Title | Eradication of large established tumors in mice by combination immunotherapy that engages innate and adaptive immune responses. |
Publication Type | Journal Article |
Year of Publication | 2016 |
Authors | Moynihan KD, Opel CF, Szeto GL, Tzeng A, Zhu EF, Engreitz JM, Williams RT, Rakhra K, Zhang MH, Rothschilds AM, Kumari S, Kelly RL, Kwan BH, Abraham W, Hu K, Mehta NK, Kauke MJ, Suh H, Cochran JR, Lauffenburger DA, K Wittrup D, Irvine DJ |
Journal | Nat Med |
Volume | 22 |
Issue | 12 |
Pagination | 1402-1410 |
Date Published | 2016 12 |
ISSN | 1546-170X |
Keywords | Adaptive Immunity, Animals, Antineoplastic Agents, Cancer Vaccines, Cell Line, Tumor, Cytokines, Drug Therapy, Combination, Flow Cytometry, Gene Knockout Techniques, Immunity, Innate, Immunoblotting, Immunotherapy, Interleukin-2, Intramolecular Oxidoreductases, Lung Neoplasms, Mammary Neoplasms, Experimental, Melanoma, Experimental, Mice, Programmed Cell Death 1 Receptor, T-Lymphocytes |
Abstract | Checkpoint blockade with antibodies specific for cytotoxic T lymphocyte-associated protein (CTLA)-4 or programmed cell death 1 (PDCD1; also known as PD-1) elicits durable tumor regression in metastatic cancer, but these dramatic responses are confined to a minority of patients. This suboptimal outcome is probably due in part to the complex network of immunosuppressive pathways present in advanced tumors, which are unlikely to be overcome by intervention at a single signaling checkpoint. Here we describe a combination immunotherapy that recruits a variety of innate and adaptive immune cells to eliminate large tumor burdens in syngeneic tumor models and a genetically engineered mouse model of melanoma; to our knowledge tumors of this size have not previously been curable by treatments relying on endogenous immunity. Maximal antitumor efficacy required four components: a tumor-antigen-targeting antibody, a recombinant interleukin-2 with an extended half-life, anti-PD-1 and a powerful T cell vaccine. Depletion experiments revealed that CD8 T cells, cross-presenting dendritic cells and several other innate immune cell subsets were required for tumor regression. Effective treatment induced infiltration of immune cells and production of inflammatory cytokines in the tumor, enhanced antibody-mediated tumor antigen uptake and promoted antigen spreading. These results demonstrate the capacity of an elicited endogenous immune response to destroy large, established tumors and elucidate essential characteristics of combination immunotherapies that are capable of curing a majority of tumors in experimental settings typically viewed as intractable. |
DOI | 10.1038/nm.4200 |
Alternate Journal | Nat. Med. |
PubMed ID | 27775706 |
PubMed Central ID | PMC5209798 |
Grant List | P30 CA014051 / CA / NCI NIH HHS / United States T32 GM008334 / GM / NIGMS NIH HHS / United States R01 CA174795 / CA / NCI NIH HHS / United States F32 CA180586 / CA / NCI NIH HHS / United States / / Howard Hughes Medical Institute / United States |
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