Antitumor Effects of Chimeric Receptor Engineered Human T Cells Directed to Tumor Stroma

Abstract

Cancer-associated fibroblasts (CAFs), the principle component of the tumor-associated stroma, form a highly protumorigenic and immunosuppressive microenvironment that mediates therapeutic resistance. Co-targeting CAFs in addition to cancer cells may therefore augment the antitumor response. Fibroblast activation protein-α (FAP), a type 2 dipeptidyl peptidase, is expressed on CAFs in a majority of solid tumors making it an attractive immunotherapeutic target. To target FAP-positive CAFs in the tumor-associated stroma, we genetically modified T cells to express a FAP-specific chimeric antigen receptor (CAR). The resulting FAP-specific T cells recognized and killed FAP-positive target cells as determined by proinflammatory cytokine release and target cell lysis. In an established A549 lung cancer model, adoptive transfer of FAP-specific T cells significantly reduced FAP-positive stromal cells, with a concomitant decrease in tumor growth. Combining these FAP-specific T cells with T cells that targeted the EphA2 antigen on the A549 cancer cells themselves significantly enhanced overall antitumor activity and conferred a survival advantage compared to either alone. Our study underscores the value of co-targeting both CAFs and cancer cells to increase the benefits of T-cell immunotherapy for solid tumors.

Fibroblast activation protein augments progression and metastasis of pancreatic ductal adenocarcinoma

“…Reports demonstrating that FAP can regulate PTEN/PI3K/AKT and Ras/ERK signaling pathways to enhance tumor cells undergoing EMT, migration, invasion, and metastasis support this hypothesis (7,14). Upregulation of FAP in PDA cells undergoing EMT may offer an opportunity to target these cells therapeutically with chimeric antigen receptor T cells as previously reported (23,(28)(29)(30)(31). Careful examination and dissection of the antitumor effect achieved by targeting FAP + stromal cells and/or FAP + EMT tumor cells would be critical in future studies.…”

PSCA and MUC1 in non-small-cell lung cancer as targets of chimeric antigen receptor T cells

“…37, 38 The use of these few non-cancer-specific antigens, which include FAP, 39 EGFR, 40 mesothelin 41 and glypican-3, 17 has led to poor or undefined therapeutic outcomes in patients. It is therefore important to broaden the NSCLC-specific targets of CAR T cells.…”

Hurdles of CAR-T cell-based cancer immunotherapy directed against solid tumors

“…The stroma is composed of heterogeneous cell types including tumor fibroblasts, connective tissue cells, vascular endothelial cells, and immune subtypes such as lymphocytes, granulocytes, and macrophages. Kakarla et al and Wang et al have consistently reported that inhibiting tumor growth by targeting tumor stroma with CAR-T cells directed to fibroblast activation protein (FAP) can be safe and effective (Kakarla et al, 2013;Wang et al, 2014). Targeting tumor vasculature provides another means for therapy against multiple solid tumor types.…”