Matrix-binding checkpoint immunotherapies enhance antitumor efficacy and reduce adverse events
File(s)
Accepted version
Author(s)
Type
Journal Article
Abstract
Immune checkpoint blockade exhibits considerable antitumor activity, but previous studies have reported instances of severe treatment-related adverse events. We sought to explore local immune checkpoint blockade, with an antibody (Ab) form that would be retained intra- or peritumorally, limiting systemic exposure. To accomplish this, we conjugated the checkpoint blockade Abs to an extracellular matrix (ECM)–super-affinity peptide derived from placenta growth factor–2 (PlGF-2123–144). We show enhanced tissue retention and lower Ab concentrations in blood plasma after PlGF-2123–144 conjugation, reducing systemic side effects such as the risk of autoimmune diabetes. Peritumoral injections of PlGF-2123–144–anti-CTLA4 (cytotoxic T lymphocyte antigen 4) and PlGF-2123–144–anti–PD-L1 (programmed death ligand 1) Abs delayed tumor growth and prolonged survival compared to the unmodified Abs in genetically engineered murine tumor models of melanoma and breast cancer. The PlGF-2123–144–Abs increased tumor-infiltrating activated CD8+ and CD4+ T cells, resulting in a delay of distant tumor growth as well. This simple and translatable approach of engineered ECM-binding Abs may present a viable and safer approach in checkpoint blockade.
Date Issued
2017-11-08
Date Acceptance
2017-09-27
Citation
Science Translational Medicine, 2017, 9 (415), pp.1-16
ISSN
1946-6234
Publisher
American Association for the Advancement of Science (AAAS)
Start Page
1
End Page
16
Journal / Book Title
Science Translational Medicine
Volume
9
Issue
415
Copyright Statement
© 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works http://www.sciencemag.org/about/science-licenses-journal-article-reuse
This is an article distributed under the terms of the Science Journals Default License. This is the author’s version of the work. It is posted here by permission of the AAAS for personal use, not for redistribution. The definitive version was published in Science Translational Medicine on [Volume number 9 and 08 Nov 2017], DOI: https://doi.org/10.1126/scitranslmed.aan0401
This is an article distributed under the terms of the Science Journals Default License. This is the author’s version of the work. It is posted here by permission of the AAAS for personal use, not for redistribution. The definitive version was published in Science Translational Medicine on [Volume number 9 and 08 Nov 2017], DOI: https://doi.org/10.1126/scitranslmed.aan0401
Identifier
https://stm.sciencemag.org/content/9/415/eaan0401
Subjects
06 Biological Sciences
11 Medical and Health Sciences
Publication Status
Published
Date Publish Online
2017-11-08