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.

Locke:Amgen: Consultancy; Allogene: Consultancy, Other: Institutional ; A2: Consultancy, Other: Travel support; bluebird bio: Consultancy, Other: Institutional ; BMS/Celgene: Consultancy, Other: Institutional ; Calibr: Consultancy; Caribou: Consultancy; Cellular Biomedicine Group: Consultancy; Cowen: Consultancy; Daiichi Sankyo: Consultancy; EcoR1: Consultancy; Emerging Therapy Solutions: Consultancy; GammaDelta Therapeutics: Consultancy; Gerson Lehrman Group (GLG): Consultancy; Iovance: Consultancy; Kite, a Gilead Company: Consultancy, Other: Institutional ; Janssen: Consultancy; Legend Biotech: Consultancy; Novartis: Consultancy, Other: Institutional ; Sana: Consultancy; Takeda: Consultancy; Wugen: Consultancy; Umoja: Consultancy; Individual Patents: Patents & Royalties: Several patents held by the institution in my name (unlicensed) in the field of cellular immunotherapy; Aptitude Health: Other; ASH: Other; BioPharma Communications CARE Education: Other; CERo Therapeutics: Other: Institutional; Clinical Care Options Oncology: Other; Imedex: Other; National Cancer Institute: Other: Institutional ; Leukemia and Lymphoma Society: Other: Institutional ; Society for Immunotherapy of Cancer: Other: Institutional . Munoz:Physicians' Education Resource: Honoraria; Curio: Honoraria; OncView: Honoraria; Targeted Oncology: Honoraria; Millennium: Research Funding; Genentech/Roche: Consultancy, Research Funding, Speakers Bureau; Incyte: Research Funding; Portola: Research Funding; Merck: Research Funding; Lilly/Loxo: Consultancy; TG Therapeutics: Consultancy; MEI: Consultancy; Morphosys/Incyte: Consultancy; Beigene: Consultancy, Research Funding, Speakers Bureau; Epizyme: Consultancy; ADC Therapeutics: Consultancy; Genmab: Consultancy; Karyopharm: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding, Speakers Bureau; Alexion: Consultancy; Kyowa: Honoraria, Speakers Bureau; Celgene/ Bristol-Myers Squibb: Consultancy, Speakers Bureau; Celgene: Research Funding; Pharmacyclics/ Janssen: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding, Speakers Bureau; Bayer: Consultancy, Research Funding, Speakers Bureau; Pharmacyclics/Abbvie: Consultancy, Research Funding; Acrotech/Aurobindo: Consultancy, Speakers Bureau; Verastem: Consultancy, Speakers Bureau; AstraZeneca: Consultancy, Speakers Bureau. de Vos:BeiGene: Consultancy. Nath:Actinium Pharmaceuticals: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Honoraria; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; AlloVir: Membership on an entity's Board of Directors or advisory committees; Pfizer: Current equity holder in publicly-traded company. Shouse:Kite Pharmaceuticals: Consultancy, Speakers Bureau; Beigene, Inc.: Speakers Bureau. Hamadani:Gamida Cell: Consultancy; Abbvie: Consultancy; ADC therapeutics: Consultancy, Honoraria, Research Funding, Speakers Bureau; Genmab: Consultancy; Myeloid Therapeutics: Honoraria; Genentech: Honoraria; Takeda: Research Funding; Kadmon: Consultancy; Legend Biotech: Consultancy; MorphoSys: Consultancy; Novartis: Consultancy; SeaGen: Consultancy; Astra Zeneca: Speakers Bureau; BeiGene: Speakers Bureau; Omeros: Consultancy; CRISPR: Consultancy; Sanofi Genzyme: Speakers Bureau; Astellas: Research Funding; Spectrum Pharmaceuticals: Research Funding; Genmab: Consultancy; Bristol Myers Squibb: Consultancy; Incyte: Consultancy; Kite, a Gilead Company: Consultancy, Speakers Bureau; Caribou: Consultancy; BeiGene: Speakers Bureau; AstraZeneca: Speakers Bureau. Oluwole:Allogene: Research Funding; TGR: Consultancy; Daiichi Sankyo: Research Funding; Novartis: Consultancy; Nektar: Consultancy; Kite, a Gilead Company/ Gilead: Consultancy, Research Funding; Epizyme: Consultancy; Caribou: Consultancy; Cargo: Consultancy; ADC: Consultancy, Speakers Bureau; AbbVie: Consultancy; Pfizer: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria. Perales:Vor Biopharma: Consultancy, Honoraria; Kite: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Syncopation: Honoraria; Allovir: Consultancy; Nektar Therapeutics: Consultancy, Honoraria, Research Funding; Miltenyi Biotec: Honoraria; Cidara Therapeutics: Consultancy, Other; BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; NexImmune: Consultancy, Current equity holder in publicly-traded company; Sellas Life Sciences: Consultancy; Servier: Other; Adicet: Honoraria; Merck: Consultancy, Honoraria; VectivBio AG: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; MorphoSys: Consultancy, Honoraria; Miltenyi Biotec: Consultancy, Honoraria, Research Funding; DSMB: Other; Medigene: Consultancy, Other; Celgene: Honoraria; Caribou: Consultancy, Honoraria; Equillium: Consultancy, Honoraria; Exevir: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Allogene: Research Funding; Orcabio: Consultancy, Current equity holder in publicly-traded company, Honoraria; Omeros: Consultancy, Current equity holder in publicly-traded company, Honoraria. Miklos:Janssen: Consultancy, Honoraria, Other: Travel support; Kite, a Gilead Company: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy; Miltenyi: Consultancy, Research Funding; Adicet: Research Funding; Fate Therapeutics: Research Funding; NA: Patents & Royalties: cGVHD patent holder for Ibrutinib as cGVHD therapy but no compensation; A2 Biotherapeutics: Consultancy, Current holder of stock options in a privately-held company, Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria; Mustang Bio: Consultancy, Honoraria; Navan Technologies: Consultancy, Current holder of stock options in a privately-held company, Honoraria; Pharmacyclics: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Juno Therapeutics: Consultancy, Honoraria, Patents & Royalties: rights to royalties from Fred Hutch for patents licensed to Juno, Research Funding; MorphoSys: Consultancy, Honoraria; Adaptive Biotechnologies: Consultancy; Allogene: Research Funding; 2Seventy Bio: Research Funding; Amgen: Consultancy, Honoraria; Legend Biotech: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Umoja: Consultancy, Honoraria; Bioline Rx: Membership on an entity's Board of Directors or advisory committees. Nguyen:Allogene Therapeutics: Current Employment. Feng:Allogene Therapeutics: Current Employment. Navale:Allogene Therapeutics: Current Employment. Murray:Allogene Therapeutics: Current Employment. Kaufman:Allogene Therapeutics: Current Employment. Kai:Allogene Therapeutics: Current Employment. Le Gall:Allogene Therapeutics: Current Employment. Neelapu:Sellas Life Sciences: Consultancy, Other: Advisory board member; Bluebird Bio: Consultancy, Other: Advisory board member; Incyte: Consultancy, Other: Advisory board member; Athenex: Consultancy, Other: Advisory board member; Carsgen: Consultancy; Synthekine: Consultancy, Other: Advisory board member; Orna Therapeutics: Consultancy, Other: Advisory board member; Takeda: Consultancy, Other: Advisory board member; Morphosys: Consultancy, Other: Advisory board member; Astellas Pharma: Consultancy, Other: Advisory board member; Chimagen: Consultancy, Other: Advisory board member; N/A: Patents & Royalties: Related to cell therapy and the safety switch described (intellectual property); Bristol Myers Squibb: Consultancy, Other: Advisory Board Member, Research Funding; Merck: Consultancy, Other: Advisory Board Member; Fosun Kite: Consultancy, Other: Advisory board member; Sana Biotechnology: Consultancy, Other: Advisory board member, Research Funding; Kite, A Gilead Company: Consultancy, Other: Advisory Board Member, Research Funding; Immunoadoptive Cell Therapy Private Limited: Consultancy, Other: Scientific Advisory Board; Allogene: Consultancy, Other: Advisory board member, Research Funding; Janssen: Consultancy, Other: Advisory board member; Caribou: Consultancy, Other: Advisory board member; Adicet Bio: Consultancy, Other: Advisory board member, Research Funding; Precision Biosciences: Research Funding; Longbow Immunotherapy: Current holder of stock options in a privately-held company.

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2023
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