had minimal residual disease–negative CR). All patients achieving CR remained progression free at median follow-up of 53 months.CONCLUSION Conditioning chemotherapy and 19–28z CAR T cells were acceptably tolerated across investigated dose levels in heavily pretreated patients with R/R CLL and indolent B-NHL, and a subgroup of patients achieved durable CR. Ibrutinib therapy may modulate autologous T cell phenotype.TRIAL REGISTRATION ClinicalTrials.gov NCT00466531.FUNDING Juno Therapeutics and NIH/National Cancer Institute Cancer Center Support Grant (P30-CA08748).

Authors

Mark B. Geyer, Isabelle Rivière, Brigitte Sénéchal, Xiuyan Wang, Yongzeng Wang, Terence J. Purdon, Meier Hsu, Sean M. Devlin, M. Lia Palomba, Elizabeth Halton, Yvette Bernal, Dayenne G. van Leeuwen, Michel Sadelain, Jae H. Park, Renier J. Brentjens

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Figure 5

Peak levels of immunoregulatory cytokines following CAR T cell infusion.

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Peak levels of immunoregulatory cytokines following CAR T cell infusion....
Dot plots depicting fold increase in cytokine levels from prior to the first day of CAR T cell infusion to the peak within 1 month of infusion in 10 evaluable patients with CLL who received conditioning chemotherapy and CAR T cell infusion, stratified by whether ibrutinib naive (n = 5, open red circles) or on ibrutinib (IBR) at or immediately prior to CAR T cell infusion (n = 5, blue “X” marks). Median fold changes for each group are marked with black bars. Patients with ongoing or recent ibrutinib exposure at the time of CAR T cell infusion exhibited a significantly greater median fold increase in IL-6 and IL-10 (Wilcoxon-Mann-Whitney test). CLL, chronic lymphocytic leukemia. Note log scale.