Alberta Cellular and Immunotherapy (ACIT) 001, Updated Results of Decentralized Production of Second Generation, Anti-CD19/41BB/CD3z Chimeric Antigen Receptor (CAR) T-Cells in Relapsed/Refractory (R/R) Acute Lymphoblastic Leukemia (ALL) and Aggressive Non-Hodgkin Lymphoma (NHL)

Purpose Anti-CD19 CAR T-cells are a standard treatment for aggressive B-cell cancers. Decentralized production may improve access to this important treatment and provide a platform for additional translational science in a single payer, public health care system such as Canada where implementation of CAR T-cells has been non-uniform. ACIT001/EXC002 is a phase 1b/2 clinical trial examining the feasibility, safety, and efficacy of decentralized production of anti-CD19 CAR T-cell using the CliniMACS Prodigy bioreactor to treat R/R ALL and NHL patients. We report the updated phase 1b and phase 2 lymphoma results in adults. Methods We previously reported the preliminary results of the phase 1b study, a 3+3 dose escalation design. CD19 expression was confirmed on their fresh or archival tumor samples and all patients had received a minimum of 2 prior lines of therapy. Patients with transformed disease or central nervous system (CNS) involvement were allowed to participate. Anti-CD19 CAR T-cells were manufactured using freshly apheresed peripheral blood T-cells using a Lentigen anti-CD19 vector. Patients received cyclophosphamide (500 mg/m2) and fludarabine (30 mg/m2) as outpatient intravenous lymphodepleting chemotherapy on Days -5, -4 and -3 prior to infusion of CAR T-cells. Infusion of fresh CAR T-cells was favored but cryopreservation was permitted if clinical circumstances dictated a delay between apheresis and treatment. Patients were suggested to remain in hospital for 7 days at minimum but length of stay was not mandated. Safety and efficacy was met to proceed to phase 2 in NHL and ALL patients. Herein we report the aggregated, updated results on the phase 2 and phase 1b patients. Results In total, 30 patients have been accrued to date of which there were 7 ALL patients and 23 NHL (including 5 transformed); 5 had CNS involvement. In-specification products were manufactured for all but one patient (failed manufacturing, excluded from study); 28 patients received fresh CAR T-cells (1 cryopreserved due to contracting respiratory infection shortly after apheresis) at a median 14 days after apheresis (“vein-to-vein”, range 14-28 days) for <$100,000 CAD per product. Grade 1 or 2 cytokine release syndrome (CRS) occurred in 16 (55%) of patients with no grade 3 or higher incidents; tocilizumab was used in 14 (48%) of patients. Grade 1 or 2 Neurotoxicity (ICANS) occurred in 4 (14%) patients, and responded to limited dexamethasone. Median length of stay in hospital was 11 days (range 9-17 days). Investigator-assessed, objective response rate was 79% (n=23) including complete response (CR) in all ALL patients and 58% of NHL patients. With a median 16 months of follow-up time, 18 patients remain in remission. Summary Our combined phase 1b/2 results provide evidence that decentralized production is feasible in a single payer, public health care system. With a consistent vein-to-vein time of 14 days, we remove the inconsistency of manufacturing windows from standard of care products and have direct control over supply of CAR T- cells for our patient population. This method also implies that having smaller local manufacturing facilities allows a savings of scale while promoting improved and faster service than the creation and maintenance of a large, centralized manufacturing facility. This particular CAR T-cell product demonstrates a safety profile and efficacy similar to standard-of-care products through. These results have prompted expansion to earlier line of therapy and additional B-cell subtypes.

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