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Temozolomide lymphodepletion enhances CAR abundance and correlates with antitumor efficacy against established glioblastoma
Adoptive transfer of T cells expressing chimeric antigen receptors (CARs) is an effective immunotherapy for B-cell malignancies but has failed in some solid tumors clinically. Intracerebral tumors may pose challenges that are even more significant. In order to devise a treatment strategy for patient...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Taylor & Francis
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5980382/ https://www.ncbi.nlm.nih.gov/pubmed/29872570 http://dx.doi.org/10.1080/2162402X.2018.1434464 |
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author | Suryadevara, Carter M. Desai, Rupen Abel, Melissa L. Riccione, Katherine A. Batich, Kristen A. Shen, Steven H. Chongsathidkiet, Pakawat Gedeon, Patrick C. Elsamadicy, Aladine A. Snyder, David J. Herndon, James E. Healy, Patrick Archer, Gary E. Choi, Bryan D. Fecci, Peter E. Sampson, John H. Sanchez-Perez, Luis |
author_facet | Suryadevara, Carter M. Desai, Rupen Abel, Melissa L. Riccione, Katherine A. Batich, Kristen A. Shen, Steven H. Chongsathidkiet, Pakawat Gedeon, Patrick C. Elsamadicy, Aladine A. Snyder, David J. Herndon, James E. Healy, Patrick Archer, Gary E. Choi, Bryan D. Fecci, Peter E. Sampson, John H. Sanchez-Perez, Luis |
author_sort | Suryadevara, Carter M. |
collection | PubMed |
description | Adoptive transfer of T cells expressing chimeric antigen receptors (CARs) is an effective immunotherapy for B-cell malignancies but has failed in some solid tumors clinically. Intracerebral tumors may pose challenges that are even more significant. In order to devise a treatment strategy for patients with glioblastoma (GBM), we evaluated CARs as a monotherapy in a murine model of GBM. CARs exhibited poor expansion and survival in circulation and failed to treat syngeneic and orthotopic gliomas. We hypothesized that CAR engraftment would benefit from host lymphodepletion prior to immunotherapy and that this might be achievable by using temozolomide (TMZ), which is standard treatment for these patients and has lymphopenia as its major side effect. We modelled standard of care temozolomide (TMZ(SD)) and dose-intensified TMZ (TMZ(DI)) in our murine model. Both regimens are clinically approved and provide similar efficacy. Only TMZ(DI) pretreatment prompted dramatic CAR proliferation and enhanced persistence in circulation compared to treatment with CARs alone or TMZ(SD) + CARs. Bioluminescent imaging revealed that TMZ(DI) + CARs induced complete regression of 21-day established brain tumors, which correlated with CAR abundance in circulation. Accordingly, TMZ(DI) + CARs significantly prolonged survival and led to long-term survivors. These findings are highly consequential, as it suggests that GBM patients may require TMZ(DI) as first line chemotherapy prior to systemic CAR infusion to promote CAR engraftment and antitumor efficacy. On this basis, we have initiated a phase I trial in patients with newly diagnosed GBM incorporating TMZ(DI) as a preconditioning regimen prior to CAR immunotherapy (NCT02664363). |
format | Online Article Text |
id | pubmed-5980382 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Taylor & Francis |
record_format | MEDLINE/PubMed |
spelling | pubmed-59803822018-06-05 Temozolomide lymphodepletion enhances CAR abundance and correlates with antitumor efficacy against established glioblastoma Suryadevara, Carter M. Desai, Rupen Abel, Melissa L. Riccione, Katherine A. Batich, Kristen A. Shen, Steven H. Chongsathidkiet, Pakawat Gedeon, Patrick C. Elsamadicy, Aladine A. Snyder, David J. Herndon, James E. Healy, Patrick Archer, Gary E. Choi, Bryan D. Fecci, Peter E. Sampson, John H. Sanchez-Perez, Luis Oncoimmunology Original Research Adoptive transfer of T cells expressing chimeric antigen receptors (CARs) is an effective immunotherapy for B-cell malignancies but has failed in some solid tumors clinically. Intracerebral tumors may pose challenges that are even more significant. In order to devise a treatment strategy for patients with glioblastoma (GBM), we evaluated CARs as a monotherapy in a murine model of GBM. CARs exhibited poor expansion and survival in circulation and failed to treat syngeneic and orthotopic gliomas. We hypothesized that CAR engraftment would benefit from host lymphodepletion prior to immunotherapy and that this might be achievable by using temozolomide (TMZ), which is standard treatment for these patients and has lymphopenia as its major side effect. We modelled standard of care temozolomide (TMZ(SD)) and dose-intensified TMZ (TMZ(DI)) in our murine model. Both regimens are clinically approved and provide similar efficacy. Only TMZ(DI) pretreatment prompted dramatic CAR proliferation and enhanced persistence in circulation compared to treatment with CARs alone or TMZ(SD) + CARs. Bioluminescent imaging revealed that TMZ(DI) + CARs induced complete regression of 21-day established brain tumors, which correlated with CAR abundance in circulation. Accordingly, TMZ(DI) + CARs significantly prolonged survival and led to long-term survivors. These findings are highly consequential, as it suggests that GBM patients may require TMZ(DI) as first line chemotherapy prior to systemic CAR infusion to promote CAR engraftment and antitumor efficacy. On this basis, we have initiated a phase I trial in patients with newly diagnosed GBM incorporating TMZ(DI) as a preconditioning regimen prior to CAR immunotherapy (NCT02664363). Taylor & Francis 2018-02-21 /pmc/articles/PMC5980382/ /pubmed/29872570 http://dx.doi.org/10.1080/2162402X.2018.1434464 Text en © 2018 The Author(s). Published with license by Taylor & Francis Group, LLC http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way. |
spellingShingle | Original Research Suryadevara, Carter M. Desai, Rupen Abel, Melissa L. Riccione, Katherine A. Batich, Kristen A. Shen, Steven H. Chongsathidkiet, Pakawat Gedeon, Patrick C. Elsamadicy, Aladine A. Snyder, David J. Herndon, James E. Healy, Patrick Archer, Gary E. Choi, Bryan D. Fecci, Peter E. Sampson, John H. Sanchez-Perez, Luis Temozolomide lymphodepletion enhances CAR abundance and correlates with antitumor efficacy against established glioblastoma |
title | Temozolomide lymphodepletion enhances CAR abundance and correlates with antitumor efficacy against established glioblastoma |
title_full | Temozolomide lymphodepletion enhances CAR abundance and correlates with antitumor efficacy against established glioblastoma |
title_fullStr | Temozolomide lymphodepletion enhances CAR abundance and correlates with antitumor efficacy against established glioblastoma |
title_full_unstemmed | Temozolomide lymphodepletion enhances CAR abundance and correlates with antitumor efficacy against established glioblastoma |
title_short | Temozolomide lymphodepletion enhances CAR abundance and correlates with antitumor efficacy against established glioblastoma |
title_sort | temozolomide lymphodepletion enhances car abundance and correlates with antitumor efficacy against established glioblastoma |
topic | Original Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5980382/ https://www.ncbi.nlm.nih.gov/pubmed/29872570 http://dx.doi.org/10.1080/2162402X.2018.1434464 |
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