P1125: DURABLES RESPONSES ACHIEVED WITH ANTI-CD19 ALLOGENEIC CAR T ALLO-501/501A IN PHASE 1 TRIALS OF AUTOLOGOUS CAR T-NAÏVE PATIENTS WITH RELAPSED/REFRACTORY LARGE B-CELL LYMPHOMA (R/R LBCL)

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Topic: 19. Aggressive Non-Hodgkin lymphoma - Clinical Background: Despite recent progress in treating LBCL, approximately 50% to 60% of pts will either not achieve a complete response (CR) or will relapse with current first- or second-line treatments and require additional therapy. With their unmatched efficacy, autologous anti-CD19 chimeric antigen receptor (CAR) T cells have revolutionized the care of patients whose disease progresses following standard therapies; however, patient-specific manufacturing processes and long wait times to treatment initiation prevent broader and more equitable use of these agents. In contrast, allogeneic (healthy-donor-derived), off-the-shelf CAR T cells promise to provide more patients with rapid access to one-dose treatment with curative intent. ALLO-501/501A is a pre-manufactured, allogeneic, CD52-knock-out/TCRα-knock-out, anti-CD19 CAR T cell product that uses Cellectis’ technologies. Conditioning with a regimen of fludarabine (F)/cyclophosphamide (C)/ALLO-647 (A, a humanized anti-CD52 monoclonal IgG1) targets host CD52+ immune cells for elimination while allowing subsequently infused CD52-knock-out ALLO-501/501A cells to persist. TCR-knock-out prevents the host immune system from recognizing MHC disparities between donor and host cells, and greatly reduces the risk of graft-versus-host disease (GvHD). Initial phase 1 data for the anti-CD19 AlloCAR T™ products ALLO-501 (NCT03939026) and successor ALLO-501A (NCT04416984) demonstrated a manageable safety profile with no dose-limiting toxicities (DLTs); efficacy outcomes were comparable to published results for autologous CAR T therapy in pts with r/r LBCL. Aims: This update provides data on the durability of response with the optimized AlloCAR T regimen (ALLO-501/501A following conditioning with ALLO-647 in FCA) that will be evaluated further in phase 2 trials. Methods: In these two multicenter, single-arm, open-label phase 1 trials, autologous CAR T-naïve pts with r/r LBCL underwent 3-day lymphodepletion (LD) followed by a single dose of ALLO-501/501A to identify the optimal regimen. FCA90 conditioning (F 30 mg/m2/day; C 300 mg/m2/day; A 30 mg/day [total dose: 90 mg]) followed by a single dose (120 X 106 CAR+ cells) of ALLO-501 or ALLO-501A produced by the Alloy manufacturing process was selected as the optimal regimen for development. Results: As of the Jan 26, 2023, cutoff, 12 pts received the FCA90 LD regimen and AlloCAR T therapy; 100% received the product per specifications with a median time of 3 days from enrollment to LD. Median follow-up time was 7.1 months (range: 1.4, 36.0). No DLTs were observed nor were any events of severe (Gr3+) cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome (ICANS); no GvHD events occurred. In this cohort of 12 pts, the overall response rate was 66.7% with 58.3% achieving a best overall response of CR. Among pts with the opportunity to be followed for 6 months, 5 of 8 (62.5%) achieved CR and 4 of 8 (50.0%) maintained CR through 6 months with the longest CR ongoing at 36 months; median duration of response (DOR) was 23.1 months. Summary/Conclusion: A single dose of AlloCAR T therapy following FCA90 conditioning provided durable responses with a manageable safety profile in autologous CAR T-naïve pts with r/r LBCL. Among 8 pts who received FCA90 and ALLO-501/501A and had the opportunity to be evaluated for 6 months, 50% maintained that response for at least 6 months, with a median DOR of 23.1 months. These findings support broader evaluation of ALLO-501A/ALLO-647 in the ongoing, first potentially pivotal phase 2 trial (ALPHA2) of AlloCAR T therapy. Keywords: CAR-T, Allogeneic, Clinical trial, Diffuse large B cell lymphoma

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