A single dose of peripherally infused EGFRvIII-directed CAR T cells mediates antigen loss and induces adaptive resistance in patients with recurrent glioblastoma
Mené sur 10 patients atteints d'un glioblastome récidivant, cet essai de phase I évalue la faisabilité et la toxicité d'un traitement par injection intraveineuse d'une dose de lymphocytes T autologues modifiés génétiquement pour cibler le récepteur muté EGFRvIII
Chimeric antigen receptor (CAR) T cells have been successfully implemented for treating leukemia and are now being investigated for solid tumors. O’Rourke et al. conducted a phase 1 safety study of autologous CAR T cells targeted to EGFR variant III in glioblastoma patients. Treatment seemed to be well tolerated, which is critical because other CAR T cell products have been implicated in devastating central nervous system complications. Of the 10 patients enrolled, 7 had surgical intervention, allowing for some analysis of the tumors and T cells in patients’ brains. The results of this trial indicate that CAR T cell therapy is a viable option for treating glioblastoma.We conducted a first-in-human study of intravenous delivery of a single dose of autologous T cells redirected to the epidermal growth factor receptor variant III (EGFRvIII) mutation by a chimeric antigen receptor (CAR). We report our findings on the first 10 recurrent glioblastoma (GBM) patients treated. We found that manufacturing and infusion of CAR-modified T cell (CART)–EGFRvIII cells are feasible and safe, without evidence of off-tumor toxicity or cytokine release syndrome. One patient has had residual stable disease for over 18 months of follow-up. All patients demonstrated detectable transient expansion of CART-EGFRvIII cells in peripheral blood. Seven patients had post–CART-EGFRvIII surgical intervention, which allowed for tissue-specific analysis of CART-EGFRvIII trafficking to the tumor, phenotyping of tumor-infiltrating T cells and the tumor microenvironment in situ, and analysis of post-therapy EGFRvIII target antigen expression. Imaging findings after CART immunotherapy were complex to interpret, further reinforcing the need for pathologic sampling in infused patients. We found trafficking of CART-EGFRvIII cells to regions of active GBM, with antigen decrease in five of these seven patients. In situ evaluation of the tumor environment demonstrated increased and robust expression of inhibitory molecules and infiltration by regulatory T cells after CART-EGFRvIII infusion, compared to pre–CART-EGFRvIII infusion tumor specimens. Our initial experience with CAR T cells in recurrent GBM suggests that although intravenous infusion results in on-target activity in the brain, overcoming the adaptive changes in the local tumor microenvironment and addressing the antigen heterogeneity may improve the efficacy of EGFRvIII-directed strategies in GBM.