Eradication of large established tumors in mice by combination immunotherapy that engages innate and adaptive immune responses
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 outco...
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| Format: | Article |
| Language: | en_US |
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Nature Publishing Group
2017
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| Online Access: | http://hdl.handle.net/1721.1/109826 https://orcid.org/0000-0001-7604-1333 https://orcid.org/0000-0001-7316-6923 https://orcid.org/0000-0003-3789-1516 https://orcid.org/0000-0002-5754-1719 https://orcid.org/0000-0003-2371-0470 https://orcid.org/0000-0002-4772-4570 https://orcid.org/0000-0003-2705-7245 https://orcid.org/0000-0001-5003-9104 https://orcid.org/0000-0002-9851-7029 https://orcid.org/0000-0003-3480-6750 https://orcid.org/0000-0002-0013-3941 https://orcid.org/0000-0003-0787-298X https://orcid.org/0000-0003-2398-5896 |
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| author | 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 Rothschilds, Adrienne Marie Kumari, Sudha Kelly, Ryan Lewis Kwan, Byron Hua Abraham, Wuhbet Hu, Kevin Mehta, Naveen Kauke, Monique Jacqueline Suh, Heikyung Lauffenburger, Douglas A Wittrup, Karl Dane Irvine, Darrell J |
| author2 | Broad Institute of MIT and Harvard |
| author_facet | Broad Institute of MIT and Harvard 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 Rothschilds, Adrienne Marie Kumari, Sudha Kelly, Ryan Lewis Kwan, Byron Hua Abraham, Wuhbet Hu, Kevin Mehta, Naveen Kauke, Monique Jacqueline Suh, Heikyung Lauffenburger, Douglas A Wittrup, Karl Dane Irvine, Darrell J |
| author_sort | Cochran, Jennifer R |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T13:11:40Z |
| format | Article |
| id | mit-1721.1/109826 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T13:11:40Z |
| publishDate | 2017 |
| publisher | Nature Publishing Group |
| record_format | dspace |
| spelling | mit-1721.1/1098262022-09-28T12:33:14Z Eradication of large established tumors in mice by combination immunotherapy that engages innate and adaptive immune responses 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 Rothschilds, Adrienne Marie Kumari, Sudha Kelly, Ryan Lewis Kwan, Byron Hua Abraham, Wuhbet Hu, Kevin Mehta, Naveen Kauke, Monique Jacqueline Suh, Heikyung Lauffenburger, Douglas A Wittrup, Karl Dane Irvine, Darrell J 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 Moynihan, Kelly Dare Opel, Cary Francis Szeto, Gregory Tzeng, Alice Zhu, Eric Franklin Engreitz, Jesse Michael Williams, Robert T. Rakhra, Kavya Zhang, Michael H Rothschilds, Adrienne Marie Kumari, Sudha Kelly, Ryan Lewis Kwan, Byron Hua Abraham, Wuhbet Hu, Kevin Mehta, Naveen Kauke, Monique Jacqueline Suh, Heikyung Lauffenburger, Douglas A Wittrup, Karl Dane Irvine, Darrell J 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. National Cancer Institute (U.S.) (P30-CA14051) United States. National Institutes of Health (CA174795) United States. National Institutes of Health (NIH #T32GM008334) United States. National Institutes of Health (CA180586) 2017-06-13T18:03:16Z 2017-06-13T18:03:16Z 2016-10 2016-03 Article http://purl.org/eprint/type/JournalArticle 1078-8956 1546-170X http://hdl.handle.net/1721.1/109826 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 https://orcid.org/0000-0001-7604-1333 https://orcid.org/0000-0001-7316-6923 https://orcid.org/0000-0003-3789-1516 https://orcid.org/0000-0002-5754-1719 https://orcid.org/0000-0003-2371-0470 https://orcid.org/0000-0002-4772-4570 https://orcid.org/0000-0003-2705-7245 https://orcid.org/0000-0001-5003-9104 https://orcid.org/0000-0002-9851-7029 https://orcid.org/0000-0003-3480-6750 https://orcid.org/0000-0002-0013-3941 https://orcid.org/0000-0003-0787-298X https://orcid.org/0000-0003-2398-5896 en_US http://dx.doi.org/10.1038/nm.4200 Nature Medicine Creative Commons Attribution-Noncommercial-Share Alike http://creativecommons.org/licenses/by-nc-sa/4.0/ application/pdf Nature Publishing Group PMC |
| spellingShingle | 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 Rothschilds, Adrienne Marie Kumari, Sudha Kelly, Ryan Lewis Kwan, Byron Hua Abraham, Wuhbet Hu, Kevin Mehta, Naveen Kauke, Monique Jacqueline Suh, Heikyung Lauffenburger, Douglas A Wittrup, Karl Dane Irvine, Darrell J Eradication of large established tumors in mice by combination immunotherapy that engages innate and adaptive immune responses |
| title | Eradication of large established tumors in mice by combination immunotherapy that engages innate and adaptive immune responses |
| title_full | Eradication of large established tumors in mice by combination immunotherapy that engages innate and adaptive immune responses |
| title_fullStr | Eradication of large established tumors in mice by combination immunotherapy that engages innate and adaptive immune responses |
| title_full_unstemmed | Eradication of large established tumors in mice by combination immunotherapy that engages innate and adaptive immune responses |
| title_short | Eradication of large established tumors in mice by combination immunotherapy that engages innate and adaptive immune responses |
| title_sort | eradication of large established tumors in mice by combination immunotherapy that engages innate and adaptive immune responses |
| url | http://hdl.handle.net/1721.1/109826 https://orcid.org/0000-0001-7604-1333 https://orcid.org/0000-0001-7316-6923 https://orcid.org/0000-0003-3789-1516 https://orcid.org/0000-0002-5754-1719 https://orcid.org/0000-0003-2371-0470 https://orcid.org/0000-0002-4772-4570 https://orcid.org/0000-0003-2705-7245 https://orcid.org/0000-0001-5003-9104 https://orcid.org/0000-0002-9851-7029 https://orcid.org/0000-0003-3480-6750 https://orcid.org/0000-0002-0013-3941 https://orcid.org/0000-0003-0787-298X https://orcid.org/0000-0003-2398-5896 |
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