نبذة مختصرة : Despite de advances in surgery and chemotherapy, the outcome of ovarian cancer patients has improved very little over the last 40 years. Given that ovarian cancer is an immunogenic tumor, immunotherapies offer a great promise as treatment of this dismal disease. We show that follicle-stimulating hormone (FSH) receptor can be a very specific target that is expressed in >56% of human ovarian carcinomas and is a negative prognostic factor. Accordingly, we designed chimeric receptors expressing full-length FSH to redirect T-cell cytotoxic activity against these more aggressive tumors. In vivo, fully murine FSH-targeted T-cells and low affinity anti-mesothelin scFv-targeted Chimeric Antigen Receptor (CAR) T-cells were similarly safe and effective at increasing the survival of immunocompetent mice with established and aggressive ovarian carcinomas. Notably, both chimeric receptors enhanced the ability of endogenous, pre-existing tumor-reactive T-cells to abrogate malignant progression upon adoptive transfer into naïve recipients subsequently challenged with the same tumor. Interestingly, chimeric receptor-expressing CD4 T-cells were superior contributors to these consistent therapeutic benefits, compared to their CD8 counterparts. We also found that although chimeric receptor-targeted T-cells were able to persist as memory lymphocytes without noticeable PD-1-dependent exhaustion during end-stage disease, the shedding of FSH receptor from tumor cells diverted the effector activity of chimeric receptor-transduced T-cells away from targeted tumor cells. Accordingly, although tumor cells remained sensitive to chimeric receptor-driven activities, re-directed lymphocytes ultimately disappeared from tumor beds. Thus, although tumor microenvironmental factors could limit their effectiveness against established and aggressive epithelial tumors, lymphocytes redirected against tumor cells with full-length hormones or low-affinity scFvs induce significant therapeutic benefits by boosting endogenous anti-tumor immunity and show negligible toxicity even in the presence of cognate targets in tumor-free tissues.
نبذة مختصرة : Despite de advances in surgery and chemotherapy, the outcome of ovarian cancer patients has improved very little over the last 40 years. Given that ovarian cancer is an immunogenic tumor, immunotherapies offer a great promise as treatment of this dismal disease. We show that follicle-stimulating hormone (FSH) receptor can be a very specific target that is expressed in >56% of human ovarian carcinomas and is a negative prognostic factor. Accordingly, we designed chimeric receptors expressing full-length FSH to redirect T-cell cytotoxic activity against these more aggressive tumors. In vivo, fully murine FSH-targeted T-cells and low affinity anti-mesothelin scFv-targeted Chimeric Antigen Receptor (CAR) T-cells were similarly safe and effective at increasing the survival of immunocompetent mice with established and aggressive ovarian carcinomas. Notably, both chimeric receptors enhanced the ability of endogenous, pre-existing tumor-reactive T-cells to abrogate malignant progression upon adoptive transfer into naïve recipients subsequently challenged with the same tumor. Interestingly, chimeric receptor-expressing CD4 T-cells were superior contributors to these consistent therapeutic benefits, compared to their CD8 counterparts. We also found that although chimeric receptor-targeted T-cells were able to persist as memory lymphocytes without noticeable PD-1-dependent exhaustion during end-stage disease, the shedding of FSH receptor from tumor cells diverted the effector activity of chimeric receptor-transduced T-cells away from targeted tumor cells. Accordingly, although tumor cells remained sensitive to chimeric receptor-driven activities, re-directed lymphocytes ultimately disappeared from tumor beds. Thus, although tumor microenvironmental factors could limit their effectiveness against established and aggressive epithelial tumors, lymphocytes redirected against tumor cells with full-length hormones or low-affinity scFvs induce significant therapeutic benefits by boosting endogenous anti-tumor immunity and show negligible toxicity even in the presence of cognate targets in tumor-free tissues.
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