Chimeric antigen receptor (CAR)-T cell therapy for glioblastoma: what can we learn from the early clinical trials? A systematic review

Abstract Background Glioblastoma is a malignant brain tumour with poor outcomes. Chimeric antigen receptor-T (CAR-T) cell therapy is a possible new intervention in solid tumours using T-cells engineered with cancer-specific antigens. This approach is challenged by limited T-cell trafficking to solid tumours, the immunosuppressive tumour microenvironment, and glioblastoma-specific uncertainties. Several first-in-human trials have now trialled CAR-T therapy for glioblastoma. We undertake a systematic review of these Phase 1 trials to draw early lessons about the safety and feasibility of this approach. Methods Systematic review of all published clinical trials using CAR-T therapy for glioblastoma on 31 July 2024 from 5 databases. Results 13 published studies of Phase 1 trials of CAR-T therapy for glioblastoma (n=128 patients). Six molecular targets were used, most commonly EGFR family (7 studies) and IL13a2 (4 studies). There were 141 severe adverse effects (SAEs) and 2 dose-limiting toxicities. SAEs were most commonly neurological or haematological, and most commonly observed with doses over 1x107 cells. Routes of delivery included intravenous, intraventricular, intracavitary and intratumoural. Several participants across trials demonstrated transient responses, but efficacy across trials was difficult to compare, given heterogenous reporting of outcomes. Conclusions Several CAR-T strategies have now been trialled preliminarily for glioblastoma. There appears to be a signal of efficacy, with 56 of 128 reported patients demonstrating at least some measure of response. Central delivery of CAR-T cells appears safe with doses up to 2.5x107 cells well-tolerated. Subsequent CAR-T trials should standardise reporting of outcomes for better comparison across trials.