Nanobody-based Naturally Selected CD7-Targeted CAR-T Therapy for Acute Myeloid Leukemia

• Nanobody-based CD7 CAR-T therapy demonstrated a high complete remission rate for treating CD7-positive AML patients.

• CD7 loss may be more frequent in AML patients after CAR-T therapy.

Approximately 30% of acute myeloid leukemia (AML) patients express CD7 on their myeloblasts. We have previously demonstrated that scFv-based "naturally selected" CD7 CAR-T (NS7CAR-T) therapy shows significant efficacy with a favorable safety profile in T-cell lymphoid malignancies. Here we derived dual nanobody-based dVHH NS7CAR-T cells that have superior CD7 binding specificity, affinity to their scFv-based counterparts and improved proliferative capability. In this phase I clinical trial, we evaluated the efficacy and safety of dVHH NS7CAR-T cells in patients with CD7-positive refractory/relapsed (r/r) AML. A cohort of ten patients received dVHH NS7CAR-T cells across two dosage levels of 5×105/kg and 1×106/kg. Before enrollment, patients had undergone a median of 8 (range: 3-17) prior lines of therapy. Seven patients had prior transplants. Following NS7CAR-T cell infusion, 7/10 (70%) patients achieved complete remission (CR). The median observation time was 178 days (28-776 days). Among the seven patients who achieved CR, 3 who relapsed from prior transplants underwent a second allogeneic hematopoietic stem cell transplant (allo-HSCT). One patient remained leukemia-free on day 401, and the other two died on day 241 and day 776 from non-relapse-related causes. Three CR patients without consolidative allo-HSCT relapsed within 90 days. All the nonresponders and relapsed patients had CD7 loss. The treatment was well-tolerated, with 80% experiencing mild cytokine release syndrome and none had neurotoxicity. This trial underscores the potential promising treatment of dVHH NS7CAR-T in providing clinical benefits with a manageable safety profile to CD7-positive AML patients, warranting further investigation. NCT04938115