Naturally Selected CD7 CAR-T Therapy without Genetic Manipulations for T-ALL/LBL: First-in-human Phase I Clinical Trial

Derivation of CD7-targeted chimeric antigen receptor (7CAR) T cells often requires genetic manipulations to ablate the CD7 gene or block CD7 cell surface expression. Our novel approach deriving naturally selected 7CAR-T cells (NS7CAR) from bulk T cells were able to overcome major fratricide by minimizing accessible CD7 epitopes. The CD7 molecules of NS7CAR-T cells were masked or sequestered by the CD7-targeting CAR. Compared to sorted CD7-negative 7CAR-T cells and CD7 knocked-out 7CAR-T cells, NS7CAR exhibited similar or superior therapeutic properties including a greater percentage of CAR+ cells and a higher proportion of CD8+ central memory T cells. In our first-in-human phase 1 trial (NCT04572308), 20 patients with relapsed/refractory T-cell acute lymphoblastic leukemia (T-ALL, n=14) and lymphoblastic lymphoma (T-LBL, n=6) were treated with NS7CAR. Nineteen patients achieved minimal residual disease negative complete remission (CR) in the bone marrow by Day 28 and 5 of 9 patients achieved extramedullary CR. With a median follow-up of 142.5 (32-311) days post infusion, 14 patients subsequently received allogeneic hematopoietic stem cell transplant (10 consolidative, 4 salvage) following NS7CAR infusion with no relapses to date. Of the six patients who did not receive a transplant, four remained in CR at a median time of 54 (32-180) days. Eighteen patients experienced mild cytokine release syndrome (CRS, Grade ≤2), one developed Grade 3 CRS, and two had Grade 1 neurotoxicity. These results indicate that NS7CAR-T therapy is a safe and highly effective treatment for T-ALL/T-LBL. More patients and longer follow-up are needed for validation. Clinical Trial can be found at NCT04572308, https://clinicaltrials.gov/