206. Follicle-Stimulating Hormone Receptor as a Target in the Redirected T-Cell Therapy for Cancer

Adoptive transfer of T-cells engineered to express chimeric immune receptors is an effective strategy to treat hematological cancers, however, such therapy for solid cancers such as ovarian cancer remains challenging because a safe and effective immunotherapeutic target has not yet been identified. Here, we constructed and evaluated a novel redirected T-cell-based immunotherapy targeting human follicle-stimulating hormone receptor (FSHR), a highly conserved molecule in vertebrate animals with expression limited to gonadal tissues, ovarian cancer and cancer-associated vasculature. Receptor ligand-based anti-FSHR immune receptors were constructed that contained small binding fragments from the ligand for FSHR, follicle stimulating hormone (FSH), fused to T-cell transmembrane and T-cell signaling domains. Human T-cells transduced to express anti-FSHR immune receptors were specifically immunoreactive against FSHR-expressing human and mouse ovarian cancer cell lines in a MHC-non-restricted manner, and produced more than one Th1 type of proinflammatory cytokine. This observation is of special interest, as it provides the opportunity to address potential, but unpredicted, toxicity issues associated with targeting of FSHR in preclinical in vivo studies. Moreover, anti-FSHR-IR T-cells specifically upregulated surface expression of the activation marker CD69 in the presence of FSHR positive targets, but not FSHR-deficient the 293T cell line. Additionally, specific activation of anti-FSHR-IR T-cells by FSHR expressed on tumor cell surface led to efficient tumor cell killing in vitro. Furthermore, to assess the anti-tumor effect of anti-FSHR T-cells, we established human OvCa xenografts in NSG mice by subcutaneous flank injection of CaOV3 cancer cell line followed by two intravenous redirected T-cell administrations. As shown by caliper measurements, FSHR-redirected T-cells elicited anti-tumor potential with suppressed outgrowth of established tumor. Tumor growth was statistically reduced in comparison to control, GFP engineered T-cell treated group or PBS treated animals. These data suggest that systemic delivery of anti-FSHR T-cells to mice bearing FSHR-expressing tumors may result in tumor trafficking, activation, and lysis at location of tumor.In summary, we have successfully exploited for the first time a novel therapeutic antigen, the FSHR protein, expressed on tumor cell surface, to deliver T-cell based immune-therapy of cancer. Given its highly restricted expression in cancer, cancer-associated vessels and gonadal tissues, the rationale for FSHR targeting is strong and supports further exploration of FSHR-targeted immune therapy approaches for cancer patients.