Purpose
Define the safety and effectiveness of T-cells re-directed against Follicle-Stimulating Hormone Receptor (FSHR)-expressing ovarian cancer cells.
Experimental Design
FSHR expression was determined by Western-blot, immunohistochemistry and Q-PCR in 77 human ovarian cancer specimens from 6 different histological subtypes and 20 human healthy tissues. The effectiveness of human T-cells targeted with full-length FSH in vivo was determined against a panel of patient-derived xenografts. Safety and effectiveness were confirmed in immunocompetent tumor-bearing mice, using constructs targeting murine FSHR and syngeneic T-cells.
Results
FSHR is expressed in gynecologic malignancies of different histological types, but not in non-ovarian healthy tissues. Accordingly, T-cells expressing full-length FSHR-re-directed chimeric receptors mediate significant therapeutic effects (including tumor rejection) against a panel of patient-derived tumors in vivo. In immunocompetent mice growing syngeneic, orthotopic, and aggressive ovarian tumors, fully murine FSHR-targeted T-cells also increased survival without any measurable toxicity. Notably, chimeric receptors enhanced the ability of endogenous tumor-reactive T-cells to abrogate malignant progression upon adoptive transfer into naïve recipients subsequently challenged with the same tumor. Interestingly, FSHR-targeted T-cells persisted as memory lymphocytes without noticeable PD-1-dependent exhaustion during end-stage disease, in the absence of tumor cell immunoediting. However, exosomes in advanced tumor ascites diverted the effector activity of this and other chimeric receptor-transduced T-cells away from targeted tumor cells.
Conclusions
T-cells redirected against FSHR+ tumor cells with full-length FSH represent a promising therapeutic alternative against a broad range of ovarian malignancies, with negligible toxicity even in the presence of cognate targets in tumor-free ovaries.