CAR T Cell Therapy for Sarcoma

Sarcomas are malignant tumors of mesenchymal origin with more than fifty distinct histologic subtypes. This disease can be found anywhere in the assets, 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. Unluckily, many patients are youthfull. Fresh therapeutic strategies are clearly needed.

Immunotherapy is emerging as a fresh therapeutic treatment that has been unequivocally shown to work in some cancer patients. We propose to develop a novel immunotherapeutic treatment, using genetically engineered chimeric antigen receptor voicing T cells (CAR T cells), to target Fibroblast Activation Protein (FAP). Albeit not usually found on tumors, we have recently identified FAP as a good target because it is very voiced on tumor-associated fibroblasts (TAFs). Albeit FAP is also voiced 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 very voiced on sarcoma tumor cells. We confirmed this expression ourselves by immunostaining frozen sarcoma tissues and also demonstrated high expression of FAP on a multitude 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 brief term objective 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 Two) 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 extra grants, philanthropy, and institutional support. If our strategy proves to be safe and effective, this project will likely have extra significance beyond sarcoma, since FAP could be targeted in a broad diversity of solid tumors.

CAR T Cell Therapy for Sarcoma – Sarcoma Foundation of America – Sarcoma Foundation of America

CAR T Cell Therapy for Sarcoma

Sarcomas are malignant tumors of mesenchymal origin with more than fifty distinct histologic subtypes. This disease can be found anywhere in the bod, 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. Unluckily, many patients are youthful. Fresh therapeutic strategies are clearly needed.

Immunotherapy is emerging as a fresh therapeutic treatment that has been unequivocally shown to work in some cancer patients. We propose to develop a novel immunotherapeutic treatment, using genetically engineered chimeric antigen receptor voicing T cells (CAR T cells), to target Fibroblast Activation Protein (FAP). Albeit not usually found on tumors, we have recently identified FAP as a good target because it is very voiced on tumor-associated fibroblasts (TAFs). Albeit FAP is also voiced 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 very voiced on sarcoma tumor cells. We confirmed this expression ourselves by immunostaining frozen sarcoma tissues and also displayed high expression of FAP on a multiplicity 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 brief term purpose 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 Two) 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 extra grants, philanthropy, and institutional support. If our strategy proves to be safe and effective, this project will likely have extra significance beyond sarcoma, since FAP could be targeted in a broad diversity of solid tumors.

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