Lymphodepletion mitigates anti-CAR immunity in pediatric and young adult patients with recurrent or refractory brain tumors: clinical trial results

Outcomes for high-grade pediatric brain tumor patients remain poor, but there is optimism that chimeric antigen receptor (CAR) T cell therapy can improve prognosis. We present the results from a phase I clinical trial of IL13BBz-CAR T cells infused weekly into the cerebral ventricles in pediatric and young adult patients with recurrent or refractory brain tumors. The trial met its primary objectives of feasibility, safety, and tolerability, with one dose-limiting toxicity. 8 of 16 patients evaluable for response experienced radiographic size decreases consistent with biologic activity and with an anti-tumor response. Two patients met protocol criteria for response. Median survival for patients receiving lymphodepletion was 20.5 months from diagnosis and 6.9 months from treatment for patients with midline glioma, and 187 months from diagnosis and 7.5 months from treatment for patients with ependymoma. Importantly, patients who did not receive lymphodepletion developed anti-CAR humoral and cellular immune responses detectable in the CSF and peripheral blood, whereas patients receiving lymphodepletion had no evidence of CSF anti-CAR immunity. Taken together, these findings demonstrate the safety, tolerability, and biological activity of locoregionally-delivered IL13BBz-CAR T cells for children and young adults with CNS tumors. Moreover, we show that anti-CAR immune responses arise in patients not receiving lymphodepletion, but not in the CSF of patients receiving systemic lymphodepletion. Further investigation of adoptive cellular therapies combined with immunosuppression is warranted in this patient population. ClinicalTrials.gov registration: NCT04510051.