Integrin-targeted cancer immunotherapy elicits protective adaptive immune responses

Author:

Kwan Byron H.12ORCID,Zhu Eric F.23,Tzeng Alice12ORCID,Sugito Harun R.12,Eltahir Ahmed A.24ORCID,Ma Botong25,Delaney Mary K.234,Murphy Patrick A.26,Kauke Monique J.23,Angelini Alessandro2,Momin Noor12,Mehta Naveen K.12,Maragh Alecia M.12,Hynes Richard O.26ORCID,Dranoff Glenn7,Cochran Jennifer R.89ORCID,Wittrup K. Dane123ORCID

Affiliation:

1. Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139

2. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139

3. Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139

4. Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139

5. Department of Mathematics, Massachusetts Institute of Technology, Cambridge, MA 02139

6. Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139

7. Novartis Institutes for BioMedical Research, Cambridge, MA 02139

8. Department of Bioengineering, Stanford University, Stanford, CA 94305

9. Department of Chemical Engineering, Stanford University, Stanford, CA 94305

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.

Funder

National Institutes of Health

Stanford Wallace H. Coulter Translational Partnership

NIH

Howard Hughes Medical Institute

National Science Foundation

National Institute of General Medical Sciences

Siebel Scholarship

Swiss National Science Foundation

Ludwig Cancer Research Center

Publisher

Rockefeller University Press

Subject

Immunology,Immunology and Allergy

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