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Engineering CD19-specific T lymphocytes with interleukin-15 and a suicide gene to enhance their anti-lymphoma/leukemia effects and safety
T lymphocytes expressing a chimeric antigen receptor (CAR) targeting the CD19 antigen (CAR.19) may be of value for the therapy of B-cell malignancies. Because the in vivo survival, expansion and anti-lymphoma activity of CAR.19(+) T cells remain suboptimal even when the CAR contains a CD28 costimula...
Autores principales: | , , , , , , , , , |
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Formato: | Texto |
Lenguaje: | English |
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2010
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2888148/ https://www.ncbi.nlm.nih.gov/pubmed/20428207 http://dx.doi.org/10.1038/leu.2010.75 |
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author | Hoyos, Valentina Savoldo, Barbara Quintarelli, Concetta Mahendravada, Aruna Zhang, Ming Vera, Juan Heslop, Helen E Rooney, Cliona M. Brenner, Malcolm K Dotti, Gianpietro |
author_facet | Hoyos, Valentina Savoldo, Barbara Quintarelli, Concetta Mahendravada, Aruna Zhang, Ming Vera, Juan Heslop, Helen E Rooney, Cliona M. Brenner, Malcolm K Dotti, Gianpietro |
author_sort | Hoyos, Valentina |
collection | PubMed |
description | T lymphocytes expressing a chimeric antigen receptor (CAR) targeting the CD19 antigen (CAR.19) may be of value for the therapy of B-cell malignancies. Because the in vivo survival, expansion and anti-lymphoma activity of CAR.19(+) T cells remain suboptimal even when the CAR contains a CD28 costimulatory endodomain, we generated a novel construct that also incorporates the interleukin-15 (IL15) gene and an inducible caspase-9-based suicide gene (iC9/CAR.19/IL15). We found that compared to CAR.19(+) T cells, iC9/CAR.19/IL15(+) T cells had: (i) greater numeric expansion upon antigen stimulation (10-fold greater expansion in vitro, and 3 to 15 fold greater expansion in vivo) and reduced cell death rate (Annexin-V(+)/7-AAD(+) cells 10% ± 6% for iC9/CAR.19/IL15(+) T cells and 32% ± 19% CAR.19(+) T cells); (ii) reduced expression of the programmed death 1 (PD-1) receptor upon antigen stimulation (PD-1(+) cells <15% for iC9/CAR.19/IL15(+) T cells versus >40% for CAR.19(+) T cells); (iii) improved anti-tumor effects in vivo (from 4.7 to 5.4-fold reduced tumor growth). In addition, iC9/CAR.19/IL15(+) T cells were efficiently eliminated upon pharmacologic activation of the suicide gene. In summary, this strategy safely increases the anti-lymphoma/leukemia effects of CAR.19-redirected T lymphocytes and may be a useful approach for treatment of patients with B-cell malignancies. |
format | Text |
id | pubmed-2888148 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2010 |
record_format | MEDLINE/PubMed |
spelling | pubmed-28881482010-12-01 Engineering CD19-specific T lymphocytes with interleukin-15 and a suicide gene to enhance their anti-lymphoma/leukemia effects and safety Hoyos, Valentina Savoldo, Barbara Quintarelli, Concetta Mahendravada, Aruna Zhang, Ming Vera, Juan Heslop, Helen E Rooney, Cliona M. Brenner, Malcolm K Dotti, Gianpietro Leukemia Article T lymphocytes expressing a chimeric antigen receptor (CAR) targeting the CD19 antigen (CAR.19) may be of value for the therapy of B-cell malignancies. Because the in vivo survival, expansion and anti-lymphoma activity of CAR.19(+) T cells remain suboptimal even when the CAR contains a CD28 costimulatory endodomain, we generated a novel construct that also incorporates the interleukin-15 (IL15) gene and an inducible caspase-9-based suicide gene (iC9/CAR.19/IL15). We found that compared to CAR.19(+) T cells, iC9/CAR.19/IL15(+) T cells had: (i) greater numeric expansion upon antigen stimulation (10-fold greater expansion in vitro, and 3 to 15 fold greater expansion in vivo) and reduced cell death rate (Annexin-V(+)/7-AAD(+) cells 10% ± 6% for iC9/CAR.19/IL15(+) T cells and 32% ± 19% CAR.19(+) T cells); (ii) reduced expression of the programmed death 1 (PD-1) receptor upon antigen stimulation (PD-1(+) cells <15% for iC9/CAR.19/IL15(+) T cells versus >40% for CAR.19(+) T cells); (iii) improved anti-tumor effects in vivo (from 4.7 to 5.4-fold reduced tumor growth). In addition, iC9/CAR.19/IL15(+) T cells were efficiently eliminated upon pharmacologic activation of the suicide gene. In summary, this strategy safely increases the anti-lymphoma/leukemia effects of CAR.19-redirected T lymphocytes and may be a useful approach for treatment of patients with B-cell malignancies. 2010-04-29 2010-06 /pmc/articles/PMC2888148/ /pubmed/20428207 http://dx.doi.org/10.1038/leu.2010.75 Text en Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms |
spellingShingle | Article Hoyos, Valentina Savoldo, Barbara Quintarelli, Concetta Mahendravada, Aruna Zhang, Ming Vera, Juan Heslop, Helen E Rooney, Cliona M. Brenner, Malcolm K Dotti, Gianpietro Engineering CD19-specific T lymphocytes with interleukin-15 and a suicide gene to enhance their anti-lymphoma/leukemia effects and safety |
title | Engineering CD19-specific T lymphocytes with interleukin-15 and a suicide gene to enhance their anti-lymphoma/leukemia effects and safety |
title_full | Engineering CD19-specific T lymphocytes with interleukin-15 and a suicide gene to enhance their anti-lymphoma/leukemia effects and safety |
title_fullStr | Engineering CD19-specific T lymphocytes with interleukin-15 and a suicide gene to enhance their anti-lymphoma/leukemia effects and safety |
title_full_unstemmed | Engineering CD19-specific T lymphocytes with interleukin-15 and a suicide gene to enhance their anti-lymphoma/leukemia effects and safety |
title_short | Engineering CD19-specific T lymphocytes with interleukin-15 and a suicide gene to enhance their anti-lymphoma/leukemia effects and safety |
title_sort | engineering cd19-specific t lymphocytes with interleukin-15 and a suicide gene to enhance their anti-lymphoma/leukemia effects and safety |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2888148/ https://www.ncbi.nlm.nih.gov/pubmed/20428207 http://dx.doi.org/10.1038/leu.2010.75 |
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