Early Observations on the Use of EGFRvIII-directed CART cells for Human Glioblastoma: Clinical Results and Future Directions
Donald M. O’Rourke, M.D, Department of Neurosurgery, University of Pennsylvania School of Medicine, The Abramson Cancer Center, Philadelphia
Date & Time:
Wednesday, 24 May 2017, 13:30
We initiated a first-in-human pilot study of intravenous delivery of a single dose of autologous T cells re-directed to the EGFR variant III (EGFRvIII) mutation by means of a lentiviral vector encoding a chimeric antigen receptor (CAR). We report our findings on the first ten recurrent glioblastoma (GBM) patients treated. We found that manufacturing and infusion of CART- EGFRvIII cells is 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 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, further reinforcing the need for pathologic sampling in infused patients. We found trafficking of CART-EGFRvIII cells across the blood brain barrier to regions of active glioblastoma accompanied by CART cell activation, 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 infusion, compared to pre-CART infusion tumor specimens. Our initial experience with CAR T cells in recurrent glioblastoma suggests that although intravenous infusion results in CART cell bioactivity 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.