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Redirecting Specificity of T cells Using the Sleeping Beauty System to Express Chimeric Antigen Receptors by Mix-and-Matching of V(L) and V(H) Domains Targeting CD123(+) Tumors
Adoptive immunotherapy infusing T cells with engineered specificity for CD19 expressed on B- cell malignancies is generating enthusiasm to extend this approach to other hematological malignancies, such as acute myelogenous leukemia (AML). CD123, or interleukin 3 receptor alpha, is overexpressed on m...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4993583/ https://www.ncbi.nlm.nih.gov/pubmed/27548616 http://dx.doi.org/10.1371/journal.pone.0159477 |
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author | Thokala, Radhika Olivares, Simon Mi, Tiejuan Maiti, Sourindra Deniger, Drew Huls, Helen Torikai, Hiroki Singh, Harjeet Champlin, Richard E. Laskowski, Tamara McNamara, George Cooper, Laurence J. N. |
author_facet | Thokala, Radhika Olivares, Simon Mi, Tiejuan Maiti, Sourindra Deniger, Drew Huls, Helen Torikai, Hiroki Singh, Harjeet Champlin, Richard E. Laskowski, Tamara McNamara, George Cooper, Laurence J. N. |
author_sort | Thokala, Radhika |
collection | PubMed |
description | Adoptive immunotherapy infusing T cells with engineered specificity for CD19 expressed on B- cell malignancies is generating enthusiasm to extend this approach to other hematological malignancies, such as acute myelogenous leukemia (AML). CD123, or interleukin 3 receptor alpha, is overexpressed on most AML and some lymphoid malignancies, such as acute lymphocytic leukemia (ALL), and has been an effective target for T cells expressing chimeric antigen receptors (CARs). The prototypical CAR encodes a V(H) and V(L) from one monoclonal antibody (mAb), coupled to a transmembrane domain and one or more cytoplasmic signaling domains. Previous studies showed that treatment of an experimental AML model with CD123-specific CAR T cells was therapeutic, but at the cost of impaired myelopoiesis, highlighting the need for systems to define the antigen threshold for CAR recognition. Here, we show that CARs can be engineered using V(H) and V(L) chains derived from different CD123-specific mAbs to generate a panel of CAR(+) T cells. While all CARs exhibited specificity to CD123, one V(H) and V(L) combination had reduced lysis of normal hematopoietic stem cells. This CAR’s in vivo anti-tumor activity was similar whether signaling occurred via chimeric CD28 or CD137, prolonging survival in both AML and ALL models. Co-expression of inducible caspase 9 eliminated CAR(+) T cells. These data help support the use of CD123-specific CARs for treatment of CD123(+) hematologic malignancies. |
format | Online Article Text |
id | pubmed-4993583 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-49935832016-09-12 Redirecting Specificity of T cells Using the Sleeping Beauty System to Express Chimeric Antigen Receptors by Mix-and-Matching of V(L) and V(H) Domains Targeting CD123(+) Tumors Thokala, Radhika Olivares, Simon Mi, Tiejuan Maiti, Sourindra Deniger, Drew Huls, Helen Torikai, Hiroki Singh, Harjeet Champlin, Richard E. Laskowski, Tamara McNamara, George Cooper, Laurence J. N. PLoS One Research Article Adoptive immunotherapy infusing T cells with engineered specificity for CD19 expressed on B- cell malignancies is generating enthusiasm to extend this approach to other hematological malignancies, such as acute myelogenous leukemia (AML). CD123, or interleukin 3 receptor alpha, is overexpressed on most AML and some lymphoid malignancies, such as acute lymphocytic leukemia (ALL), and has been an effective target for T cells expressing chimeric antigen receptors (CARs). The prototypical CAR encodes a V(H) and V(L) from one monoclonal antibody (mAb), coupled to a transmembrane domain and one or more cytoplasmic signaling domains. Previous studies showed that treatment of an experimental AML model with CD123-specific CAR T cells was therapeutic, but at the cost of impaired myelopoiesis, highlighting the need for systems to define the antigen threshold for CAR recognition. Here, we show that CARs can be engineered using V(H) and V(L) chains derived from different CD123-specific mAbs to generate a panel of CAR(+) T cells. While all CARs exhibited specificity to CD123, one V(H) and V(L) combination had reduced lysis of normal hematopoietic stem cells. This CAR’s in vivo anti-tumor activity was similar whether signaling occurred via chimeric CD28 or CD137, prolonging survival in both AML and ALL models. Co-expression of inducible caspase 9 eliminated CAR(+) T cells. These data help support the use of CD123-specific CARs for treatment of CD123(+) hematologic malignancies. Public Library of Science 2016-08-22 /pmc/articles/PMC4993583/ /pubmed/27548616 http://dx.doi.org/10.1371/journal.pone.0159477 Text en © 2016 Thokala et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Thokala, Radhika Olivares, Simon Mi, Tiejuan Maiti, Sourindra Deniger, Drew Huls, Helen Torikai, Hiroki Singh, Harjeet Champlin, Richard E. Laskowski, Tamara McNamara, George Cooper, Laurence J. N. Redirecting Specificity of T cells Using the Sleeping Beauty System to Express Chimeric Antigen Receptors by Mix-and-Matching of V(L) and V(H) Domains Targeting CD123(+) Tumors |
title | Redirecting Specificity of T cells Using the Sleeping Beauty System to Express Chimeric Antigen Receptors by Mix-and-Matching of V(L) and V(H) Domains Targeting CD123(+) Tumors |
title_full | Redirecting Specificity of T cells Using the Sleeping Beauty System to Express Chimeric Antigen Receptors by Mix-and-Matching of V(L) and V(H) Domains Targeting CD123(+) Tumors |
title_fullStr | Redirecting Specificity of T cells Using the Sleeping Beauty System to Express Chimeric Antigen Receptors by Mix-and-Matching of V(L) and V(H) Domains Targeting CD123(+) Tumors |
title_full_unstemmed | Redirecting Specificity of T cells Using the Sleeping Beauty System to Express Chimeric Antigen Receptors by Mix-and-Matching of V(L) and V(H) Domains Targeting CD123(+) Tumors |
title_short | Redirecting Specificity of T cells Using the Sleeping Beauty System to Express Chimeric Antigen Receptors by Mix-and-Matching of V(L) and V(H) Domains Targeting CD123(+) Tumors |
title_sort | redirecting specificity of t cells using the sleeping beauty system to express chimeric antigen receptors by mix-and-matching of v(l) and v(h) domains targeting cd123(+) tumors |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4993583/ https://www.ncbi.nlm.nih.gov/pubmed/27548616 http://dx.doi.org/10.1371/journal.pone.0159477 |
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