Alum-anchored intratumoral retention improves the tolerability and antitumor efficacy of type I interferon therapies
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pnas.2205983119.pdf
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Published version
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1.79 MB
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Checksum (MD5)
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Author(s)
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
Date Issued
2022
Journal
Proceedings of the National Academy of Sciences of the United States of America
Publisher
Proceedings of the National Academy of Sciences
Citation
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).
Version
Final published version
Abstract
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.
MIT Department
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
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Creative Commons Attribution-NonCommercial-NoDerivs License
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DOI of Published Version
https://doi.org/10.1073/PNAS.2205983119
