Glioblastoma (GBM) is the most common and aggressive primary malignant brain tumor in adults, accounting for approximately 50% of all gliomas. Despite significant advances in diagnosis and treatment, GBM remains a highly lethal disease, with a median survival of only 12-15 months even with standard therapy. The difficulty in treating GBM is due to a variety of factors. One of the primary challenges is the highly invasive nature of GBM. Tumor cells infiltrate and spread throughout the brain, making complete surgical resection nearly impossible. Even when surgery is combined with radiation and chemotherapy, tumor recurrence is common. Another challenge is the heterogeneity of GBM. Tumors may contain a variety of cell types with different genetic and epigenetic alterations, making targeted therapies difficult. In addition, GBM tumors have a unique microenvironment that includes abnormal blood vessels, immune cells, and extracellular matrix components that can promote tumor growth and resistance to therapy. Moreover, the blood-brain barrier (BBB) makes it difficult to deliver drugs to the tumor. The BBB is a specialized system of endothelial cells that separates the brain from the circulating blood and regulates the passage of molecules between the two compartments. This barrier can prevent the delivery of therapeutic agents to the tumor and limit the efficacy of chemotherapy and immunotherapy.
Chimeric antigen receptor (CAR)-T cell therapy is a promising treatment for hematological malignancies. However, its efficacy in solid malignancies is limited. CAR-T cells must infiltrate and distribute homogeneously throughout the tumor microenvironment (TME) and exert potent anti-tumor function to achieve a durable response. The ideal target epitope for CAR-T cell therapy should be expressed exclusively on tumor cells while being absent in normal cells. Epidermal growth factor receptor variant III (EGFRvIII) is an attractive therapeutic target for glioblastoma (GBM) as it is present in a significant proportion of GBM but absent from normal tissues.
In new research led by investigators led by Rakesh K. Jain, Ph.D., director of the E.L. Steele Laboratories for Tumor Biology at Massachusetts General Hospital and the Andrew Werk Cook Professor of Radiation Oncology at Harvard Medical School and published in the Journal for ImmunoTherapy of Cancer suggests that drugs that correct abnormalities in a solid tumor’s blood vessels can improve the delivery and function of CAR-T cell therapy.
The research team aimed to investigate whether normalizing the GBM TME with an anti-VEGF agent would improve the infiltration and function of EGFRvIII-CAR-T cells in preclinical models of GBM. The researchers used two preclinical models of GBM that recapitulate different features in human GBM: CT2A (limited neoantigen load) and GSC005 (stem-cell like). The researchers targeted VEGF using an anti-VEGF antibody (B20) and investigated its effects on the delivery and efficacy of EGFRvIII-CAR-T cells in these GBM models.
The research showed that treatment with B20 increased both delivery and efficacy of EGFRvIII-CAR-T cells in the preclinical models of GBM. B20 treatment led to increased infiltration of CAR-T cells into the GBM TME, resulting in improved anti-tumor function and increased efficacy of CAR-T cells.
These findings suggest that normalization of the GBM TME with anti-VEGF agents could be a promising strategy to improve the efficacy of CAR-T cell therapy in GBM. These results are consistent with previous studies showing that blocking VEGF-signaling can improve the efficacy of various anticancer therapies, including T cell-based immunotherapy. Further studies are needed to investigate the safety and efficacy of this approach in clinical trials.
In conclusion, this study shows that targeting VEGF using an anti-VEGF antibody can improve the infiltration and function of EGFRvIII-CAR-T cells in preclinical models of GBM. These findings suggest that normalization of the GBM TME with anti-VEGF agents could be a promising strategy to improve the efficacy of CAR-T cell therapy in GBM. Further studies are needed to investigate the safety and efficacy of this approach in clinical trials.
Anti-VEGF therapy improves EGFR-vIII-CAR-T cell delivery and efficacy in syngeneic glioblastoma models in mice, Journal for ImmunoTherapy of Cancer (2023). DOI: 10.1136/jitc-2022-005583