Clinical Response in Relapsed/Refractory (R/R) B-NHL Treated with the CD19-Directed CAR T-Cell Product JWCAR029

Introduction

JWCAR029 is a CD19-directed 4-1BB chimeric antigen receptor (CAR) T cell product with a 4-1BB costimulatory domain, of which CD4 and CD8 CAR T cells are produced together and transfused in non-fixed ratio. We conducted a single arm, open-label, dose escalation Phase I trial of JWCAR029 in relapsed and refractory B-cell non-Hodgkin lymphoma (NCT03344367 and NCT03355859).

Methods

Eligible pts had confirmed B-cell NHL with R/R disease after ≥2 prior lines of therapy. All subjects received lymphodepleting chemotherapy prior to receiving JWCAR029. After lymphodepleting chemotherapy, JWCAR029 was administrated as a single infusion in escalating dose levels, from 25×10⁶ CAR T cells (dose level 1, DL1), 50×10⁶ CAR T cells (dose level 2, DL2), 100×10⁶ CAR T cells (dose level 3, DL3) to 150×10⁶ CAR T cells (dose level 4, DL4) according to mTPI-2 algorithm. Circulating blood counts, serum biochemistry, coagulation status, and cytokines were followed up after infusion. Cytokines were assessed on a Luminex platform. Tumor evaluation was evaluated per the Lugano criteria by PET-CT (Cheson, 2014) and safety and disease status was followed at approximately 1, 3, 6, 9, 12, 18 and 24 months after receiving JWCAR029. PK was measured by flow cytometry and real-time quantitative polymerase chain reaction system. All the adverse events were recorded for 24 months after infusion. The study was approved by Beijing Cancer Hospital and Shanghai Rui Jin Hospital Review Board with informed consent obtained in accordance with the Declaration of Helsinki.

Results

As of July 5, 2019, 44 patients were screened and 32 patients were enrolled and received treatment in two study sites in China. Twenty nine patients are evaluable and have been followed for at least 6 months: 20 diffuse large B cell lymphoma (DLBCL) and 9 follicular lymphoma, mantle cell lymphoma and extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue lymphoma. Median age was 52 years (range 29 to 68 years). The demographic characteristics of the patients are shown in Table 1. All patients received immunochemotherapy as induction and a median of four lines of salvage treatment (range 2 to 7). Eleven (34%) patients received bridging chemotherapy after T cell collection due to rapid tumor progression, followed by re-evaluation before CAR T cell infusion. Lymphodepletion consisted of fludarabine 25mg/m²/d and cyclophosphamide 250mg/m²/d on Day -4 to Day -2, followed by CAR T cell infusion on Day 0. Median time to peak CAR+ T cell expansion was 11 (8-15) days. No DLTs were reported. There were no treatment-related deaths. Seventeen patients (53.1%) reported cytokine release syndrome (CRS) with 16 grade 1 or 2 (50%) and 1 (3.1%) grade 3. No grade 4 or 5 CRS was observed. Main symptoms were fever (>39.0 degrees), fatigue, and muscle soreness. The rate of CRS was similar across dose level groups. Grade 1 and 2 neurotoxicity was observed in 5 patients (15.6%). No grade ≥3 neurotoxicity was reported. Most common adverse events (frequency >20%) included leukopenia (Gr 3-4: 21.9%, Gr 1-2: 43.8%), lymphopenia (Gr 1-2: 21.9%, Gr 3-4: 21.9%), neutropenia (Gr 1-2: 37.5%, Gr 3-4: 28.2%), thrombocytopenia (Gr 1-2: 21.9%, Gr 3-4: 3.1%), pyrexia (Gr 1-2: 21.9%) and immunoglobulins decreased (Gr 1: 28.1%). Among all 29 efficacy-evaluable patients (6 of DL1, 6 of DL2, 8 of DL3 and 9 of DL4), the best ORR was 89.7%; 85% for DLBCL patients. ORR/CRR of all evaluable patients at 1, 3 and 6 months were 86.2%/65.5%, 69%/62.1% and 58.6%/55.2%, respectively, and for the 20 DLBCL patients the ORR/CRR was 80%/60%, 55%/55%, and 45%/45%, respectively (Table 2).

Conclusion

Although longer follow-up is needed, the data from 29 evaluable patients in this Phase I trial have demonstrated high response rates and a favorable safety profile of JWCAR029 in relapsed and refractory B-cell non-Hodgkin lymphoma. A Ph II trial that further assess safety and efficacy of JWCAR029 in DLBCL and FL patients has been initiated and is open for enrollment.

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