Abstract A62: Inhibition of tumor growth by novel CART redirected against cells expressing high levels of fibroblast activation protein

Abstract

Abstract Cancer-associated fibroblasts (CAFs) support tumor growth and metastasis of virtually all solid tumors, making them a potential “universal therapeutic target.” However, there are challenges to designing CAF targeted therapies. First, CAFs are heterogeneous, consisting of tumor-promoting and tumor-restraining populations. Second, molecular targets expressed strictly by tumor-promoting CAFs have yet to be defined. Nonetheless, Fibroblast Activation Protein (FAP) is selectively overexpressed on tumor-promoting CAFs. Moreover, deleting FAP+ cells inhibits tumor growth in preclinical models due to reductions in stroma-dependent signals that support tumor cell survival, growth, and progression and in stroma-derived immunosuppressive factors and can enhance efficacy of other therapies when given in combination. Prior studies in preclinical models suggest, however, that selective elimination of FAPhigh cells while sparing normal FAP+ cells that typically express lower levels of FAP may be necessary to avoid toxicity due to on-target, off-tumor effects. Thus, the aim of this study was to generate a FAP-chimeric antigen receptor (CAR) that selectively targets FAPhigh cells but that exhibits minimal activity against FAPlow cells for use in future clinical trials. We generated a FAP-CAR containing a scFv based on a monoclonal antibody (mAb) we generated that reacts with human and mouse FAP, the CD8 transmembrane region, and the CD3z and 41BB cytoplasmic domains. We show that primary human T cells transduced with this novel FAP-CAR exhibit strong reactivity against cells expressing high levels of human or mouse FAP but not FAPlow or FAP-negative cells. Moreover, these FAP-CART cells inhibited the growth of human FAP-negative A549 tumor xenografts infiltrated by FAP+ murine CAFs in NSG mice. Based on these characteristics, this novel FAP-CAR will be developed for use in clinical trials for human cancer patients. Citation Format: Estela Noguera-Ortega, Leslie Todd, James Monslow, Jing Sun, Steven M. Albelda, Ellen Pure. Inhibition of tumor growth by novel CART redirected against cells expressing high levels of fibroblast activation protein [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr A62.