Genetic Approaches to Optimize CAR T cells for Glioblastoma Therapy

Project: Research project

Project Details

Description

Glioblastoma (GBM), the most frequently occurring and aggressive primary brain tumor, remains virtually incurable. Thus, there is an urgent need to develop new therapies. Genetically modified T cells expressing chimeric antigen receptors (CARs) have the potential to serve as a unique cytotoxic tool to specifically target GBM. CAR T cell therapy has been successful for hematological malignancies, but multiple challenges posed by the brain tumor environment require a multifaceted approach for CAR T cells to succeed for GBM. To study this, we have developed a single-chain variable fragment (scFv) specific for IL13Rα2, a GBM-associated tumor antigen, and have generated an IL13Rα2-CAR. IL13Rα2-CAR T cells only recognize IL13Rα2-positive glioma cells and had anti-glioma activity in preclinical xenograft and immune-competent animal models. However, tumors eventually recurred, paralleling the situation in humans. Major causes of treatment failure include (i) the inability of CAR T cells to persist within an immunosuppressive tumor environment, (ii) antigen-loss variants when a single antigen is targeted, and (iii) the inability of CAR T cells to efficiently traffic to tumor sites due to a mismatch between chemokines produced by the tumor and chemokine receptors expressed by CAR T cells. In mechanistic studies, we have demonstrated limited IL13Rα2-CAR T cell persistence and the development of antigen-loss variants. In addition, we showed in xenograft models that transgenic expression of IL15 in CAR T cells enhances their persistence and anti-glioma activity. However, these xenograft studies are limited; the goal of this R01 is to perform mechanistic studies in immune-competent animal models and evaluate genetic approaches to enhance the anti-glioma activity of IL13Rα2-CAR T cells. Thus, we now hypothesize that IL13Rα2-CAR T cells can be further genetically engineered to optimize their anti-GBM activity by enhancing their persistence, targeting multiple tumor antigens, and improving their trafficking to tumor sites. Aim 1 investigates whether IL15-expressing CAR T cells can resist the immunosuppressive tumor environment in syngeneic GBM models. Aim 2 optimizes CAR T cells to target both IL13Rα2 and EphA2, two glioma-associated antigens. Aim 3 investigates if trafficking of CAR T cells to GBMs can be improved by the transgenic expression of CCR2, a chemokine receptor that recognizes CCL2, a chemokine produced by GBMs. At the conclusion of the grant, we will have addressed three major hurdles of CAR T cell therapy for GBM. While we will use our data to justify the development of a future clinical study utilizing optimized IL13Rα2-CAR T cells for patients with GBMs; our modified approach to T cell therapy should be applicable to a broad range of solid tumors.
StatusActive
Effective start/end date9/30/188/31/23

Funding

  • National Institute of Neurological Disorders and Stroke (5R01NS106379-03)

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