title: Combination OX40 agonism/CTLA-4 blockade with HER2 vaccination reverses T-cell anergy and promotes survival in tumor-bearing mice.
abstract: Immunotherapy is gathering momentum as a primary therapy for cancer patients. However, monotherapies have limited efficacy in improving outcomes and benefit only a subset of patients. Combination therapies targeting multiple pathways can augment an immune response to improve survival further. Here, we demonstrate that dual aOX40 (anti-CD134)/aCTLA-4 (anti-cytotoxic T-lymphocyte-associated protein 4) immunotherapy generated a potent antigen-specific CD8 T-cell response, enhancing expansion, effector function, and memory T-cell persistence. Importantly, OX40 and CTLA-4 expression on CD8 T cells was critical for promoting their maximal expansion following combination therapy. Animals treated with combination therapy and vaccination using anti-DEC-205 (dendritic and epithelial cells, 205 kDa)-HER2 (human epidermal growth factor receptor 2) had significantly improved survival in a mammary carcinoma model. Vaccination with combination therapy uniquely restricted Th2-cytokine production by CD4 cells, relative to combination therapy alone, and enhanced IFNγ production by CD8 and CD4 cells. We observed an increase in MIP-1α (macrophage inflammatory protein-1α)/CCL3 [chemokine (C-C motif) ligand 3], MIP-1β/CCL4, RANTES (regulated on activation, normal T-cell expressed and excreted)/CCL5, and GM-CSF production by CD8 and CD4 T cells following treatment. Furthermore, this therapy was associated with extensive tumor destruction and T-cell infiltration into the tumor. Notably, in a spontaneous model of prostate adenocarcinoma, vaccination with combination therapy reversed anergy and enhanced the expansion and function of CD8 T cells recognizing a tumor-associated antigen. Collectively, these data demonstrate that the addition of a vaccine with combined aOX40/aCTLA-4 immunotherapy augmented antitumor CD8 T-cell function while limiting Th2 polarization in CD4 cells and improved overall survival.
authors.affiliation: Robert W. Franz Cancer Research Center, Earle A. Chiles Research Institute, Providence Portland Medical Center, Portland, OR 97213;
authors.forename: Stefanie N
authors.initials: SN
authors.lastname: Linch
authors.affiliation: Robert W. Franz Cancer Research Center, Earle A. Chiles Research Institute, Providence Portland Medical Center, Portland, OR 97213;
authors.forename: Melissa J
authors.initials: MJ
authors.lastname: Kasiewicz
authors.affiliation: Robert W. Franz Cancer Research Center, Earle A. Chiles Research Institute, Providence Portland Medical Center, Portland, OR 97213;
authors.forename: Michael J
authors.initials: MJ
authors.lastname: McNamara
authors.affiliation: Robert W. Franz Cancer Research Center, Earle A. Chiles Research Institute, Providence Portland Medical Center, Portland, OR 97213;
authors.forename: Ian F
authors.initials: IF
authors.lastname: Hilgart-Martiszus
authors.affiliation: Robert W. Franz Cancer Research Center, Earle A. Chiles Research Institute, Providence Portland Medical Center, Portland, OR 97213; Cell, Developmental, and Cancer Biology Department, Oregon Health and Science University, Portland, OR 97239.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Farhad
authors.affiliation: Robert W. Franz Cancer Research Center, Earle A. Chiles Research Institute, Providence Portland Medical Center, Portland, OR 97213; william.redmond@providence.org.
authors.forename: William L
authors.identifier: http://orcid.org/0000-0002-2572-1731
authors.initials: WL
authors.lastname: Redmond
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D060908:CTLA-4 Antigen / Q000276:immunology*; D002460:Cell Line; D016764:Cell Polarity; D049109:Cell Proliferation; D017635:Clonal Anergy / Q000276:immunology*; D003131:Combined Modality Therapy; D005260:Female; D007156:Immunologic Memory; D007167:Immunotherapy; D008297:Male; D015674:Mammary Neoplasms, Animal / Q000276:immunology / Q000473:pathology / Q000628:therapy; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D011471:Prostatic Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology*; D053262:Receptors, OX40 / Q000819:agonists* / Q000378:metabolism; D016019:Survival Analysis; D018418:Th2 Cells / Q000166:cytology; D014611:Vaccination
chemical_list: D060908:CTLA-4 Antigen; D018719:Erb-b2 Receptor Tyrosine Kinases; D053262:Receptors, OX40
keywords: CD8 T cell; CTLA-4; OX40; anti–DEC-205/HER2; costimulation