CAR T Cell Therapy for Sarcoma
Sarcomas are malignant tumors of mesenchymal origin with more than 50 distinct histologic subtypes. This disease can be found anywhere in the body, and it has a high rate of early metastasis. Despite advances in surgery and chemotherapy, the 5-year survival rate remains at 60-70% for patients with localized disease, and as low as 20-30% for patients with metastasis. Unfortunately, many patients are young. New therapeutic strategies are clearly needed. Immunotherapy is emerging as a new therapeutic approach that has been unequivocally shown to work in some cancer patients. We propose to develop a novel immunotherapeutic approach, using genetically engineered chimeric antigen receptor expressing T cells (CAR T cells), to target Fibroblast Activation Protein (FAP). Although not usually found on tumors, we have recently identified FAP as a good target because it is highly expressed on tumor-associated fibroblasts (TAFs). Although FAP is also expressed during embryonic development, in tissues of healing wounds, and in chronic inflammatory and fibrotic conditions, expression of FAP is not detected in benign tumors or normal adult tissues. Recently our work and work of others has shown that T cells targeted to FAP can inhibit lung cancer and mesothelioma tumor growth by eliminating TAFs without significant systemic toxicity. In our literature review, however, we found reports that FAP was also highly expressed on sarcoma tumor cells. We confirmed this expression ourselves by immunostaining frozen sarcoma tissues and also showed high expression of FAP on a variety of sarcoma tumor cell lines. We hypothesize that sarcomas may be uniquely sensitive to FAP-CAR T cells since both the mesenchymal-like sarcoma tumor cells and tumor associated fibroblasts express FAP The short term goal of this proposal will be to: 1) demonstrate the efficacy of FAP-CAR T cells to inhibit the growth of human sarcoma in immunodeficient mice, and 2) evaluate the combination of FAP-CAR T cells with chemotherapy in sarcoma. Completion of these aims will provide part of the preclinical data needed to implement a clinical trial in sarcoma cancer patients. This is feasible using the already established infrastructure at Penn, including a cell production facility capable of making clinical grade mRNA or lentivirally-transduced T cells. Drs. Albelda (Dr Wang’s mentor) and June are already conducting a trial of CAR T cells targeting mesothelin-expressing tumor cells in patients with solid tumors. Funding for a potential FAP-CAR clinical trial is not requested in this proposal, but will be obtained through additional grants, philanthropy, and institutional support. If our strategy proves to be safe and effective, this project will likely have additional significance beyond sarcoma, since FAP could be targeted in a wide variety of solid tumors.