Eradication of large established tumors in mice by combination immunotherapy that engages innate and adaptive immune responses
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Eradication of large.pdf
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Author(s)
Cochran, Jennifer R
Moynihan, Kelly Dare
Opel, Cary Francis
Szeto, Gregory
Tzeng, Alice
Zhu, Eric Franklin
Engreitz, Jesse Michael
Williams, Robert T.
Rakhra, Kavya
Zhang, Michael H
Date Issued
October 2016
Journal
Nature Medicine
Publisher
Nature Publishing Group
Citation
Moynihan, Kelly D; Opel, Cary F; Szeto, Gregory L; Tzeng, Alice; Zhu, Eric F; Engreitz, Jesse M; Williams, Robert T et al. “Eradication of Large Established Tumors in Mice by Combination Immunotherapy That Engages Innate and Adaptive Immune Responses.” Nature Medicine 22, no. 12 (October 2016): 1402–1410 © 2016 Macmillan Publishers Limited, part of Springer Nature
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Author's final manuscript
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.
MIT Department
Broad Institute of MIT and Harvard
Massachusetts Institute of Technology. Department of Biological Engineering
Massachusetts Institute of Technology. Department of Biology
Massachusetts Institute of Technology. Department of Chemical Engineering
Massachusetts Institute of Technology. Department of Materials Science and Engineering
Ragon Institute of MGH, MIT and Harvard
Koch Institute for Integrative Cancer Research at MIT
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DOI of Published Version
https://doi.org/10.1038/nm.4200
