Polymorphonuclear myeloid-derived suppressor cells impair the anti-tumor efficacy of GD2.CAR T-cells in patients with neuroblastoma

Abstract The outcome of patients affected by high-risk or metastatic neuroblastoma (NB) remains grim, with ≥ 50% of the children experiencing relapse or progression of the disease despite multimodal, intensive treatment. In order to identify new strategies to improve the overall survival and the qua...

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Autores principales:	Nicola Tumino, Gerrit Weber, Francesca Besi, Francesca Del Bufalo, Valentina Bertaina, Paola Paci, Linda Quatrini, Laura Antonucci, Matilde Sinibaldi, Concetta Quintarelli, Enrico Maggi, Biagio De Angelis, Franco Locatelli, Lorenzo Moretta, Paola Vacca, Ignazio Caruana
Formato:	article
Lenguaje:	EN
Publicado:	BMC 2021
Materias:	Neuroblastoma Polymorphonuclear myeloid-derived suppressor cells GD2.CAR T-cells Clinical response T-cell functionality Long-term response Diseases of the blood and blood-forming organs RC633-647.5 Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/51f0504736a347c6a8f2d674f1b4901c
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spelling	oai:doaj.org-article:51f0504736a347c6a8f2d674f1b4901c2021-11-14T12:05:40ZPolymorphonuclear myeloid-derived suppressor cells impair the anti-tumor efficacy of GD2.CAR T-cells in patients with neuroblastoma10.1186/s13045-021-01193-01756-8722https://doaj.org/article/51f0504736a347c6a8f2d674f1b4901c2021-11-01T00:00:00Zhttps://doi.org/10.1186/s13045-021-01193-0https://doaj.org/toc/1756-8722Abstract The outcome of patients affected by high-risk or metastatic neuroblastoma (NB) remains grim, with ≥ 50% of the children experiencing relapse or progression of the disease despite multimodal, intensive treatment. In order to identify new strategies to improve the overall survival and the quality of life of these children, we recently developed and optimized a third-generation GD2-specific chimeric antigen receptor (CAR) construct, which is currently under evaluation in our Institution in a phase I/II clinical trial (NCT03373097) enrolling patients with relapsed/refractory NB. We observed that our CAR T-cells are able to induce marked tumor reduction and even achieve complete remission with a higher efficiency than that of other CAR T-cells reported in previous studies. However, often responses are not sustained and relapses occur. Here, we demonstrate for the first time a mechanism of resistance to GD2.CAR T-cell treatment, showing how polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC) increase in the peripheral blood (PB) of NB patients after GD2.CAR T-cell treatment in case of relapse and loss of response. In vitro, isolated PMN-MDSC demonstrate to inhibit the anti-tumor cytotoxicity of different generations of GD2.CAR T-cells. Gene-expression profiling of GD2.CAR T-cells “conditioned” with PMN-MDSC shows downregulation of genes involved in cell activation, signal transduction, inflammation and cytokine/chemokine secretion. Analysis of NB gene-expression dataset confirms a correlation between expression of these genes and patient outcome. Moreover, in patients treated with GD2.CAR T-cells, the frequency of circulating PMN-MDSC inversely correlates with the levels of GD2.CAR T-cells, resulting more elevated in patients who did not respond or lost response to the treatment. The presence and the frequency of PMN-MDSC in PB of high-risk and metastatic NB represents a useful prognostic marker to predict the response to GD2.CAR T-cells and other adoptive immunotherapy. This study underlines the importance of further optimization of both CAR T-cells and clinical trial in order to target elements of the tumor microenvironment.Nicola TuminoGerrit WeberFrancesca BesiFrancesca Del BufaloValentina BertainaPaola PaciLinda QuatriniLaura AntonucciMatilde SinibaldiConcetta QuintarelliEnrico MaggiBiagio De AngelisFranco LocatelliLorenzo MorettaPaola VaccaIgnazio CaruanaBMCarticleNeuroblastomaPolymorphonuclear myeloid-derived suppressor cellsGD2.CAR T-cellsClinical responseT-cell functionalityLong-term responseDiseases of the blood and blood-forming organsRC633-647.5Neoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENJournal of Hematology & Oncology, Vol 14, Iss 1, Pp 1-7 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Neuroblastoma Polymorphonuclear myeloid-derived suppressor cells GD2.CAR T-cells Clinical response T-cell functionality Long-term response Diseases of the blood and blood-forming organs RC633-647.5 Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	Neuroblastoma Polymorphonuclear myeloid-derived suppressor cells GD2.CAR T-cells Clinical response T-cell functionality Long-term response Diseases of the blood and blood-forming organs RC633-647.5 Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Nicola Tumino Gerrit Weber Francesca Besi Francesca Del Bufalo Valentina Bertaina Paola Paci Linda Quatrini Laura Antonucci Matilde Sinibaldi Concetta Quintarelli Enrico Maggi Biagio De Angelis Franco Locatelli Lorenzo Moretta Paola Vacca Ignazio Caruana Polymorphonuclear myeloid-derived suppressor cells impair the anti-tumor efficacy of GD2.CAR T-cells in patients with neuroblastoma
description	Abstract The outcome of patients affected by high-risk or metastatic neuroblastoma (NB) remains grim, with ≥ 50% of the children experiencing relapse or progression of the disease despite multimodal, intensive treatment. In order to identify new strategies to improve the overall survival and the quality of life of these children, we recently developed and optimized a third-generation GD2-specific chimeric antigen receptor (CAR) construct, which is currently under evaluation in our Institution in a phase I/II clinical trial (NCT03373097) enrolling patients with relapsed/refractory NB. We observed that our CAR T-cells are able to induce marked tumor reduction and even achieve complete remission with a higher efficiency than that of other CAR T-cells reported in previous studies. However, often responses are not sustained and relapses occur. Here, we demonstrate for the first time a mechanism of resistance to GD2.CAR T-cell treatment, showing how polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC) increase in the peripheral blood (PB) of NB patients after GD2.CAR T-cell treatment in case of relapse and loss of response. In vitro, isolated PMN-MDSC demonstrate to inhibit the anti-tumor cytotoxicity of different generations of GD2.CAR T-cells. Gene-expression profiling of GD2.CAR T-cells “conditioned” with PMN-MDSC shows downregulation of genes involved in cell activation, signal transduction, inflammation and cytokine/chemokine secretion. Analysis of NB gene-expression dataset confirms a correlation between expression of these genes and patient outcome. Moreover, in patients treated with GD2.CAR T-cells, the frequency of circulating PMN-MDSC inversely correlates with the levels of GD2.CAR T-cells, resulting more elevated in patients who did not respond or lost response to the treatment. The presence and the frequency of PMN-MDSC in PB of high-risk and metastatic NB represents a useful prognostic marker to predict the response to GD2.CAR T-cells and other adoptive immunotherapy. This study underlines the importance of further optimization of both CAR T-cells and clinical trial in order to target elements of the tumor microenvironment.
format	article
author	Nicola Tumino Gerrit Weber Francesca Besi Francesca Del Bufalo Valentina Bertaina Paola Paci Linda Quatrini Laura Antonucci Matilde Sinibaldi Concetta Quintarelli Enrico Maggi Biagio De Angelis Franco Locatelli Lorenzo Moretta Paola Vacca Ignazio Caruana
author_facet	Nicola Tumino Gerrit Weber Francesca Besi Francesca Del Bufalo Valentina Bertaina Paola Paci Linda Quatrini Laura Antonucci Matilde Sinibaldi Concetta Quintarelli Enrico Maggi Biagio De Angelis Franco Locatelli Lorenzo Moretta Paola Vacca Ignazio Caruana
author_sort	Nicola Tumino
title	Polymorphonuclear myeloid-derived suppressor cells impair the anti-tumor efficacy of GD2.CAR T-cells in patients with neuroblastoma
title_short	Polymorphonuclear myeloid-derived suppressor cells impair the anti-tumor efficacy of GD2.CAR T-cells in patients with neuroblastoma
title_full	Polymorphonuclear myeloid-derived suppressor cells impair the anti-tumor efficacy of GD2.CAR T-cells in patients with neuroblastoma
title_fullStr	Polymorphonuclear myeloid-derived suppressor cells impair the anti-tumor efficacy of GD2.CAR T-cells in patients with neuroblastoma
title_full_unstemmed	Polymorphonuclear myeloid-derived suppressor cells impair the anti-tumor efficacy of GD2.CAR T-cells in patients with neuroblastoma
title_sort	polymorphonuclear myeloid-derived suppressor cells impair the anti-tumor efficacy of gd2.car t-cells in patients with neuroblastoma
publisher	BMC
publishDate	2021
url	https://doaj.org/article/51f0504736a347c6a8f2d674f1b4901c
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Polymorphonuclear myeloid-derived suppressor cells impair the anti-tumor efficacy of GD2.CAR T-cells in patients with neuroblastoma

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