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Cited by 524

The DOI matches its Crossref record; 9 of the 9 references it cites were found in a registry or an index.

Eradication of large established tumors in mice by combination immunotherapy that engages innate and adaptive immune responses

Open access
Moynihan, Kelly D, Opel, Cary F, Szeto, Gregory L, Tzeng, Alice, Zhu, Eric F, Engreitz, Jesse M, Williams, Robert T, Rakhra, Kavya, Zhang, Michael H, Rothschilds, Adrienne M, Kumari, Sudha, Kelly, Ryan L, Kwan, Byron H, Abraham, Wuhbet, Hu, Kevin, Mehta, Naveen K, Kauke, Monique J, Suh, Heikyung, Cochran, Jennifer R, Lauffenburger, Douglas A, Wittrup, K Dane, Irvine, Darrell J·2016·Nature Medicine
DOI 10.1038/nm.4200
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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.

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Metadata

Authors
Moynihan, K. D., Opel, C. F., Szeto, G. L., Tzeng, A., Zhu, E. F., Engreitz, J. M., Williams, R. T., Rakhra, K., Zhang, M. H., Rothschilds, A. M., Kumari, S., Kelly, R. L., Kwan, B. H., Abraham, W., Hu, K., Mehta, N. K., Kauke, M. J., Suh, H., Cochran, J. R., Lauffenburger, D. A., Wittrup, K. D., & Irvine, D. J.
Venue
Nature Medicine
Publisher
Springer Science and Business Media LLC
Published
2016-10-24
Volume
22
Issue
12
Pages
1402-1410
ISSN
  • 1078-8956 (ISSN-L)
  • 1546-170X
DOI
10.1038/nm.4200
OpenAlex
W2534772180
Cited by
524
References
9
FWCI
27.97
Type
journal article
Language
en
Open access
bronze

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