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 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 1 clinical trial investigating CD19-targeted CAR T-cells incorporating a CD28 costimulatory domain (19-28z). Seventeen of 20 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 grades 3 and 4 CRS and neurological events were uncommon (10% for each). Ex vivo expansion of T-cells and proportions of CD4+/CD8+ CAR T-cells with CD62L+CD127+ immunophenotype were significantly greater in patients on ibrutinib at leukapheresis. Three of 12 evaluable CLL patients receiving conditioning chemotherapy achieved CR (two 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.

Keywords: Cancer immunotherapy; Clinical Trials; Immunology; Leukemias.

Conflict of interest statement

Conflict of interest: MBG has received an honorarium from DAVA Oncology. JHP has consulted and played an advisory role for Amgen and Juno Therapeutics and has received research funding from Juno Therapeutics and Genentech/Roche. IR and RJB have consulted and played an advisory role for, have a royalty sharing agreement with, have research funding from, and own stock in Juno Therapeutics. MS has consulted and played an advisory role for, has a royalty sharing agreement with, and owns stock in Juno Therapeutics.

Figures

Figure 1. Enrollment of patients in the clinical study.

Status of enrolled patients and schematic of study stages on which patients were treated. 19–28z, 19–28z CAR T cells; Cy, cyclophosphamide; Inv. Choice, investigator’s choice; WM/LPL, Waldenstrom macroglobulinemia/lymphoplasmacytic lymphoma

Figure 2. Kinetics of ex vivo T cell expansion.

Cumulative fold T cell expansion ex vivo is depicted for patients with CLL on ibrutinib (IBR) at the time of leukapheresis (blue lines) versus IBR-naive patients (red lines) versus patients previously on ibrutinib (green line). Note log scale.

Figure 3. Survival outcomes.

EFS (A) and OS (B) are depicted for patients with CLL (blue lines) and patients with other B-NHL (red lines), measured from the time of first 19–28z CAR T cell infusion, using the Kaplan-Meier method. B-NHL, B cell non-Hodgkin lymphoma; CLL, chronic lymphocytic leukemia; EFS, event-free survival; OS, overall survival.

Figure 4. CAR T cell expansion in vivo.

(A) 19–28z CAR T cell expansion, measured in vector copy numbers per ml (vcn/ml) in peripheral blood among patients with CLL with quantifiable CAR T cell expansion after infusion. (B) 19–28z CAR T cell expansion by FACS (CAR+ T cells/ml) in the 2 patients achieving MRD-negative CR. Note log scale. The 2 patients achieving MRD-negative CR (**) exhibited significantly greater peak CAR T cell expansion in PB by qPCR (P = 0.011) and FACS (P = 0.00057) compared with all other patients (Wilcoxon-Mann-Whitney test). CLL, chronic lymphocytic leukemia; CR, complete response; MRD, minimal residual disease; PB, peripheral blood; qPCR, quantitative PCR.

Figure 5. 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.