CR rates in relapsed/refractory (R/R) aggressive B-NHL treated with the CD19-directed CAR T-cell product JCAR017 (TRANSCEND NHL 001).

Abstract

7513 Background: JCAR017 is a second-generation, CD19-directed, 4-1BB CAR T cell product comprising CD8 and CD4 CAR T cells in a 1:1 ratio. A multicenter phase 1 trial of JCAR017 in R/R B-cell NHL (NCT02631044) is underway. Methods: Patients with R/R DLBCL, PMBCL, FL grade 3B, or MCL and adequate organ function are eligible. There was no minimum ALC requirement for apheresis; no test expansion was required. Treatment includes lymphodepletion with fludarabine and cyclophosphamide, followed by JCAR017. Multiple dose levels (DLs)/administration schedules of JCAR017 are being evaluated. Study objectives include safety, PK, and antitumor response. Results: As of November 23, 2016, 28 patients have been treated and are evaluable for safety and efficacy. Nineteen were male, 9 female; 25 DLBCL, 2 MCL, and 1 FL grade 3B. Median age was 63 years (range 37-79), median number of prior therapies was 4 (range 1-8), 23 (82%) were refractory to their last chemotherapy, and 16 (57%) had prior transplant. No severe cytokine release syndrome (sCRS) was observed; 10 patients had grade 1-2 CRS (1 received tocilizumab). Five patients developed neurotoxicity, including 4 grade 3-4; all events resolved in the 4 patients who had adequate follow up. Median onset of CRS and neurotoxicity were 5 and 11 days, respectively. Four deaths after disease progression occurred, none related to JCAR017. In 20 patients treated at DL1 (5×107 cells), the RR was 80% with 60% achieving CR. One patient with secondary CNS involvement achieved CR without neurotoxicity. JCAR017 was detected at 3 and 6 months in responding patients, including some who relapsed; higher mean peak levels were detected in patients with durable response at 3 months. Data on patients treated at DL2 (1×108 cells), alternative dose schedules, tumor biopsy, and additional biomarkers will be presented. Conclusions: Treatment with JCAR017 results in high CR rate in patients with heavily pretreated R/R DLBCL. Relapses can occur despite persistence of JCAR017, suggesting tumor immune evasion mechanisms may contribute to relapse. Observed toxicities are manageable and occurred at rates lower than those reported for other CD19-directed CAR T cell products. Clinical trial information: NCT02631044.

Chimeric antigen receptor T-cell therapies for lymphoma

“…Findings of a multicentre trial of the JCAR017 anti-CD19 CAR-T-cell product containing a 4-1BB co-stimulatory domain, preceded by a fludarabine and cyclophosphamide conditioning chemotherapy regimen, showed an ORR of 80% and a 60% CR rate in 20 patients who were evaluable for lymphoma response 93 . A total of 28 patients were evaluable for safety outcomes (25 with DLBCL, two with MCL, and one with FL), with CRS and neurological toxicities reported to be manageable; 14% of patients had at least one grade 3 or 4 neurological toxicity 93 . CTL019, consisting of T cells expressing an anti-CD19 CAR containing a 4-1BB co-stimulatory domain, is now being evaluated in an international multicentre study involving patients with DLBCL 94 .…”

Chimeric antigen-receptor T-cell therapy for hematological malignancies and solid tumors: Clinical data to date, current limitations and perspectives

“…As shown in Table 2, the two largest studies to date investigating the use of anti-CD19 CAR T-cells for aggressive R/R NHL are the JULIET [19] and the TRANSCEND NHL-001 [20] trials. Interim analyses for both trials were presented at the International Conference on Malignant Lymphoma meeting in 2017.…”

Adoptive immunotherapy with CAR modified T cells in cancer current landscape and future perspectives

“…There were 2 deaths due to toxicity, one related to CRS, and the second to neurotoxicity. The TRANSCEND-001 multicenter trial is testing JCAR017 in relapsed/refractory B cell lymphomas, including DLBCL, transformed FL, grade 3B FL, mantle cell lymphoma, and primary mediastinal B cell lymphoma (28). Bridging therapy is allowed, lymphodepleting chemotherapy consists of fludarabine 30 mg/m 2 and cyclophosphamide 300 mg/m 2 for 3 days, and different dose levels of infused cells are tested.…”