Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 214, Issue 6, Pages 1679-1690Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20160831
Keywords
-
Categories
Funding
- National Institutes of Health (NIH) [CA174795]
- Stanford Wallace H. Coulter Translational Partnership Award, NIH [U54CA163109]
- Howard Hughes Medical Institute
- National Science Foundation graduate fellowship
- NIH/National Institute of General Medical Sciences Biotechnology Training Program
- Siebel Scholarship
- NIH [K99HL125727]
- Swiss National Science Foundation [PP00P3_123524/1]
- Ludwig Cancer Research Center Postdoctoral Fellowship
- Swiss National Science Foundation (SNF) [PP00P3_123524] Funding Source: Swiss National Science Foundation (SNF)
Ask authors/readers for more resources
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available