Alum-anchored intratumoral retention improves the tolerability and antitumor efficacy of type I interferon therapies
<jats:p>Effective antitumor immunity in mice requires activation of the type I interferon (IFN) response pathway. IFNα and IFNβ therapies have proven promising in humans, but suffer from limited efficacy and high toxicity. Intratumoral IFN retention ameliorates systemic toxicity, but given the...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Proceedings of the National Academy of Sciences
2023
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| Online Access: | https://hdl.handle.net/1721.1/146987 |
| _version_ | 1826189116232957952 |
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| author | Lutz, Emi A Agarwal, Yash Momin, Noor Cowles, Sarah C Palmeri, Joseph R Duong, Ellen Hornet, Vladlena Sheen, Allison Lax, Brianna M Rothschilds, Adrienne M Irvine, Darrell J Spranger, Stefani Wittrup, K Dane |
| author2 | Koch Institute for Integrative Cancer Research at MIT |
| author_facet | Koch Institute for Integrative Cancer Research at MIT Lutz, Emi A Agarwal, Yash Momin, Noor Cowles, Sarah C Palmeri, Joseph R Duong, Ellen Hornet, Vladlena Sheen, Allison Lax, Brianna M Rothschilds, Adrienne M Irvine, Darrell J Spranger, Stefani Wittrup, K Dane |
| author_sort | Lutz, Emi A |
| collection | MIT |
| description | <jats:p>Effective antitumor immunity in mice requires activation of the type I interferon (IFN) response pathway. IFNα and IFNβ therapies have proven promising in humans, but suffer from limited efficacy and high toxicity. Intratumoral IFN retention ameliorates systemic toxicity, but given the complexity of IFN signaling, it was unclear whether long-term intratumoral retention of type I IFNs would promote or inhibit antitumor responses. To this end, we compared the efficacy of IFNα and IFNβ that exhibit either brief or sustained retention after intratumoral injection in syngeneic mouse tumor models. Significant enhancement in tumor retention, mediated by anchoring these IFNs to coinjected aluminum-hydroxide (alum) particles, greatly improved both their tolerability and efficacy. The improved efficacy of alum-anchored IFNs could be attributed to sustained pleiotropic effects on tumor cells, immune cells, and nonhematopoietic cells. Alum-anchored IFNs achieved high cure rates of B16F10 tumors upon combination with either anti-PD-1 antibody or interleukin-2. Interestingly however, these alternative combination immunotherapies yielded disparate T cell phenotypes and differential resistance to tumor rechallenge, highlighting important distinctions in adaptive memory formation for combinations of type I IFNs with other immunotherapies.</jats:p> |
| first_indexed | 2024-09-23T08:09:47Z |
| format | Article |
| id | mit-1721.1/146987 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T08:09:47Z |
| publishDate | 2023 |
| publisher | Proceedings of the National Academy of Sciences |
| record_format | dspace |
| spelling | mit-1721.1/1469872023-07-07T20:17:37Z Alum-anchored intratumoral retention improves the tolerability and antitumor efficacy of type I interferon therapies Lutz, Emi A Agarwal, Yash Momin, Noor Cowles, Sarah C Palmeri, Joseph R Duong, Ellen Hornet, Vladlena Sheen, Allison Lax, Brianna M Rothschilds, Adrienne M Irvine, Darrell J Spranger, Stefani Wittrup, K Dane Koch Institute for Integrative Cancer Research at MIT Massachusetts Institute of Technology. Department of Biological Engineering Massachusetts Institute of Technology. Department of Chemical Engineering Massachusetts Institute of Technology. Department of Biology Massachusetts Institute of Technology. Department of Materials Science and Engineering Ragon Institute of MGH, MIT and Harvard <jats:p>Effective antitumor immunity in mice requires activation of the type I interferon (IFN) response pathway. IFNα and IFNβ therapies have proven promising in humans, but suffer from limited efficacy and high toxicity. Intratumoral IFN retention ameliorates systemic toxicity, but given the complexity of IFN signaling, it was unclear whether long-term intratumoral retention of type I IFNs would promote or inhibit antitumor responses. To this end, we compared the efficacy of IFNα and IFNβ that exhibit either brief or sustained retention after intratumoral injection in syngeneic mouse tumor models. Significant enhancement in tumor retention, mediated by anchoring these IFNs to coinjected aluminum-hydroxide (alum) particles, greatly improved both their tolerability and efficacy. The improved efficacy of alum-anchored IFNs could be attributed to sustained pleiotropic effects on tumor cells, immune cells, and nonhematopoietic cells. Alum-anchored IFNs achieved high cure rates of B16F10 tumors upon combination with either anti-PD-1 antibody or interleukin-2. Interestingly however, these alternative combination immunotherapies yielded disparate T cell phenotypes and differential resistance to tumor rechallenge, highlighting important distinctions in adaptive memory formation for combinations of type I IFNs with other immunotherapies.</jats:p> 2023-01-05T19:14:31Z 2023-01-05T19:14:31Z 2022 2023-01-05T19:05:50Z Article http://purl.org/eprint/type/JournalArticle https://hdl.handle.net/1721.1/146987 Lutz, Emi A, Agarwal, Yash, Momin, Noor, Cowles, Sarah C, Palmeri, Joseph R et al. 2022. "Alum-anchored intratumoral retention improves the tolerability and antitumor efficacy of type I interferon therapies." Proceedings of the National Academy of Sciences of the United States of America, 119 (36). en 10.1073/PNAS.2205983119 Proceedings of the National Academy of Sciences of the United States of America Creative Commons Attribution-NonCommercial-NoDerivs License http://creativecommons.org/licenses/by-nc-nd/4.0/ application/pdf Proceedings of the National Academy of Sciences PNAS |
| spellingShingle | Lutz, Emi A Agarwal, Yash Momin, Noor Cowles, Sarah C Palmeri, Joseph R Duong, Ellen Hornet, Vladlena Sheen, Allison Lax, Brianna M Rothschilds, Adrienne M Irvine, Darrell J Spranger, Stefani Wittrup, K Dane Alum-anchored intratumoral retention improves the tolerability and antitumor efficacy of type I interferon therapies |
| title | Alum-anchored intratumoral retention improves the tolerability and antitumor efficacy of type I interferon therapies |
| title_full | Alum-anchored intratumoral retention improves the tolerability and antitumor efficacy of type I interferon therapies |
| title_fullStr | Alum-anchored intratumoral retention improves the tolerability and antitumor efficacy of type I interferon therapies |
| title_full_unstemmed | Alum-anchored intratumoral retention improves the tolerability and antitumor efficacy of type I interferon therapies |
| title_short | Alum-anchored intratumoral retention improves the tolerability and antitumor efficacy of type I interferon therapies |
| title_sort | alum anchored intratumoral retention improves the tolerability and antitumor efficacy of type i interferon therapies |
| url | https://hdl.handle.net/1721.1/146987 |
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