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Abstract PR16: Genetically engineered T cells redirected against cancer-associated fibroblasts to potentiate immunotherapeutic effects.

Adoptive T-cell therapy has had considerable success in effectuating anti-tumor responses, however complete eradication of bulky solid tumors is rarely observed. This limited efficacy can in part be attributed to the tumor associated stroma; an immunosuppressive microenvironment that greatly decreases the efficacy of the T-cell product. Specifically, cancer associated fibroblasts (CAFs); the central component of the tumor stroma, secrete inhibitory factors and nutrient depleting enzymes that are detrimental to effector T cell function. In addition, CAFs secrete components of the extra-cellular matrix that contributes to desmoplasia and tumor growth. Recent reports also suggest a more pivotal role of the CAFs in regulating the self-renewing cancer stem cell (CSC) niche. 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 antitumor 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. To analyze the effects of targeting the tumor associated stroma in vivo we utilized 1) a locoregional model using the FAP negative lymphoblastoid cell line (LCL) tumor and 2) a systemic model using the FAP negative A549 lung adenocarcinoma. In the local model, mice receiving a subcutaneous admixture of FAP-specific T cells and LCL showed a significant decrease in tumor engraftment and growth. Both untreated and control T cell treated mice showed progressive tumor growth with a concomitant induction of murine FAP rich supportive stroma. In our systemic model, the FAP negative non-small cell lung carcinoma (NSCLC) A549 cell line induced the expression of a murine FAP positive reactive stroma in the lungs when injected intravenously through the tail vein. Treatment with FAP-specific T cells showed a significant decrease in murine FAP expression in the lungs with a concomitant decrease in tumor growth and improved survival. Thus targeting FAP in the tumor stroma alone, resulted in a significant anti-tumor effect both in our local and systemic models.

Given the reciprocal relationship between tumor cells and CAFs, we hypothesized that co-targeting the tumor cells and CAFs would result in enhanced anti-tumor response than targeting either alone. Erythropoietin-producing hepatocellular carcinoma-A2 (EphA2) CAR positive T cells were used to target the A549 tumor cells. EphA2-specific T cells when administered together with FAP-T cells, resulted in a significant decrease in tumor growth and increased survival compared to mice that received either EphA2 or FAP-T cells alone. Our research therefore underscores the importance of targeting the tumor associated stroma in addition to tumor targeting for a more efficacious therapeutic response.

This abstract is also presented as Poster A91. 

Citation Format: Sunitha Kakarla, Kevin Chow, Melinda Mata, Xiao-Tong Song, Meng-Fen Wu, Hao Liu, Lisa Wang, David Rowley, Klaus Pfizenmaier, Stephen Gottschalk. Genetically engineered T cells redirected against cancer-associated fibroblasts to potentiate immunotherapeutic effects. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances; Dec 2-5, 2012; Miami, FL. Philadelphia (PA): AACR; Cancer Res 2013;73(1 Suppl):Abstract nr PR16.