A novel T-cell-based immunotherapy for brain cancer
Cancer immunotherapy represents a new paradigm in cancer treatment with the goal of harnessing the immune system to selectively attack a patient’s tumor. T-cell-based immunotherapies encompass chimeric antigen receptor (CAR)-T cells, tumor-infiltrating lymphocytes, and other ex vivo engineered immune cells for re-infusion into the patient and subsequent honing and targeting of cancer cells. However, many of these T cell therapies have limited efficacy in solid cancers such as glioblastoma, where barriers like tumor heterogeneity, restricted trafficking and infiltration, and T cell exhaustion prevent tumor cell cytotoxicity. Intra-tumoral heterogeneity is a primary barrier to T cell therapy, as many cancers possess few and variable tumor specific-antigens making targeting of one protein less effective. Thus, the development of superior T cell therapies requires more pan-cancer targets that result in optimal efficacy.
Duke inventors have developed a chimeric apoptotic signal targeting lymphocyte (CASTL) specific for a phospholipid exposed on the surface of tumor cells. This is intended to be used for glioblastoma patients, and potentially other solid cancer types, for whom conventional treatment fails, or possibly as an adjuvant with radiotherapy. Specifically, the engineered T cells use an extracellular protein named TIM-4 to target phosphatidylserine (PS). TIM-4 can strongly bind PS that is exposed on the extracellular surface of tumor cells. PS exposure is typically immune inhibiting so, the inventors utilize T cell activation moieties in the targeting construct to bypass inhibition effects and promote killing. This has been demonstrated in murine cancer cell lines including for glioblastoma and melanoma, highlighting the applicability of the technology to multiple cancer types. TIM-4 CASTLs were shown to kill tumor cells significantly better than non-TIM-4 CASTLs and other antigen-targeting CAR T cells. They were also shown to synergize with irradiation, whereby binding and cytotoxicity of tumor cells by TIM-4 CASTLs increased when administered after radiation therapy.
This technology could also be used for other solid cancers for which intra-tumor heterogeneity represents a barrier to therapy efficacy.
- Phospholipid-targeting rather than protein-targeting is broader, thus avoiding drawbacks of antigen-specific CAR T cell therapy
- Efficacy synergy with radiotherapy motivates its use as an adjuvant therapy for glioblastoma
- Potential to mask immune tolerance for tumor-intrinsic non-CASTL cytotoxic T cells