Journal
CLINICAL CANCER RESEARCH
Volume 23, Issue 2, Pages 441-453Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-16-0492
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Funding
- Ann Schreiber Mentored Investigator Award (OCRF)
- Cancer Center Support Grant (CCSG) [CA010815]
- Jayne Koskinas & Ted Giovanis Breast Cancer Research Consortium at Wistar
- Ovarian Cancer Research Fund Program Project Development
- [R01CA157664]
- [R01CA124515]
- [R01CA178687]
- [P30CA10815]
- [T32CA009171]
- [T32CA009140]
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Purpose: To define the safety and effectiveness of T cells redirected against follicle-stimulating hormone receptor (FSHR)expressing ovarian cancer cells. Experimental Design: FSHR expression was determined by Western blotting, immunohistochemistry, and qPCR in 77 human ovarian cancer specimens from 6 different histologic 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 histologic types but not in nonovarian healthy tissues. Accordingly, T cells expressing full-length FSHR-redirected 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 tumorreactive T cells to abrogate malignant progression upon adoptive transfer into naive 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. (C) 2016 AACR.
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