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

Adoptive T-cell immunotherapy for solid tumors though promising has shown limited efficacy in clinical studies. The hindrance to achieving an objective and durable therapeutic response is, in part, mediated by the dynamic nature of the tumor and its complex microenvironment. Tumor-directed therapies fail to eliminate components of the microenvironment, which can reinstate a tumorigenic milieu and contribute to recurrence. Cancer associated fibroblasts (CAFs), the most preponderant cell type in the microenvironment, contribute to desmoplasia, tumor growth and therapeutic resistance. CAFs express fibroblast activation protein alpha (FAP), a membrane bound serine protease, in a number of a solid tumors making it an attractive immunotherapeutic target. We hypothesized that targeting CAFs with FAP-specific T cells will destroy the 'tumor promoting haven', resulting in significant anti-tumor effects.

To test this hypothesis, we successfully generated FAP-specific T cells using a second-generation chimeric antigen receptor (CAR) specific for FAP. A prototypical CAR combines the antigen specificity of an antibody with the signaling function of a T-cell. The resulting genetically engineered FAP-specific T cells recognized and killed human as well as murine FAP-positive target cells ex vivo. FAP-specific T cells also led to a significant decrease of FAP-positive murine lung stromal cells with a concomitant reduction in A549 lung tumor growth and improved survial when administered systemically into SCID mice. Targeting FAP-positive CAFs alone, therefore induces a significant anti-tumor response indicative of its important role in tumor progression.

Finally, given the reciprocal relationship between tumor cells and CAFs, we hypothesized that co-targeting these two compartments would result in enhanced anti-tumor response than targeting either alone. Erythropoietin-producing hepatocellular carcinoma-A2 (EphA2)-specific CAR T cells were used to target the A549 tumor cells. EphA2-specific T cells when administered together with FAP-specific T cells, resulted in a significant decrease in tumor growth and increased survival compared to mice that received either EphA2- or FAP-specific T cells 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.