Synergistic effect of CTLA-4 blockade and cancer chemotherapy in the induction of anti-tumor immunity.

Several chemotherapeutics exert immunomodulatory effects. One of these is the nucleoside analogue gemcitabine, which is widely used in patients with lung cancer, ovarian cancer, breast cancer, mesothelioma and several other types of cancer, but with limited efficacy. We hypothesized that the immunop...

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Autores principales:	W Joost Lesterhuis, Joanne Salmons, Anna K Nowak, Esdy N Rozali, Andrea Khong, Ian M Dick, Julie A Harken, Bruce W Robinson, Richard A Lake
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/356226740b7c4b4bb74348ae13186b28
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spelling	oai:doaj.org-article:356226740b7c4b4bb74348ae13186b282021-11-18T07:48:23ZSynergistic effect of CTLA-4 blockade and cancer chemotherapy in the induction of anti-tumor immunity.1932-620310.1371/journal.pone.0061895https://doaj.org/article/356226740b7c4b4bb74348ae13186b282013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23626745/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203Several chemotherapeutics exert immunomodulatory effects. One of these is the nucleoside analogue gemcitabine, which is widely used in patients with lung cancer, ovarian cancer, breast cancer, mesothelioma and several other types of cancer, but with limited efficacy. We hypothesized that the immunopotentiating effects of this drug are partly restrained by the inhibitory T cell molecule CTLA-4 and thus could be augmented by combining it with a blocking antibody against CTLA-4, which on its own has recently shown beneficial clinical effects in the treatment of patients with metastatic melanoma. Here we show, using two non-immunogenic murine tumor models, that treatment with gemcitabine chemotherapy in combination with CTLA-4 blockade results in the induction of a potent anti-tumor immune response. Depletion experiments demonstrated that both CD4(+) and CD8(+) T cells are required for optimal therapeutic effect. Mice treated with the combination exhibited tumor regression and long-term protective immunity. In addition, we show that the efficacy of the combination is moderated by the timing of administration of the two agents. Our results show that immune checkpoint blockade and cytotoxic chemotherapy can have a synergistic effect in the treatment of cancer. These results provide a basis to pursue combination therapies with anti-CTLA-4 and immunopotentiating chemotherapy and have important implications for future studies in cancer patients. Since both drugs are approved for use in patients our data can be immediately translated into clinical trials.W Joost LesterhuisJoanne SalmonsAnna K NowakEsdy N RozaliAndrea KhongIan M DickJulie A HarkenBruce W RobinsonRichard A LakePublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 4, p e61895 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q W Joost Lesterhuis Joanne Salmons Anna K Nowak Esdy N Rozali Andrea Khong Ian M Dick Julie A Harken Bruce W Robinson Richard A Lake Synergistic effect of CTLA-4 blockade and cancer chemotherapy in the induction of anti-tumor immunity.
description	Several chemotherapeutics exert immunomodulatory effects. One of these is the nucleoside analogue gemcitabine, which is widely used in patients with lung cancer, ovarian cancer, breast cancer, mesothelioma and several other types of cancer, but with limited efficacy. We hypothesized that the immunopotentiating effects of this drug are partly restrained by the inhibitory T cell molecule CTLA-4 and thus could be augmented by combining it with a blocking antibody against CTLA-4, which on its own has recently shown beneficial clinical effects in the treatment of patients with metastatic melanoma. Here we show, using two non-immunogenic murine tumor models, that treatment with gemcitabine chemotherapy in combination with CTLA-4 blockade results in the induction of a potent anti-tumor immune response. Depletion experiments demonstrated that both CD4(+) and CD8(+) T cells are required for optimal therapeutic effect. Mice treated with the combination exhibited tumor regression and long-term protective immunity. In addition, we show that the efficacy of the combination is moderated by the timing of administration of the two agents. Our results show that immune checkpoint blockade and cytotoxic chemotherapy can have a synergistic effect in the treatment of cancer. These results provide a basis to pursue combination therapies with anti-CTLA-4 and immunopotentiating chemotherapy and have important implications for future studies in cancer patients. Since both drugs are approved for use in patients our data can be immediately translated into clinical trials.
format	article
author	W Joost Lesterhuis Joanne Salmons Anna K Nowak Esdy N Rozali Andrea Khong Ian M Dick Julie A Harken Bruce W Robinson Richard A Lake
author_facet	W Joost Lesterhuis Joanne Salmons Anna K Nowak Esdy N Rozali Andrea Khong Ian M Dick Julie A Harken Bruce W Robinson Richard A Lake
author_sort	W Joost Lesterhuis
title	Synergistic effect of CTLA-4 blockade and cancer chemotherapy in the induction of anti-tumor immunity.
title_short	Synergistic effect of CTLA-4 blockade and cancer chemotherapy in the induction of anti-tumor immunity.
title_full	Synergistic effect of CTLA-4 blockade and cancer chemotherapy in the induction of anti-tumor immunity.
title_fullStr	Synergistic effect of CTLA-4 blockade and cancer chemotherapy in the induction of anti-tumor immunity.
title_full_unstemmed	Synergistic effect of CTLA-4 blockade and cancer chemotherapy in the induction of anti-tumor immunity.
title_sort	synergistic effect of ctla-4 blockade and cancer chemotherapy in the induction of anti-tumor immunity.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/356226740b7c4b4bb74348ae13186b28
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Synergistic effect of CTLA-4 blockade and cancer chemotherapy in the induction of anti-tumor immunity.

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