title: Eradication of large established tumors in mice by combination immunotherapy that engages innate and adaptive immune responses.
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.
authors: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts, USA.|Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.|Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts, USA.
authors: Kelly D
authors: 0000-0001-6200-7863
authors: KD
authors: Moynihan
authors: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts, USA.|Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors: Cary F
authors: CF
authors: Opel
authors: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts, USA.|Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.|Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts, USA.
authors: Gregory L
authors: 0000-0001-7604-1333
authors: GL
authors: Szeto
authors: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts, USA.|Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors: Alice
authors: 0000-0001-7316-6923
authors: A
authors: Tzeng
authors: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts, USA.|Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors: Eric F
authors: EF
authors: Zhu
authors: Division of Health, Science and Technology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.|The Broad Institute of MIT and Harvard University, Cambridge, Massachusetts, USA.
authors: Jesse M
authors: 0000-0002-5754-1719
authors: JM
authors: Engreitz
authors: Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors: Robert T
authors: RT
authors: Williams
authors: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts, USA.
authors: Kavya
authors: K
authors: Rakhra
authors: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts, USA.
authors: Michael H
authors: MH
authors: Zhang
authors: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts, USA.|Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors: Adrienne M
authors: AM
authors: Rothschilds
authors: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts, USA.
authors: Sudha
authors: S
authors: Kumari
authors: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts, USA.|Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors: Ryan L
authors: RL
authors: Kelly
authors: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts, USA.|Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors: Byron H
authors: BH
authors: Kwan
authors: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts, USA.
authors: Wuhbet
authors: W
authors: Abraham
authors: Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors: Kevin
authors: K
authors: Hu
authors: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts, USA.|Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors: Naveen K
authors: NK
authors: Mehta
authors: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts, USA.|Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors: Monique J
authors: MJ
authors: Kauke
authors: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts, USA.
authors: Heikyung
authors: H
authors: Suh
authors: Department of Bioengineering, Stanford University, Stanford, California, USA.|Department of Chemical Engineering, Stanford University, Stanford, California, USA.|Stanford Cancer Institute, Stanford, California, USA.
authors: Jennifer R
authors: JR
authors: Cochran
authors: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts, USA.|Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.|Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts, USA.
authors: Douglas A
authors: DA
authors: Lauffenburger
authors: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts, USA.|Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.|Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors: K Dane
authors: KD
authors: Wittrup
authors: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts, USA.|Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.|Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts, USA.|Department of Materials Science and Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.|Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.
authors: Darrell J
authors: DJ
authors: Irvine
mesh_terms: D056704:Adaptive Immunity; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D019496:Cancer Vaccines / Q000494:pharmacology*; D045744:Cell Line, Tumor; D016207:Cytokines / Q000187:drug effects* / Q000276:immunology; D004359:Drug Therapy, Combination; D005434:Flow Cytometry; D055786:Gene Knockout Techniques; D007113:Immunity, Innate; D015151:Immunoblotting; D007167:Immunotherapy / Q000379:methods*; D007376:Interleukin-2 / Q000494:pharmacology*; D019746:Intramolecular Oxidoreductases / Q000235:genetics; D008175:Lung Neoplasms / Q000188:drug therapy*; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy*; D008546:Melanoma, Experimental / Q000188:drug therapy*; D051379:Mice; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors*; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology
chemical_list: D000970:Antineoplastic Agents; D019496:Cancer Vaccines; D016207:Cytokines; D007376:Interleukin-2; D061026:Programmed Cell Death 1 Receptor; D019746:Intramolecular Oxidoreductases; C042501:dopachrome isomerase