UCLA researchers from the Department of Microbiology, Immunology, and Molecular Genetics have engineered chimeric antigen receptor (CAR)-T cells that co-express defined immunostimulatory cytokines to enhance therapeutic efficiency against glioblastoma (GBM).
BACKGROUND: Glioblastoma Multiforme (GBM) is the most common primary malignant brain tumor in adults, with a 5-year survival rate of <7%. There are no cures for the disease, and therapies are minimally effective, largely due to the heterogenous nature of GBM and its immunosuppressive tumor microenvironment (TME). Chimeric antigen receptor (CAR)-T cell therapies have proved to be effective in treating many blood cancers, but they have not been effective for GBM due in part to the escape of tumors that do not express the targeted antigen, as well as the TME suppressing T-cell activity and limiting T-cell persistence. Thus, developing a CAR-T cell therapy for GBM and other aggressive and treatment-resistant cancers is a major unmet medical need.
INNOVATION: UCLA researchers, led by Dr. Yvonne Chen, have developed CAR-T cells that both recognize a tumor-associated antigen and secrete a defined combination of immunostimulatory cytokines: IL-12 and decoy-resistant IL-18 (DR-18). Researchers developed this strategy by systematically evaluating combinatorial immunomodulatory outputs and identified agents that could synergistically enhance anti-tumor activity. IL-12 promotes T-cell activation and enhances cytotoxic function, while DR-18 amplifies inflammatory signaling and supports recruitment of endogenous immune cells. Together, these cytokines allow CAR-T cells to more effectively kill tumor cells directly, remodel the TME, and recruit endogenous immune populations. Researchers showed in murine orthotopic GBM models that CAR-T cells expressing IL-12 and DR-18 exhibit substantially improved anti-tumor activity and survival outcomes, including in mice bearing heterogeneous tumors that do not uniformly express the antigen targeted by the CAR. They further demonstrated the ability to reject antigen-heterogeneous tumors, including tumor re-challenges, is supported by the recruitment of endogenous immune cells against the tumor. Thus, these engineered CAR-T cells hold potential as a novel therapeutic modality for tumors like GBM that are resistant to current treatments.
POTENTIAL APPLICATIONS:
- Cell-based immunotherapy for treating GBM and other treatment-resistant cancers
- Developing other CAR-T cell therapies using combinations of cytokines/chemokines
- Boosting endogenous immunity against tumors
ADVANTAGES:
- Ability to not only recognize a particular antigen, but to take advantage of the patient’s endogenous immunity to target the tumor
- Synergistic cytokine combination improves efficacy beyond single cytokine approaches
- Improving anti-tumor immune response of a cell-based therapy that is already used routinely in multiple cancer types
- Ability to customize the CAR-T cells to secret different combinations of immunostimulatory agents that may work more effectively for other tumors
DEVELOPMENT-TO-DATE: UCLA researchers have engineered CAR-T cells that encode both tumor-targeting CAR constructs and inducible expression of IL-12 and DR-18. They showed these CAR-T cells enhance tumor control and improve survival in murine orthotopic GBM models, including mice bearing antigen-heterogeneous tumors.
KEYWORDS: CAR T-cells, glioblastoma, cell-based therapy, cytokines, chemokines, immunomodulating, immunotherapy, chimeric antigen receptor, treatment resistance