Calibrated CAR Signaling Enables Low-Dose Therapy in Large B-Cell Lymphoma

Area of Science:

• Immunology
• Oncology
• Cell Therapy

Background:

• Conventional CD19-targeted chimeric antigen receptor (CAR) T-cells utilize CD28/CD3z or 4-1BB/CD3z signaling modules.
• Relapsed/refractory large B-cell lymphoma (LBCL) remains a significant unmet medical need, necessitating novel therapeutic approaches.

Purpose of the Study:

• To evaluate the safety and efficacy of a novel CD19-targeted CAR T-cell therapy with a calibrated 1XX signaling module in patients with relapsed/refractory LBCL.
• To investigate the potential of the 1XX CAR T-cell therapy to achieve high response rates at low cell doses.

Main Methods:

• A first-in-human, phase 1 clinical trial was conducted involving patients with relapsed/refractory LBCL.
• Four doubling dose levels of 19(T2)28z-1XX CAR T cells were investigated, starting from 25x10^6 CAR T cells.
• Patient responses, including overall response rate (ORR) and complete response (CR) rate, were assessed along with event-free survival (EFS), cytokine release syndrome (CRS), and immune effector cell-associated neurotoxicity syndrome (ICANS).

Main Results:

• The overall cohort (n=28) achieved an 82% ORR and 71% CR rate.
• Patients treated at the lowest dose of 25x10^6 CAR T cells showed an 88% ORR and 75% CR rate.
• With a median follow-up of 24 months, the 1-year EFS was 61%. Grade ≥3 CRS and ICANS occurred at low rates of 4% and 7%, respectively.

Conclusions:

• The 1XX CAR T-cell therapy demonstrates significant efficacy and a favorable safety profile in patients with relapsed/refractory LBCL.
• The calibrated potency of the 1XX CAR enables effective treatment at low cell doses, suggesting potential applicability to other hematological malignancies, solid tumors, and autoimmune diseases.