Alberta Cellular and Immunotherapy (ACIT) 001, 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 and slow. 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 phase 1b results in adults. Methods ACIT001/EXC002 launched following ethics approval with 2 manufacturing sites to service 4 clinical delivery sites. The phase 1b study used a 3+3 dose escalation design with two arms, one for adults (NHL or ALL, competitive enrollment) and one for children (ALL). 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 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. Results 10 patients were accrued to the phase 1b portion of the study. One extra patient was accrued due to an unexpected, treatment unrelated death (COVID 19). In-specification products were manufactured for each of the 9 evaluable patients (5 NHL and 4 ALL) and all patients received fresh CAR T-cells a median of 14 days after apheresis ("vein-to-vein", range 14-15 days). Grade 1 or 2 cytokine release syndrome (CRS) occurred in 7 (78%) of patients; tocilizumab was used in 5 (56%) of patients. Grade 1 or 2 Neurotoxicity (ICANS) occurred in 2 (22%) 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 78% (7 of 9). All 4 ALL patients demonstrated a complete response (CR) to therapy with 3 negative for minimal residual disease (MRD) by flow cytometry (10-4). 3 (75%) of NHL patients showed a response to therapy including 2 CR's. With a median 8 months of follow-up time, 5 patients remain in remission (3 ALL, 2 NHL). Of 3 NHL patients demonstrating progression on trial, 1 had partial response prior to progression and 2 had refractory disease. T-cell exhaustion was associated with poor response to CAR T-cell therapy (see related abstract). Additional correlative analyses and health economics analyses are underway. Summary Our phase 1b 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 completion of the phase 1b portion of this trial. These results have prompted expansion to phase 2 in separate arms for ALL and NHL.

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