Talicabtagene Autoleucel (humanized CD19 CAR-T) As a Second Line Therapy in r/r B-Cell Lymphoma: Sub-Analysis from a Phase I/II Trial

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Background: CAR-T cell therapy is effective and used in the second line treatment of relapsed/refractory B-cell lymphoma. However, costs of delivery remain high due to the manufacturing costs and toxicity management requiring specialized care. CARs with lower toxicity profile can improve access and cost-effectiveness of CAR-T cell therapy. We developed a humanized anti-CD19 CAR-T cell therapy, Talicabtagene autoleucel (formerly known as Actalycabtagene autoleucel) with favorable toxicity profile and demonstrated its efficacy in Phase I&II clinical trials (ASH 2022, ASH 2023) leading to its commercial approval in India. We retrospectively analyzed the cohort of patients who received CAR-T in the second line setting on the trial for the safety, efficacy, and feasibility of treatment. Methods: In this exploratory analysis from the Phase I/II trials (CTRI/2021/04/032727 and CTRI/2022/12/048211), r/r DLBCL patients were divided into two cohorts: patients received Tali-cel as second line therapy (cohort 1) or third or later line (cohort 2). Features such as Metabolic Tumor Volume (MTV), T cell characteristics of apheresis material, infusion success rate, response rates and adverse events were studied as patient related parameters. For product related parameters, manufacturing success rate, in-vivo expansion potential and T cell fitness of CAR-T cell product was studied. The post infusion clinical management was focused on utilization of ICU admission rate, duration of hospitalization and other resource utilization for toxicity management. Results: A total of 45 patients diagnosed with r/r DLBCL underwent apheresis in Phase I&II clinical trial. The cohort 1 (n=11 (24%)) had a median metabolic tumor volume of 49.31 (2.05-306) cm3, and IPI score 1(0-3). Four patients (36%) of cohort 1 had extranodal disease. In cohort 2 (n=34 (76%)), the disease phenotype was more aggressive with median MTV of 181.5 (1.91-2813) cm3, IPI score 2(1-4) and 20 patients (59%) had extranodal disease. There was no manufacturing failure in cohort 1 and only 1/34 (3%) in cohort 2. One patient in each cohort failed to receive an infusion due to disease progression. Total 36 patients (n=10 cohort 1, n=26 cohort 2) were evaluable for efficacy analysis (dose of ≥5 x 106 CAR-T cells/kg, and lymphodepletion of Cy/Flu for 3 days). The CR rate (95% CI) in cohort 1 at months 1, 3 and 6 was 70% (39.6-89.2), 70% (39.6-89.2) and 60% (31.2-83.1) respectively. In contrast, the CR rate for cohort 2 was 46% (28.7-64.5), 38% (22.4-57.3) and 27% (13.7-46.0) at months 1, 3 and 6 respectively. No incidence of ICANS (any grade) and ≥ Grade 3 CRS was reported in any group. In virtue of favorable toxicity profile, none of the patients of cohort 1 required ICU admission for toxicity management. However, the ICU admission was 16% (5/32) in cohort 2 patients. The median duration of hospitalization for both groups was 8 days. The requirement for tocilizumab and corticosteroids (cohort 1: 10% vs cohort 2: 6%) was comparable, whereas the transfusion support (cohort 1: 30% vs cohort 2: 44 %) and IVIG treatment (cohort 1: 40% vs cohort 2: 53%) was lower in the patients in cohort 1. The patients in cohort 1 showed higher peak expansion on Day 14 (median, cohort 1: 2.56x105 vs cohort 2: 0.57x105 copies/μg of DNA) and the levels further persisted until last follow-up. Immunophenotypic profiling revealed that patients receiving second line CAR-T therapy showed better T cell fitness. The CAR-T cell products from cohort 1 had a higher percentage of CD8+ naïve cells in apheresis as well as CAR-T cell product, which associated with robust CAR-T expansion and durable response. Conclusion: In this post-hoc analysis,Tali-cel was found to be more well-tolerated, more efficacious, and easier to deliver in the second line setting for r/r DLBCL. Given limited patients in each cohort, further study based on post-marketing surveillance is planned.

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