title: CTLA-4 Blockade Synergizes Therapeutically with PARP Inhibition in BRCA1-Deficient Ovarian Cancer.
abstract: Immune checkpoint blockade has shown significant therapeutic efficacy in melanoma and other solid tumors, but results in ovarian cancer have been limited. With evidence that tumor immunogenicity modulates the response to checkpoint blockade, and data indicating that BRCA-deficient ovarian cancers express higher levels of immune response genes, we hypothesized that BRCA(-) ovarian tumors would be vulnerable to checkpoint blockade. To test this hypothesis, we used an immunocompetent BRCA1-deficient murine ovarian cancer model to compare treatment with CTLA-4 or PD-1/PD-L1 antibodies alone or combined with targeted cytotoxic therapy using a PARP inhibitor. Correlative studies were performed in vitro using human BRCA1(-) cells. We found that CTLA-4 antibody, but not PD-1/PD-L1 blockade, synergized therapeutically with the PARP inhibitor, resulting in immune-mediated tumor clearance and long-term survival in a majority of animals (P < 0.0001). The survival benefit of this combination was T-cell mediated and dependent on increases in local IFNγ production in the peritoneal tumor environment. Evidence of protective immune memory was observed more than 60 days after completion of therapy. Similar increases in the cytotoxic effect of PARP inhibition in the presence of elevated levels of IFNγ in human BRCA1(-) cancer cells support the translational potential of this treatment protocol. These results demonstrate that CTLA-4 blockade combined with PARP inhibition induces protective antitumor immunity and significant survival benefit in the BRCA1(-) tumor model, and support clinical testing of this regimen to improve outcomes for women with hereditary ovarian cancer.
authors.affiliation: The University of New Mexico Cancer Center, Albuquerque, New Mexico.
authors.forename: Tomoe
authors.initials: T
authors.lastname: Higuchi
authors.affiliation: The University of New Mexico Cancer Center, Albuquerque, New Mexico.
authors.forename: Dallas B
authors.initials: DB
authors.lastname: Flies
authors.affiliation: The University of New Mexico Cancer Center, Albuquerque, New Mexico.
authors.forename: Nicole A
authors.initials: NA
authors.lastname: Marjon
authors.affiliation: Fox Chase Cancer Center, Philadelphia, Pennsylvania.
authors.forename: Gina
authors.initials: G
authors.lastname: Mantia-Smaldone
authors.affiliation: Carnegie Mellon University, Pittsburgh, Pennsylvania.
authors.forename: Lukas
authors.initials: L
authors.lastname: Ronner
authors.affiliation: The University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Phyllis A
authors.initials: PA
authors.lastname: Gimotty
authors.affiliation: The University of New Mexico Cancer Center, Albuquerque, New Mexico. SAdams@salud.unm.edu.
authors.forename: Sarah F
authors.initials: SF
authors.lastname: Adams
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D060908:CTLA-4 Antigen / Q000037:antagonists & inhibitors*; D003131:Combined Modality Therapy; D003602:Cytotoxicity, Immunologic; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005260:Female; D006801:Humans; D007156:Immunologic Memory; D007167:Immunotherapy / Q000379:methods; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D010051:Ovarian Neoplasms / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D016176:T-Lymphocyte Subsets / Q000276:immunology; D014407:Tumor Cells, Cultured; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency*
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D060908:CTLA-4 Antigen; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D007371:Interferon-gamma; C586509:Brap protein, mouse; D044767:Ubiquitin-Protein Ligases