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Treatment with a VEGFR-2 antibody results in intra-tumor immune modulation and enhances anti-tumor efficacy of PD-L1 blockade in syngeneic murine tumor models

Prolonged activation of vascular endothelial growth factor receptor-2 (VEGFR-2) due to mis-regulation of the VEGF pathway induces aberrant blood vessel expansion, which supports growth and survival of solid tumors. Therapeutic interventions that inhibit the VEGFR-2 pathway have therefore become a ma...

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Autores principales: Li, Yanxia, Amaladas, Nelusha, O’Mahony, Marguerita, Manro, Jason R., Inigo, Ivan, Li, Qi, Rasmussen, Erik R., Brahmachary, Manisha, Doman, Thompson N., Hall, Gerald, Kalos, Michael, Novosiadly, Ruslan, Puig, Oscar, Pytowski, Bronislaw, Schaer, David A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9292077/
https://www.ncbi.nlm.nih.gov/pubmed/35849586
http://dx.doi.org/10.1371/journal.pone.0268244
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author Li, Yanxia
Amaladas, Nelusha
O’Mahony, Marguerita
Manro, Jason R.
Inigo, Ivan
Li, Qi
Rasmussen, Erik R.
Brahmachary, Manisha
Doman, Thompson N.
Hall, Gerald
Kalos, Michael
Novosiadly, Ruslan
Puig, Oscar
Pytowski, Bronislaw
Schaer, David A.
author_facet Li, Yanxia
Amaladas, Nelusha
O’Mahony, Marguerita
Manro, Jason R.
Inigo, Ivan
Li, Qi
Rasmussen, Erik R.
Brahmachary, Manisha
Doman, Thompson N.
Hall, Gerald
Kalos, Michael
Novosiadly, Ruslan
Puig, Oscar
Pytowski, Bronislaw
Schaer, David A.
author_sort Li, Yanxia
collection PubMed
description Prolonged activation of vascular endothelial growth factor receptor-2 (VEGFR-2) due to mis-regulation of the VEGF pathway induces aberrant blood vessel expansion, which supports growth and survival of solid tumors. Therapeutic interventions that inhibit the VEGFR-2 pathway have therefore become a mainstay of cancer treatment. Non-clinical studies have recently revealed that blockade of angiogenesis can modulate the tumor microenvironment and enhance the efficacy of concurrent immune therapies. Ramucirumab is an FDA-approved anti-angiogenic antibody that inhibits VEGFR-2 and is currently being evaluated in clinical studies in combination with anti-programmed cell death (PD-1) axis checkpoint inhibitors (pembrolizumab, durvalumab, or sintilimab) across several cancer types. The purpose of this study is to establish a mechanistic basis for the enhanced activity observed in the combined blockade of VEGFR-2 and PD-1-axis pathways. Pre-clinical studies were conducted in murine tumor models known to be responsive to anti-PD-1 axis therapy, using monoclonal antibodies that block mouse VEGFR-2 and programmed death-ligand 1 (PD-L1). Combination therapy resulted in enhanced anti-tumor activity compared to anti-PD-L1 monotherapy. VEGFR-2 blockade at early timepoints post-anti-PD-L1 therapy resulted in a dose-dependent and transient enhanced infiltration of T cells, and establishment of immunological memory. VEGFR-2 blockade at later timepoints resulted in enhancement of anti-PD-L1-driven immune cell infiltration. VEGFR-2 and PD-L1 monotherapies induced both unique and overlapping patterns of immune gene expression, and combination therapy resulted in an enhanced immune activation signature. Collectively, these results provide new and actionable insights into the mechanisms by which concurrent VEGFR-2 and PD-L1 antibody therapy leads to enhanced anti-tumor efficacy.
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spelling pubmed-92920772022-07-19 Treatment with a VEGFR-2 antibody results in intra-tumor immune modulation and enhances anti-tumor efficacy of PD-L1 blockade in syngeneic murine tumor models Li, Yanxia Amaladas, Nelusha O’Mahony, Marguerita Manro, Jason R. Inigo, Ivan Li, Qi Rasmussen, Erik R. Brahmachary, Manisha Doman, Thompson N. Hall, Gerald Kalos, Michael Novosiadly, Ruslan Puig, Oscar Pytowski, Bronislaw Schaer, David A. PLoS One Research Article Prolonged activation of vascular endothelial growth factor receptor-2 (VEGFR-2) due to mis-regulation of the VEGF pathway induces aberrant blood vessel expansion, which supports growth and survival of solid tumors. Therapeutic interventions that inhibit the VEGFR-2 pathway have therefore become a mainstay of cancer treatment. Non-clinical studies have recently revealed that blockade of angiogenesis can modulate the tumor microenvironment and enhance the efficacy of concurrent immune therapies. Ramucirumab is an FDA-approved anti-angiogenic antibody that inhibits VEGFR-2 and is currently being evaluated in clinical studies in combination with anti-programmed cell death (PD-1) axis checkpoint inhibitors (pembrolizumab, durvalumab, or sintilimab) across several cancer types. The purpose of this study is to establish a mechanistic basis for the enhanced activity observed in the combined blockade of VEGFR-2 and PD-1-axis pathways. Pre-clinical studies were conducted in murine tumor models known to be responsive to anti-PD-1 axis therapy, using monoclonal antibodies that block mouse VEGFR-2 and programmed death-ligand 1 (PD-L1). Combination therapy resulted in enhanced anti-tumor activity compared to anti-PD-L1 monotherapy. VEGFR-2 blockade at early timepoints post-anti-PD-L1 therapy resulted in a dose-dependent and transient enhanced infiltration of T cells, and establishment of immunological memory. VEGFR-2 blockade at later timepoints resulted in enhancement of anti-PD-L1-driven immune cell infiltration. VEGFR-2 and PD-L1 monotherapies induced both unique and overlapping patterns of immune gene expression, and combination therapy resulted in an enhanced immune activation signature. Collectively, these results provide new and actionable insights into the mechanisms by which concurrent VEGFR-2 and PD-L1 antibody therapy leads to enhanced anti-tumor efficacy. Public Library of Science 2022-07-18 /pmc/articles/PMC9292077/ /pubmed/35849586 http://dx.doi.org/10.1371/journal.pone.0268244 Text en © 2022 Li et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Li, Yanxia
Amaladas, Nelusha
O’Mahony, Marguerita
Manro, Jason R.
Inigo, Ivan
Li, Qi
Rasmussen, Erik R.
Brahmachary, Manisha
Doman, Thompson N.
Hall, Gerald
Kalos, Michael
Novosiadly, Ruslan
Puig, Oscar
Pytowski, Bronislaw
Schaer, David A.
Treatment with a VEGFR-2 antibody results in intra-tumor immune modulation and enhances anti-tumor efficacy of PD-L1 blockade in syngeneic murine tumor models
title Treatment with a VEGFR-2 antibody results in intra-tumor immune modulation and enhances anti-tumor efficacy of PD-L1 blockade in syngeneic murine tumor models
title_full Treatment with a VEGFR-2 antibody results in intra-tumor immune modulation and enhances anti-tumor efficacy of PD-L1 blockade in syngeneic murine tumor models
title_fullStr Treatment with a VEGFR-2 antibody results in intra-tumor immune modulation and enhances anti-tumor efficacy of PD-L1 blockade in syngeneic murine tumor models
title_full_unstemmed Treatment with a VEGFR-2 antibody results in intra-tumor immune modulation and enhances anti-tumor efficacy of PD-L1 blockade in syngeneic murine tumor models
title_short Treatment with a VEGFR-2 antibody results in intra-tumor immune modulation and enhances anti-tumor efficacy of PD-L1 blockade in syngeneic murine tumor models
title_sort treatment with a vegfr-2 antibody results in intra-tumor immune modulation and enhances anti-tumor efficacy of pd-l1 blockade in syngeneic murine tumor models
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9292077/
https://www.ncbi.nlm.nih.gov/pubmed/35849586
http://dx.doi.org/10.1371/journal.pone.0268244
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