Statistics from Altmetric.com
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.
Immunotherapy is gathering momentum as a primary therapy for cancer patients. However, monotherapies have limited efficacy in improving outcomes and only benefit a subset of patients. Combination therapies targeting multiple pathways can augment an immune response to further improve survival. Here, we demonstrate that dual anti-OX40/anti-CTLA-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 to maximally promote their expansion following combination therapy. Animals treated with combination therapy and vaccination using anti-DEC-205-HER2 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 IFNα production by CD8 and CD4 cells. We observed an increase in MIP-1α/CCL3, MIP-1β/CCL4, RANTES/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, vaccination with combination therapy reversed anergy and enhanced the expansion and function of CD8 T cells recognizing a tumor-associated antigen in a spontaneous model of prostate adenocarcinoma. Collectively, these data demonstrate that the addition of an anti-DEC-205-HER2 vaccine with combined anti-OX40/anti-CTLA-4 immunotherapy augmented anti-tumor CD8 T cell function, while limiting Th2 polarization in CD4 cells and improving overall survival.