Safety and efficacy of Azer-cel, an allogeneic CD19 CAR T for the treatment of patients with relapsed/refractory non-Hodgkin lymphoma and chronic lymphocytic leukemia not previously exposed to autologous CAR T therapy.

7012 Background: Azer-cel (azercabtagene zapreleucel) is an allogeneic, off-the-shelf, CD19-directed, chimeric antigen receptor (CAR) T-cell therapy derived from healthy donor T cells. We report the outcomes of patients treated with azer-cel plus low-dose interleukin-2 (IL-2) who enrolled in a Phase 1b dose expansion cohort for patients with r/r NHL and CLL and were naive to prior autologous CAR T-cell therapy (NCT03666000). Methods: Eligible patients with an aggressive B-cell CD19+ disease included those with diffuse large B-cell lymphoma (DLBCL, not otherwise specified or transformed), high-grade B-cell lymphoma, follicular lymphoma (FL, Grade1-3a), marginal zone lymphoma (MZL), Waldenstrom macroglobulinemia (WM), primary central nervous system lymphoma (PCNSL), and CLL/small lymphocytic lymphoma. Patients must have had at least 1-2 prior lines of therapy, depending on histological subtype, and no prior treatment with an autologous CAR T-cell therapy. Prior autologous stem cell transplant (ASCT) and bispecific antibodies were allowed. Patients received lymphodepletion with fludarabine (30 mg/m ² /day) and cyclophosphamide (750 mg/m ² /day) (Aug/Cy) for 3 days, followed by azer-cel infusion (500×10 6 cells) on Day 0 and subcutaneous low-dose IL-2 (1 million IU daily) for 14 days. Peripheral blood was collected at multiple timepoints, and levels of azer-cel transgene were quantified using qPCR. Results: Nineteen patients received azer-cel with low-dose IL-2. Median age was 59 years (range: 56-73). Disease subtypes included: DLBCL (5), MZL (5), CLL (4), PCNSL (3), FL (1), and WM (1). Of these, 4 (21%) had received ≥4 prior therapies, 3 (16%) had prior bispecific antibodies, and 2 (11%) had prior ASCT. Primary refractory disease was present in 6 (32%) patients. Median tumor burden was 36 cm 2 (range: 5.5-125). The overall response rate was 81% (13/16), with a complete response (CR) rate of 31% (5/16). Objective response by subtype included: DLBCL, 60% (1 CR, 2 partial responses [PRs]); MZL, 100% (3 CRs, 1 PR); CLL, 100% (3 PRs); PCNSL, 50% (1 PR); FL, 100% (1 CR); and WM, 100% (1 PR). Pharmacokinetic analysis (n=16) showed a mean CAR T-cell peak expansion of 1.7×10 5 copies/µg genomic DNA (SEM: 0.6×10 5 ), AUC ₀-₂₈ of 9.5×10 5 copies/µg genomic DNA (SEM: 3.4×10 5 ), and time to peak expansion 5.9 days (SEM: 0.63). ICANS occurred in 7 patients (37%), with 3 Grade 1-2 events, 3 Grade 3 events, and 1 Grade 4 event. CRS was observed in 15 patients (79%), with no Grade ≥3 events. Conclusions: Azer-cel in autologous CAR T-naïve patients demonstrates promising clinical activity across a broad range of CD19+ B-cell malignancies, including MZL and CLL. Encouraging response rates, robust CAR T-cell expansion, and a manageable safety profile support further investigation. Clinical trial information: NCT03666000 .