Ligand-Induced Recruitment of CAR-T Cells to Colorectal Cancers

PROJECT SUMMARY Among the most powerful and successful new therapies to enter the cancer clinic is CAR-T cell therapy. CAR- T cell therapy has been remarkably effective for patients with certain refractory, progressive hematologic cancers, resulting in several FDA-approved CAR-T cell therapies. However, this therapy has not been successful for solid cancers, such as colorectal cancer (CRC), reflecting the need for suitable antigen targets for each disease, as well as patient, tumor, and immune factors, especially poor infiltration of solid tumors by CAR-T cells. The development of cellular therapies that can be applied to CRC without toxicity would have a remarkable impact on the landscape of solid cancer therapy. Here, we test the hypothesis that CAR-T cells can be engineered to home to CRC tumors by leveraging their endogenous chemokine milieus, increasing antitumor efficacy over conventional CAR-T cells. We have identified a chemokine + chemokine receptor axis that maintains an immunosuppressive tumor microenvironment (TME) in CRCs. Using validated human CRC models and target antigen, we will engineer CAR-T cells to express the chemokine receptor directed at this CRC chemokine and explore the safety and efficacy of this approach in mouse models. Aim 1 will define the tumor homing and efficacy of chemokine receptor-engineered CAR-T cells in vitro and in vivo using human CRC cell lines. Aim 2 will define the safety impact in mice because this approach may increase homing of CAR-T cells to not only tumors but also normal tissues, resulting in toxicity. Together, these studies will produce the necessary proof-of-concept data to develop this therapeutic approach for translation to clinical trials in patients with advanced/metastatic CRC.