Tuesday, April 23, 2024
4/23/2024
PROJECT SUMMARY Despite increasingly aggressive standard of care treatments, patients with glioblastoma (GBM) have a poor prognosis that has remained unchanged for decades, and this represents a fundamental unmet medical need. Progress in immunotherapy across a broad range of tumor types provides hope that immunological approaches, including CAR T cell therapy, may improve outcomes for patients with GBM. This is supported by the ability of CD19-targeted CAR T cells to eliminate B cell malignancies in the central nervous system (CNS), as well as early clinical experiences showing safety and disease-modifying activity of CAR T cells in GBM. One major challenge for GBM immunotherapies is the phenotypic heterogeneity of GBM tumors coupled with the scarcity of targetable tumor-associated antigens. As an approach to address this challenge we have developed a novel CAR that exploits the selective and broad GBM-binding properties of chlorotoxin (CLTX). CLTX is a 36-amino acid peptide component of scorpion venom that binds specifically to GBM and other tumors with minimal cross- reactivity to non-malignant cells. Previous early phase clinical trials have established safety of CLTX when used as a GBM-targeting peptide for imaging and radiotherapy. Our preclinical studies demonstrate that CLTX-CAR T cells mediate potent antitumor activity in vitro and in vivo, with no observable effector activity against normal human cells or when adoptively transferred into cross-reactive mouse models. We now aim, in this proposal, to clinically test the hypothesis that CLTX-CAR T cells will be safe and mediate antitumor effects when locoregionally delivered to the CNS in patients with GBM. Aim 1 will evaluate the feasibility, safety and response rates of CLTX-CAR T cells in patients with recurrent GBM in a phase 1 clinical trial. CLTX-CAR T cells will be delivered locoregionally via intratumoral [ICT] and intracerebroventricular [ICV] catheters. Aim 2 will assess CAR-mediated immunological changes associated with response and resistance. Taking advantage of our catheter-based locoregional delivery strategy that allows sampling of the CSF throughout treatment, we will monitor surrogate markers of CAR T cell activity, including CAR T cell persistence and changes in inflammatory cytokines and endogenous immune subsets. We will also compare the intrinsic characteristics across different autologous CAR T cell products with clinical response. Aim 3 will investigate pathways of GBM tumor resistance and CAR-induced tumor evolution pre- and post-therapy, investigating antigen escape pathways and adaptive immunosuppressive mechanisms to CAR T treatment. The innovative use of scorpion-derived CLTX for tumor targeting would be the first example of a natural peptide-based CAR in the clinic, potentially expanding CAR designs beyond antibody- and ligand-based targeting domains. CLTX-CAR T cell targeting of a wide range of GBM cells within individual tumors is significant in that it will expand our armamentarium and potentially help to limit antigen escape and enhance tumor eradication, thereby improving outcomes for patients with GBM.
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