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