Intratumoral C3ar/C5ar1 Antagonists Imbedded in an In Situ Forming Implant Can Robustly Suppress Solid Tumors

Solid tumors typically expand in a "cold" immunosuppressive tumor microenvironment (TME) and resist killing by CAR T cells or conventional therapy. Herein, we show that intratumoral injection of C3a and C5a receptor 1 (C3ar/C5ar1) pharmaceutical antagonists in an in situ forming implant (ISFI) can robustly suppress such tumors. Antagonizing autocrine C3ar/C5ar1 signaling in eight human and murine cancers of diverse lineages was universally anti-mitotic and pro-apoptotic in vitro, and growth-repressive in vivo. In contrast to i.p. administration of C3ar/C5ar1 antagonists to tumor-bearing mice, injecting the antagonists intratumorally in slow release poly (lactic-co-glycolic acid) (PLGA) polymer caused near-complete tumor elimination. The focused blockade of C3ar/C5ar1 GPCR signaling in an intratumoral ISFI opposed solid cancers by jointly repressing cancer cell viability/growth, tumor-associated angiogenesis, and myeloid-derived suppressor cell (MDSC) recruitment. Thus, the sustained blockade of C3ar/C5ar1 signaling in an intratumoral ISFI uninterruptedly disrupts three processes essential for solid cancer growth while avoiding adverse effects on other cell types. Our findings may apply to multiple cancer types in which discrete tumor masses can be targeted.