Expanding the Therapeutic Window for CAR T Cell Therapy in Solid Tumors: The Knowns and Unknowns of CAR T Cell Biology

A major obstacle for chimeric antigen receptor (CAR) T cell therapy in solid tumors is the lack of truly tumor-specific target antigens, which translates to the targeting of tumor-associated antigens (TAAs) overexpressed on tumors but shared with normal organs, raising safety concerns. In addition,...

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Published inFrontiers in immunology Vol. 9; p. 2486
Main Authors Watanabe, Keisuke, Kuramitsu, Shunichiro, Posey, Jr, Avery D, June, Carl H
Format Journal Article
LanguageEnglish
Published Switzerland Frontiers Media S.A 26.10.2018
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Abstract A major obstacle for chimeric antigen receptor (CAR) T cell therapy in solid tumors is the lack of truly tumor-specific target antigens, which translates to the targeting of tumor-associated antigens (TAAs) overexpressed on tumors but shared with normal organs, raising safety concerns. In addition, expression of TAAs in solid tumors is particularly heterogeneous. In this regard, it is critical to deeply understand the sensitivity of CAR T cells, especially against low-density targets and the possible therapeutic window of antigen density targeted by CAR T cells. In this review, we discuss the recent findings of mechanisms of antigen recognition through CAR, including immunological synapse formation, and the impact of target antigen density for induction of distinct T cell functions. We also discuss rational strategies to adjust and expand the therapeutic window for effective and safe targeting of solid tumors by CAR T cell platforms.
AbstractList A major obstacle for chimeric antigen receptor (CAR) T cell therapy in solid tumors is the lack of truly tumor-specific target antigens, which translates to the targeting of tumor-associated antigens (TAAs) overexpressed on tumors but shared with normal organs, raising safety concerns. In addition, expression of TAAs in solid tumors is particularly heterogeneous. In this regard, it is critical to deeply understand the sensitivity of CAR T cells, especially against low-density targets and the possible therapeutic window of antigen density targeted by CAR T cells. In this review, we discuss the recent findings of mechanisms of antigen recognition through CAR, including immunological synapse formation, and the impact of target antigen density for induction of distinct T cell functions. We also discuss rational strategies to adjust and expand the therapeutic window for effective and safe targeting of solid tumors by CAR T cell platforms.
A major obstacle for chimeric antigen receptor (CAR) T cell therapy in solid tumors is the lack of truly tumor-specific target antigens, which translates to the targeting of tumor-associated antigens (TAAs) overexpressed on tumors but shared with normal organs, raising safety concerns. In addition, expression of TAAs in solid tumors is particularly heterogeneous. In this regard, it is critical to deeply understand the sensitivity of CAR T cells, especially against low-density targets and the possible therapeutic window of antigen density targeted by CAR T cells. In this review, we discuss the recent findings of mechanisms of antigen recognition through CAR, including immunological synapse formation, and the impact of target antigen density for induction of distinct T cell functions. We also discuss rational strategies to adjust and expand the therapeutic window for effective and safe targeting of solid tumors by CAR T cell platforms.A major obstacle for chimeric antigen receptor (CAR) T cell therapy in solid tumors is the lack of truly tumor-specific target antigens, which translates to the targeting of tumor-associated antigens (TAAs) overexpressed on tumors but shared with normal organs, raising safety concerns. In addition, expression of TAAs in solid tumors is particularly heterogeneous. In this regard, it is critical to deeply understand the sensitivity of CAR T cells, especially against low-density targets and the possible therapeutic window of antigen density targeted by CAR T cells. In this review, we discuss the recent findings of mechanisms of antigen recognition through CAR, including immunological synapse formation, and the impact of target antigen density for induction of distinct T cell functions. We also discuss rational strategies to adjust and expand the therapeutic window for effective and safe targeting of solid tumors by CAR T cell platforms.
Author Watanabe, Keisuke
Posey, Jr, Avery D
Kuramitsu, Shunichiro
June, Carl H
AuthorAffiliation 4 Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania , Philadelphia, PA , United States
1 Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania , Philadelphia, PA , United States
3 Corporal Michael J. Crescenz VA Medical Center , Philadelphia, PA , United States
2 Parker Institute for Cancer Immunotherapy, University of Pennsylvania , Philadelphia, PA , United States
AuthorAffiliation_xml – name: 4 Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania , Philadelphia, PA , United States
– name: 1 Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania , Philadelphia, PA , United States
– name: 2 Parker Institute for Cancer Immunotherapy, University of Pennsylvania , Philadelphia, PA , United States
– name: 3 Corporal Michael J. Crescenz VA Medical Center , Philadelphia, PA , United States
Author_xml – sequence: 1
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  surname: Watanabe
  fullname: Watanabe, Keisuke
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  fullname: Kuramitsu, Shunichiro
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  givenname: Carl H
  surname: June
  fullname: June, Carl H
  organization: Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States
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Keywords T cell biology
chimeric antigen receptors
immune synapse formation
cancer immunology
immunotherapy
Language English
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Edited by: Salem Chouaib, Institut Gustave Roussy, France
Reviewed by: Maksim Mamonkin, Baylor College of Medicine, United States; Pappanaicken R. Kumaresan, University of Texas MD Anderson Cancer Center, United States
This article was submitted to Cancer Immunity and Immunotherapy, a section of the journal Frontiers in Immunology
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PublicationTitleAlternate Front Immunol
PublicationYear 2018
Publisher Frontiers Media S.A
Publisher_xml – name: Frontiers Media S.A
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Snippet A major obstacle for chimeric antigen receptor (CAR) T cell therapy in solid tumors is the lack of truly tumor-specific target antigens, which translates to...
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SubjectTerms Animals
Antigens, Neoplasm - immunology
cancer immunology
chimeric antigen receptors
Humans
immune synapse formation
Immunological Synapses - metabolism
Immunology
immunotherapy
Immunotherapy, Adoptive - methods
Neoplasms - immunology
Neoplasms - therapy
Receptors, Antigen, T-Cell - genetics
T cell biology
T-Lymphocytes - immunology
T-Lymphocytes - transplantation
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Title Expanding the Therapeutic Window for CAR T Cell Therapy in Solid Tumors: The Knowns and Unknowns of CAR T Cell Biology
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