UCLA researchers in the Department of Microbiology, Immunology and Molecular Genetics have built a series of chimeric antigen receptor (CAR)-T cells that target different antigens and secrete different anti-angiogenic proteins. Additionally, researchers also constructed bispecific CARs that respond to tumor antigen and pro-angiogenic molecules.
BACKGROUND: The adoptive transfer of CAR-T cells has shown robust clinical efficacy for B-cell malignancies but lacks efficacy for solid tumors. In contrast to hematological cancers, solid tumors are often characterized by highly immunosuppressive tumor microenvironments (TMEs) containing abnormal vasculature, which impairs tumor perfusion and results in local hypoxia. Impaired tumor perfusion and hypoxia further promote cancer aggressiveness, hinder immune-cell infiltration, and impair effective anti-tumor activity of immune cells, thereby limiting the efficacy of CAR-T cell therapy. Abnormal tumor vasculature is driven by elevated levels of pro-angiogenic molecules such as vascular endothelial growth factor (VEGF)-A, which can further suppress T-cell cytotoxicity while concurrently promoting the differentiation of suppressive immune cell populations within the tumor.
INNOVATION: UCLA researchers led by Dr. Yvonne Chen have engineered a series of CAR-T cells that can attack tumor cells while normalizing the tumor vasculature to improve the infiltration and efficacy of CAR-T cell therapy. Some of the engineered CARs target mesothelin, an antigen expressed in multiple cancer types. Additional engineered CARs target IL-13Rα2 and tyrosine-related protein 1. The CAR-T cells are engineered to secrete a novel anti-VEGF single-chain variable fragment (scFv), which can productively modify the TME to promote anti-tumor efficacy. In summary, this series of CARs can be used to more effectively target ovarian, pancreatic, mesothelioma, endothelial, lung-tumor cells.
POTENTIAL APPLICATIONS:
- Increase the efficacy of CAR-T cells for solid tumors.
- Promote endogenous anti-tumor immune response against solid tumors.
- Increase the range of tumors that CAR-T cells can be used for in the clinic.
ADVANTAGES:
- These engineered CAR-T cells exhibit superior anti-tumor efficacy and normalize the tumor vasculature.
- These CAR-T cells can secrete anti-angiogenic proteins that productively modify the TME to promote endogenous anti-tumor immune response.
- Increase the infiltration of efficacy of CAR-T cells and endogenous immune cells for solid tumors.
- Additional engineering strategies of armoring the T cells with specific combinations of cytokines and chemokines to overcome the aberrant tumor vasculature.
DEVELOPMENT-TO-DATE: There have been over 34 different constructs designed to target different antigens and secrete different anti-angiogenic proteins. Mesothelin- and IL-13Rα2–targeted CAR-T cells that also secrete the novel anti-VEGF scFv exhibit significantly improved tumor control of orthotopic models of ovarian cancer and glioma, respectively, in immunocompetent mouse models compared to conventional mesothelin or IL-13Rα2–targeted CAR-T cells without anti-VEGF capability.