Format

Send to

Choose Destination
Nat Med. 2016 Dec;22(12):1402-1410. doi: 10.1038/nm.4200. Epub 2016 Oct 24.

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

Author information

1
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts, USA.
2
Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
3
Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts, USA.
4
Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
5
Division of Health, Science and Technology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
6
The Broad Institute of MIT and Harvard University, Cambridge, Massachusetts, USA.
7
Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
8
Department of Bioengineering, Stanford University, Stanford, California, USA.
9
Department of Chemical Engineering, Stanford University, Stanford, California, USA.
10
Stanford Cancer Institute, Stanford, California, USA.
11
Department of Materials Science and Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
12
Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.

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.

PMID:
27775706
PMCID:
PMC5209798
DOI:
10.1038/nm.4200
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center