Talicabtagene autoleucel for relapsed or refractory B-cell malignancies: results from an open-label, multicentre, phase 1/2 study.

Background: In low-income and middle-income counties (LMICs), the outcome of relapsed or refractory B-cell malignancies is poor due to the absence of effective therapies. We report the results of a phase 1/2 study of a novel humanised anti-CD19 4-1BB chimeric antigen receptor (CAR) T-cell therapy, talicabtagene autoleucel, for patients with relapsed or refractory B-cell malignancies.

Methods: This open-label, multicentre, phase 1/2 study was done at six tertiary cancer centres in India. Phase 1 was a single-centre study done in Tata Memorial Hospital, India, in patients aged 18 years or older with relapsed or refractory B-cell lymphomas. Phase 2 was a single-arm, multicentre, basket trial done in five tertiary cancer centres in patients aged 15 years and older with relapsed or refractory B-cell acute lymphoblastic leukaemia or B-cell lymphoma. Eligible patients had a life expectancy of 12 weeks or more, an ECOG performance status of 0-1 (phase 1) or 0-2 (phase 2), and an adequate organ function. Patients underwent apheresis to obtain at least 1 × 10⁹ lymphocytes to manufacture CAR T cells. Lymphodepletion therapy was done with cyclophosphamide 500 mg/m² and fludarabine 30 mg/m² for 3 days or bendamustine 90 mg/m² for 2 days. Patients were then infused intravenously with talicabtagene autoleucel 1 × 10⁷-5 × 10⁹ CAR T cells in a fractionated schedule (10%, 30%, and 60%, on days 0, 1, and 2, respectively) during phase 1 or at least 5 × 10⁶ CAR T cells per kg (up to 2 × 10⁹ CAR T cells) on day 0 during phase 2. The primary endpoints were safety (phase 1) and overall response rate (phase 2). The efficacy analysis was done in the efficacy evaluable cohort (all patients who received the target dose and 3 days of lymphodepletion therapy). The safety analysis was done in the safety population (all patients who received talicabtagene autoleucel). The trials are registered with Clinical Trial Registry-India (CTRI/2021/04/032727 and CTRI/2022/12/048211), and enrolment is closed.

Findings: Of 64 patients, 14 were enrolled in phase 1 (from May 11, 2021, to May 13, 2022) and 50 were enrolled in phase 2 (Dec 27, 2022, to Aug 31, 2023). The median age of the overall cohort was 44 years (IQR 27-57), and 49 (77%) of 64 patients were male and 15 (23%) were female. In phase 1, no dose-limiting toxicities occurred at doses of 2 × 10⁶-17 × 10⁶ CAR T cells per kg. A dose of at least 5 × 10⁶ CAR T cells per kg was chosen for phase 2 based on a complete response in three of seven patients at this dose. The most common grade 3 or worse toxicities were haematological events: anaemia (35 [61%] of 57 patients), thrombocytopenia (37 [65%] patients), neutropenia (55 [96%] patients, and febrile neutropenia (27 [47%]) patients). There were two treatment-related deaths, one due to febrile neutropenia, immune-effector cell associated haemophagocytic lymphohistiocytosis, and septic shock, and the second due to pulmonary bleed, multiorgan dysfunction syndrome, and cytokine release syndrome. In 51 efficacy-evaluable patients (36 with B-cell lymphoma and 15 with B-cell acute lymphoblastic leukaemia), the overall response rate was 73% (37 of 51; 95% CI 59-83).

Interpretation: Talicabtagene autoleucel had a manageable safety profile and induced durable responses in patients with relapsed or refractory B-cell malignancies. This therapy addresses an important unmet need for patients with relapsed or refractory B-cell malignancies in India.

Funding: Immunoadoptive Cell Therapy (ImmunoACT) and Indian Council of Medical Research (ICMR).