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Tumor in the Crossfire: Inhibiting TGF-β to Enhance Cancer Immunotherapy
Cancer immunotherapy using monoclonal antibodies targeting immune checkpoints has undoubtedly revolutionized the cancer treatment landscape in the last decade. Immune checkpoint inhibitors can elicit long-lasting, previously unheard-of responses in a number of tumor entities. Yet, even in such tumor...
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Springer International Publishing
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8986721/ https://www.ncbi.nlm.nih.gov/pubmed/35353346 http://dx.doi.org/10.1007/s40259-022-00521-1 |
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author | Tschernia, Nicholas P. Gulley, James L. |
author_facet | Tschernia, Nicholas P. Gulley, James L. |
author_sort | Tschernia, Nicholas P. |
collection | PubMed |
description | Cancer immunotherapy using monoclonal antibodies targeting immune checkpoints has undoubtedly revolutionized the cancer treatment landscape in the last decade. Immune checkpoint inhibitors can elicit long-lasting, previously unheard-of responses in a number of tumor entities. Yet, even in such tumors as metastatic melanoma and non-small cell-lung cancer, in which immune checkpoint inhibition has become the first-line treatment of choice, only a minority of patients will benefit considerably from these treatments. This has been attributed to a number of factors, including an immune-suppressive tumor microenvironment (TME). Using different modalities to break these barriers is of utmost importance to expand the population of patients that benefit from immune checkpoint inhibition. The multifunctional cytokine transforming growth factor-β (TGF-β) has long been recognized as an immune-suppressive factor in the TME. A considerable number of drugs have been developed to target TGF-β, yet most of these have since been discontinued. The combination of anti–TGF-β agents with immune checkpoint inhibitors now has the potential to revive this target as a viable immunomodulatory therapeutic approach. Currently, a limited number of small molecular inhibitor and monoclonal antibody candidates that target TGF-β are in clinical development in combination with the following immune checkpoint inhibitors: SRK 181, an antibody inhibiting the activation of latent TGF-β1; NIS 793, a monoclonal antibody targeting TGF-β; and SHR 1701, a fusion protein consisting of an anti-PD-L1 monoclonal antibody fused with the extracellular domain of human TGF-β receptor II. Several small molecular inhibitors are also in development and are briefly reviewed: LY364947, a pyrazole-based small molecular inhibitor of the serine-threonine kinase activity of TGFβRI; SB-431542, an inhibitor targeting several TGF-β superfamily Type I activin receptor-like kinases as well as TGF-β1-induced nuclear Smad3 localization; and galunisertib, an oral small molecular inhibitor of the TGFβRI kinase. One of the most advanced agents in this area is bintrafusp alfa, a bifunctional fusion protein composed of the extracellular domain of TGF-β receptor II fused to a human IgG1 mAb blocking PD-L1. Bintrafusp alfa is currently in advanced clinical development and as an agent in this space with the most clinical experience, is a focused highlight of this review. |
format | Online Article Text |
id | pubmed-8986721 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Springer International Publishing |
record_format | MEDLINE/PubMed |
spelling | pubmed-89867212022-04-22 Tumor in the Crossfire: Inhibiting TGF-β to Enhance Cancer Immunotherapy Tschernia, Nicholas P. Gulley, James L. BioDrugs Review Article Cancer immunotherapy using monoclonal antibodies targeting immune checkpoints has undoubtedly revolutionized the cancer treatment landscape in the last decade. Immune checkpoint inhibitors can elicit long-lasting, previously unheard-of responses in a number of tumor entities. Yet, even in such tumors as metastatic melanoma and non-small cell-lung cancer, in which immune checkpoint inhibition has become the first-line treatment of choice, only a minority of patients will benefit considerably from these treatments. This has been attributed to a number of factors, including an immune-suppressive tumor microenvironment (TME). Using different modalities to break these barriers is of utmost importance to expand the population of patients that benefit from immune checkpoint inhibition. The multifunctional cytokine transforming growth factor-β (TGF-β) has long been recognized as an immune-suppressive factor in the TME. A considerable number of drugs have been developed to target TGF-β, yet most of these have since been discontinued. The combination of anti–TGF-β agents with immune checkpoint inhibitors now has the potential to revive this target as a viable immunomodulatory therapeutic approach. Currently, a limited number of small molecular inhibitor and monoclonal antibody candidates that target TGF-β are in clinical development in combination with the following immune checkpoint inhibitors: SRK 181, an antibody inhibiting the activation of latent TGF-β1; NIS 793, a monoclonal antibody targeting TGF-β; and SHR 1701, a fusion protein consisting of an anti-PD-L1 monoclonal antibody fused with the extracellular domain of human TGF-β receptor II. Several small molecular inhibitors are also in development and are briefly reviewed: LY364947, a pyrazole-based small molecular inhibitor of the serine-threonine kinase activity of TGFβRI; SB-431542, an inhibitor targeting several TGF-β superfamily Type I activin receptor-like kinases as well as TGF-β1-induced nuclear Smad3 localization; and galunisertib, an oral small molecular inhibitor of the TGFβRI kinase. One of the most advanced agents in this area is bintrafusp alfa, a bifunctional fusion protein composed of the extracellular domain of TGF-β receptor II fused to a human IgG1 mAb blocking PD-L1. Bintrafusp alfa is currently in advanced clinical development and as an agent in this space with the most clinical experience, is a focused highlight of this review. Springer International Publishing 2022-03-30 2022 /pmc/articles/PMC8986721/ /pubmed/35353346 http://dx.doi.org/10.1007/s40259-022-00521-1 Text en © This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply 2022 https://creativecommons.org/licenses/by-nc/4.0/Open AccessThis article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) . |
spellingShingle | Review Article Tschernia, Nicholas P. Gulley, James L. Tumor in the Crossfire: Inhibiting TGF-β to Enhance Cancer Immunotherapy |
title | Tumor in the Crossfire: Inhibiting TGF-β to Enhance Cancer Immunotherapy |
title_full | Tumor in the Crossfire: Inhibiting TGF-β to Enhance Cancer Immunotherapy |
title_fullStr | Tumor in the Crossfire: Inhibiting TGF-β to Enhance Cancer Immunotherapy |
title_full_unstemmed | Tumor in the Crossfire: Inhibiting TGF-β to Enhance Cancer Immunotherapy |
title_short | Tumor in the Crossfire: Inhibiting TGF-β to Enhance Cancer Immunotherapy |
title_sort | tumor in the crossfire: inhibiting tgf-β to enhance cancer immunotherapy |
topic | Review Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8986721/ https://www.ncbi.nlm.nih.gov/pubmed/35353346 http://dx.doi.org/10.1007/s40259-022-00521-1 |
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