Gall, John B. Le

PURPOSE Off-the-shelf, allogeneic CD19 chimeric antigen receptor (CAR) T-cell products may improve access to treatment versus autologous ones. We report the phase I experience of the allogeneic CD19 CAR T-cell product cemacabtagene ansegedleucel (cema-cel) and its predecessor, ALLO-501, in CD19 CAR T-naïve patients with relapsed/refractory large B-cell lymphoma (R/R LBCL). METHODS In the ALPHA2/ALPHA studies, the safety and efficacy of allogeneic CD19 CAR T cells were evaluated in CD19 CAR T treatment-naïve patients with R/R LBCL. Patients received healthy donor-derived, human leukocyte antigen–unmatched cema-cel/ALLO-501 following a 3-day lymphodepletion regimen of fludarabine (30 mg/m 2 once daily), cyclophosphamide (300 or 500 mg/m 2 once daily), and escalating doses of the anti-CD52 monoclonal antibody, ALLO-647. RESULTS As of September 26, 2024, 33 CD19 CAR T-naïve patients with LBCL (median age, 66 years; median number of previous therapies, 3) received allogeneic CAR T cells. CAR T-cell expansion was observed following infusion, with persistence observed up to 4 months. The overall and complete response (CR) rates were 58% and 42%, respectively; the median duration of response in patients with a CR was 23.1 months. The most common treatment-emergent adverse events were hematologic toxicities. No cases of graft-versus-host disease, immune effector cell–associated neurotoxicity syndrome, or grade ≥3 cytokine release syndrome were reported. CONCLUSION Allogeneic CD19 CAR T cells demonstrated promising overall and durable CR rates with a manageable safety profile in CD19 CAR T-naïve patients with R/R LBCL, supporting additional evaluation of cema-cel in patients with LBCL.

Background: While breakthroughs in hematologic malignancies with autologous CAR T-cell therapies have been met with growing clinical interest due to impressive outcomes, limitations in logistics/manufacturing, quality consistency, and product availability persist. Allogeneic CAR T-cell therapies may circumvent such challenges by providing an off-the-shelf therapeutic option derived from healthy donors. For allogeneic CAR T cells to be successful, there must be a safe and effective way to control host lymphocyte rejection of allogeneic CAR T cells (allo-rejection). ALLO-501 and ALLO-501A are allogeneic anti-CD19 CAR T-cell products that use Cellectis technologies' TALEN® gene editing to disrupt both the TCRα constant ( TRAC) and CD52 genes. CD52 disruption specifically permits use of ALLO-647, an anti-CD52 antibody, for the transient and selective depletion of host lymphocytes that enables ALLO-501 and ALLO-501A to proliferate after infusion without rapid allo-rejection. Updated phase 1 data for ALLO-501 (ALPHA; NCT03939026) and ALLO-501A (ALPHA2; NCT04416984) showed that administration of anti-CD19 allogeneic CAR T product following use of lymphodepletion that includes ALLO-647 plus fludarabine and cyclophosphamide provided durable responses and an acceptable safety profile in CAR T-cell-naive pts with r/r large B-cell lymphoma (LBCL; Locke FL, et al. ASCO 2023; #2517). Herein, we provide safety results of ALLO-647 in pts with r/r LBCL and follicular lymphoma (FL). Methods: Pts with r/r LBCL and FL enrolled in ALPHA and ALPHA2 studies received a 3 to 5-day lymphodepletion regimen consisting of fludarabine 30 mg/m 2 and cyclophosphamide 300-500 mg/m 2 (FC) and 39, 60, or 90 mg of ALLO-647 in divided doses. ALLO-501/ALLO-501A were administered after the completion of lymphodepletion. Incidence rates of grade ≥3 cytopenias (neutropenia, thrombocytopenia, anemia and pancytopenia) were assessed at 3 timepoints (Study Day 28, Day 56, and Month 4). Pts underwent weekly cytomegalovirus (CMV) monitoring. Leukocyte reconstitution was evaluated following lymphodepletion and CAR T-cell infusion. Results: As of April 20, 2023, 87 pts with r/r LBCL (n=61) and FL (n=26) were treated with ALLO-647 and included in the analysis (median age, 64 years; median number of prior regimens, 3). In total, 11 (13%), 39 (45%), and 37 (43%) pts received 39, 60, and 90 mg ALLO-647, respectively. Among the LBCL pts, 33 were CAR T-cell-naive and treated with product manufactured using the Phase 2 process. Median follow-up was 29.5 months (range, 6.8-47.5). The most common treatment-emergent adverse events (TEAEs), assessed from the time of first dose of lymphodepletion, included neutropenia (79%), anemia (61%), infusion-related reactions (IRRs, 55%), and thrombocytopenia (53%). The most common grade ≥3 TEAEs included neutropenia (74%), anemia (38%), and thrombocytopenia (38%). The proportion of pts experiencing grade ≥3 cytopenias decreased over time from Day 28 (29%) to Day 56 (20%) to Month 4 (15%), which was consistent across all lymphoma pt subgroups. ALLO-647 IRRs were typically low grade, except for 5 (6%) grade 3 events; all IRRs were managed with supportive care measures. After treatment with ALLO-501/501A, 20 pts (23%) experienced cytokine release syndrome events, which were low grade except for 1 (1%) grade 3 event. No GvHD, grade ≥3 immune effector cell-associated neurotoxicity syndrome events, or progressive multifocal leukoencephalopathy were reported. Any grade and grade ≥3 infections were reported in 50 pts (58%) and 18 pts (21%), respectively. Two pts had (2%) fatal infectious events (COVID-19 pneumonia and pneumonia, n=1 each) as previously reported. The most common infection was CMV reactivation (any grade, n=22 [25%]; grade 3, n=8 [9%]). Following lymphodepletion, the median time to absolute neutrophil count and absolute lymphocyte count recovery to grade <4 was 7 days and 28 days, respectively. T-cell counts exhibited a steady increase over time, with the majority of pts achieving full T-cell recovery (return to baseline levels) by Month 6. Detailed pharmacokinetics and pharmacodynamics data will be presented. Conclusions: These data suggest allogeneic CAR T-cell products administered following lymphodepletion consisting of FC and ALLO-647 can provide a safe and tolerable alternative to autologous CAR T-cell therapy.