Increasing TCR/Antigen sensitivity using anti-CD3 Fabs enhances anti-tumor effects but not immunotoxicity of immunotherapies blocking T cell checkpoint receptors 4778

Abstract Description Immune checkpoint inhibition (ICI) therapies, such as mAbs blocking CTLA-4 and PD-1, cause immune-related adverse effects (IRAEs) that may compromise the control of cancer progression in patients. IRAEs risk is higher in cancer patients with underlying autoimmune diseases (AIDs) that are undertreated with ICIs. Thus, enhancing ICI anti-tumor effects without enhancing immunotoxicity may allow treating a broader range of cancer patients. Targeting the T cell antigen receptor (TCR/CD3) with Fabs rigorously controls for monovalence (Mono-Fab) enhances activation of T cells. Anti-CD3 Mono-Fabs are effective against murine melanoma depending on functional T cells and tumor-associated antigens (TAAs) availability in melanoma cells. Now we show that anti-CD3 Mono-Fabs increased anti-tumor effects of anti-CTLA-4 nor anti-PD-1 mAbs depending on the immunogenicity of melanoma cells. However, immunotoxicity of neither ICI mAbs was increased when mixed with anti-CD3 Mono-Fabs, when using mice experiencing experimental autoimmune encephalomyelitis (EAE) as a reporter of T cell-mediated immune toxicity. In addition, T cell subpopulations found in peripheral lymphoid and CNS tissues with the potential to mediate EAE were down-modulated in mice treated with anti-CD3 Mono-Fabs alone or in combination with ICIs, while elevated in mice treated only with ICIs. Further experimentation is needed for the eventual translation of anti-human CD3 Mono-Fabs to improve the clinical performance of ICIs. Funding Sources NCI U01CA244314 Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)