In a phase I clinical trial, 12 young neuroblastoma patients were treated with escalating doses of GD2-targeted, kill switch-containing second generation CAR T cells and lymphodepletion. CAR T cells expansion was observed only in patients with high CAR doses (≥108 cels/m2) and prior lymphodepletion, with no dose-limiting toxicities. Although objective clinical responses did not occur, three patients in the high-dose cohort showed evidence of persistent immune activation and antitumor CAR T cell activity, particularly in bone marrow and soft tissue lesions. In post-treatment biopsies, GD2 antigen expression was maintained, but CAR T cells were not detected.
Contributed by Alex Najibi
ABSTRACT: The reprogramming of a patient's immune system through genetic modification of the T cell compartment with chimeric antigen receptors (CARs) has led to durable remissions in chemotherapy-refractory B cell cancers. Targeting of solid cancers by CAR-T cells is dependent on their infiltration and expansion within the tumor microenvironment, and thus far, fewer clinical responses have been reported. Here, we report a phase 1 study (NCT02761915) in which we treated 12 children with relapsed/refractory neuroblastoma with escalating doses of second-generation GD2-directed CAR-T cells and increasing intensity of preparative lymphodepletion. Overall, no patients had objective clinical response at the evaluation point +28 days after CAR-T cell infusion using standard radiological response criteria. However, of the six patients receiving ³10(8)/meter(2) CAR-T cells after fludarabine/cyclophosphamide conditioning, two experienced grade 2 to 3 cytokine release syndrome, and three demonstrated regression of soft tissue and bone marrow disease. This clinical activity was achieved without on-target off-tumor toxicity. Targeting neuroblastoma with GD2 CAR-T cells appears to be a valid and safe strategy but requires further modification to promote CAR-T cell longevity.