Integrin-targeted cancer immunotherapy elicits protective adaptive immune responses
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1679.full.pdf
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Author(s)
Dranoff, Glenn
Kwan, Byron Hua
Zhu, Eric Franklin
Tzeng, Alice
Sugito, Harun R.
Eltahir, Ahmed A.
Ma, Botong
Delaney, Mary K.
Murphy, Patrick A.
Kauke, Monique Jacqueline
Date Issued
May 2017
Journal
Journal of Experimental Medicine
Publisher
Rockefeller University Press
Citation
Kwan, Byron H. et al. “Integrin-Targeted Cancer Immunotherapy Elicits Protective Adaptive Immune Responses.” The Journal of Experimental Medicine 214, 6 (May 2017): 1679–1690 © 2017 Kwan et al
Version
Final published version
Abstract
Certain RGD-binding integrins are required for cell adhesion, migration, and proliferation and are overexpressed in most tumors, making them attractive therapeutic targets. However, multiple integrin antagonist drug candidates have failed to show efficacy in cancer clinical trials. In this work, we instead exploit these integrins as a target for antibody Fc effector functions in the context of cancer immunotherapy. By combining administration of an engineered mouse serum albumin/IL-2 fusion with an Fc fusion to an integrin-binding peptide (2.5F-Fc), significant survival improvements are achieved in three syngeneic mouse tumor models, including complete responses with protective immunity. Functional integrin antagonism does not contribute significantly to efficacy; rather, this therapy recruits both an innate and adaptive immune response, as deficiencies in either arm result in reduced tumor control. Administration of this integrin-targeted immunotherapy together with an anti-PD-1 antibody further improves responses and predominantly results in cures. Overall, this well-tolerated therapy achieves tumor specificity by redirecting inflammation to a functional target fundamental to tumorigenic processes but expressed at significantly lower levels in healthy tissues, and it shows promise for translation.
MIT Department
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 Mathematics
Koch Institute for Integrative Cancer Research at MIT
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Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0)
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DOI of Published Version
https://doi.org/10.1084/JEM.20160831
