A PD-L1/CD3 BISPECIFIC ANTIBODY ENHANCES THE ANTI-TUMOR EFFECTS OF REGORAFENIB AGAINST COLON CANCER.

Abstract

Colorectal cancer (CRC) is a leading cause of cancer-related deaths worldwide. The current standard of care for patients may involve surgery, chemotherapy, and immune checkpoint inhibitors (ICIs), but these approaches typically fail to secure durable responses against late-stage disease. Regorafenib (REG) is an FDA-approved tyrosine kinase inhibitor with immunomodulating properties for CRC patients who progress on standard care, but 5-year relative survival rates for individuals dosed with the drug as a monotherapy are poor. We hypothesize that REG may be more appropriately leveraged alongside immunotherapeutic agents that specifically stimulate T cell infiltration and activation within the tumor microenvironment (TME). We engineered a PD-L1/CD3 bispecific antibody (bsAb) that simultaneously binds PD-L1-expressing CRC cells and stimulates activated T cells in order to investigate combination strategies with REG in pre-clinical models of CRC. Combined REG + bsAb therapy safely initiated and sustained inhibition against MC38 and CT26 progression in vivo, and these effects correlated to improved CD8+ T cell infiltration and activity within a Type-1-prone TME. Additionally, cytotoxic CD8+ T cells from REG + bsAb-sensitized mice exhibited heightened tumor cell reactivity compared to animals treated with either agent alone. Therefore, the immunomodulatory benefits of REG can be effectively paired with a bsAb that anchors to CRC cells, diminishes immunosuppression (through PD-L1 blockade), and activates/sustains antigen-specific CD8+ T cells within the TME. Our newly described REG + bsAb regimen led to improved anti-tumor outcomes pre-clinically and may represent a promising future approach for CRC patients.