Innovative TME-specific Pro-CAR T-cells for Immunotherapy of Solid Tumors

Abstract This project seeks to develop the next generation pro CARs that are inactive in normal tissues but selectively activated in the tumor microenvironmentTMEThe project is based on our previous development of a novel class of chimeric antigen receptors on the basis of single domain antibody mimics that recognize ErbB family membersSDAErbBon the surface of cancer cellsWe propose two specific aims in this projectThe first aim is to develop a pro SDAErbB CAR that is inactive in normal tissues due to the blockade of the antigen binding sites by an N terminal prodomainbut selectively activated in TME through proteolytic cleavage of the prodomain by matrix metalloproteinase MMPhighly expressed in TME or by fibroblast activation proteinFAPabundant in the reactive tumor stromal fibroblastsThe second aim is to develop a novel class of CAR that integrates a chemotactic chemokinewhich upon being delivered by CAR T cells and locally released to TMEwill attract endogenous cytotoxic T cellsCTLsto the tumor site to provide higher and enduring antitumor efficacy in a TME specific mannerThe two complementary CAR T cell platforms have significant advantages on high efficacy and specificity to tumor cells but very low side toxicity and improved safety to normal cellsand therefore the great potential to be applied to treat numerous solid tumorsAlthough we focus on EGFRand HERspecific CARs in this projectthe same technology platform can be applied to develop numerous other CARs that target neoantigensfor the treatment of solid tumors of interest Project Narrative This project is directed at developing the next generation pro CAR T cells that are inactive in normal tissues but selectively activated in the tumor microenvironment for the treatment of ErbB expressing solid tumors