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Immune Checkpoint Inhibitors for the Treatment of Central Nervous System (CNS) Metastatic Disease

While the CNS has long been viewed as an immune-privileged environment, a paradigm shift in neuro-immunology has elevated the role of systemic immunotherapy for the treatment of metastatic disease. Increasing knowledge regarding the presence of a CNS lymphatic system and the physical and biochemical...

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Autores principales: Kamath, Suneel D., Kumthekar, Priya U.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6171475/
https://www.ncbi.nlm.nih.gov/pubmed/30319977
http://dx.doi.org/10.3389/fonc.2018.00414
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author Kamath, Suneel D.
Kumthekar, Priya U.
author_facet Kamath, Suneel D.
Kumthekar, Priya U.
author_sort Kamath, Suneel D.
collection PubMed
description While the CNS has long been viewed as an immune-privileged environment, a paradigm shift in neuro-immunology has elevated the role of systemic immunotherapy for the treatment of metastatic disease. Increasing knowledge regarding the presence of a CNS lymphatic system and the physical and biochemical alteration of the blood brain barrier (BBB) by the tumor microenvironment suggests immune cell trafficking in and out of the CNS is possible. Emerging clinical data suggest immune checkpoint inhibitors (ICIs) can stimulate T cells peripherally to in turn have anti-tumor effects in the CNS. For example, anti-programmed cell death-1 (PD-1) monotherapy with pembrolizumab has shown intracranial response rates of 20–30% in patients with melanoma or non-small cell lung cancer (NSCLC) brain metastases. The combination of nivolumab and ipilimumab [anti-PD-1 and anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4)] showed an intracranial response rate of 55% in patients with melanoma brain metastases. More data are needed to confirm these response rates and to determine mechanisms of efficacy and resistance. While local therapies such as stereotactic radiosurgery (SRS), whole-brain radiation therapy (WBRT), and surgery remain current mainstays, ICIS offer potential decreased neurotoxicity. This review summarizes the biological rationale for systemic immunotherapy to treat CNS metastatic disease, existing clinical data on ICIs in this setting and ongoing clinical trials exploring areas of unmet need.
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spelling pubmed-61714752018-10-12 Immune Checkpoint Inhibitors for the Treatment of Central Nervous System (CNS) Metastatic Disease Kamath, Suneel D. Kumthekar, Priya U. Front Oncol Oncology While the CNS has long been viewed as an immune-privileged environment, a paradigm shift in neuro-immunology has elevated the role of systemic immunotherapy for the treatment of metastatic disease. Increasing knowledge regarding the presence of a CNS lymphatic system and the physical and biochemical alteration of the blood brain barrier (BBB) by the tumor microenvironment suggests immune cell trafficking in and out of the CNS is possible. Emerging clinical data suggest immune checkpoint inhibitors (ICIs) can stimulate T cells peripherally to in turn have anti-tumor effects in the CNS. For example, anti-programmed cell death-1 (PD-1) monotherapy with pembrolizumab has shown intracranial response rates of 20–30% in patients with melanoma or non-small cell lung cancer (NSCLC) brain metastases. The combination of nivolumab and ipilimumab [anti-PD-1 and anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4)] showed an intracranial response rate of 55% in patients with melanoma brain metastases. More data are needed to confirm these response rates and to determine mechanisms of efficacy and resistance. While local therapies such as stereotactic radiosurgery (SRS), whole-brain radiation therapy (WBRT), and surgery remain current mainstays, ICIS offer potential decreased neurotoxicity. This review summarizes the biological rationale for systemic immunotherapy to treat CNS metastatic disease, existing clinical data on ICIs in this setting and ongoing clinical trials exploring areas of unmet need. Frontiers Media S.A. 2018-09-27 /pmc/articles/PMC6171475/ /pubmed/30319977 http://dx.doi.org/10.3389/fonc.2018.00414 Text en Copyright © 2018 Kamath and Kumthekar. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Oncology
Kamath, Suneel D.
Kumthekar, Priya U.
Immune Checkpoint Inhibitors for the Treatment of Central Nervous System (CNS) Metastatic Disease
title Immune Checkpoint Inhibitors for the Treatment of Central Nervous System (CNS) Metastatic Disease
title_full Immune Checkpoint Inhibitors for the Treatment of Central Nervous System (CNS) Metastatic Disease
title_fullStr Immune Checkpoint Inhibitors for the Treatment of Central Nervous System (CNS) Metastatic Disease
title_full_unstemmed Immune Checkpoint Inhibitors for the Treatment of Central Nervous System (CNS) Metastatic Disease
title_short Immune Checkpoint Inhibitors for the Treatment of Central Nervous System (CNS) Metastatic Disease
title_sort immune checkpoint inhibitors for the treatment of central nervous system (cns) metastatic disease
topic Oncology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6171475/
https://www.ncbi.nlm.nih.gov/pubmed/30319977
http://dx.doi.org/10.3389/fonc.2018.00414
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