Controllable regulation of CD3ζ and MyD88 signaling in T cells expands and enhances the neoantigen-reactive repertoire resulting in effective antitumor activity

Abstract

Abstract Background Adoptive cell therapy (ACT) of tumor-reactive T cells including tumor infiltrating lymphocytes (TIL) represents one of the most promising forms of therapies for treating patients with solid tumors. However, durable responses are observed in a small subset of patients and in certain cancer types. Major hurdles to achieving durable responses include: 1) suboptimal TCR responses due to sparse and/or weakly immunogenic tumor antigen presentation, 2) development of dysfunctional or exhausted T cells, 3) low TIL persistence, and 4) tumor infiltration. We and others have demonstrated that activating MyD88 signaling in T cells strongly amplifies weak TCR responses and imparts T cells novel anti-tumor properties. Hypothesis TILs engineered with a novel fusion protein consisting of CD3ζ:MyD88 will activate MyD88 signals in a TCR-dependent manner resulting in enhanced activity and against a broader panel of neoantigens. Method & Results CD4 and CD8 TILs from a variety of human tumors engineered CD3ζ:MyD88 demonstrated: a) dramatically improved ability to expand in vitro resulting (generating 10–100X TILs than conventional TILs within a few weeks), b) persist for months in tissue culture, c) more polyfunctional cells, d) destruction of established melanoma tumors in vivo, e) enhanced responses against a panel of antigens with no overt autoimmunity. Conclusions CD3ζ:MyD88 represents a unique and universal approach to safely enhance T cell response to tumor antigens.