Engineering better chimeric antigen receptor T cells

Zhang, Hao; Zhao, Pu; Huang, He

doi:10.1186/s40164-020-00190-2

Cited by 94CAR-T cell therapy researchImmunotherapy and Immune ResponsesT-cell and B-cell Immunology

Engineering better chimeric antigen receptor T cells

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Zhang, Hao, Zhao, Pu, Huang, He·2020·Experimental Hematology & Oncology

DOI 10.1186/s40164-020-00190-2PMC PMC7709221

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Abstract

CD19-targeted CAR T cells therapy has shown remarkable efficacy in treatment of B cell malignancies. However, relapse of primary disease remains a major obstacle after CAR T cells therapy, and the majority of relapses present a tumor phenotype with retention of target antigen (antigen-positive relapse), which highly correlate with poor CAR T cells persistence. Therefore, study on factors and mechanisms that limit the in vivo persistence of CAR T cells is crucial for developing strategies to overcome these limitations. In this review, we summarize the rapidly developing knowledge regarding the factors that influence CAR T cells in vivo persistence and the underlying mechanisms. The factors involve the CAR constructs (extracellular structures, transmembrane and intracellular signaling domains, as well as the accessory structures), activation signaling (CAR signaling and TCR engagement), methods for in vitro culture (T cells collection, purification, activation, gene transduction and cells expansion), epigenetic regulations, tumor environment, CD4/CD8 subsets, CAR T cells differentiation and exhaustion. Of note, among these influence factors, CAR T cells differentiation and exhaustion are identified as the central part due to the fact that almost all factors eventually alter the state of cells differentiation and exhaustion. Moreover, we review the potential coping strategies aiming at these limitations throughout this study.

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Early memory T cell subsets (naive, stem cell memory, and central memory T cells) are long-lived, possess high self-renewal ability, and exhibit long-term persistence and superior antitumor response in vivo.
“It is widely accepted that early memory T cell subsets (e.g., naive [TN], stem cell memory [TSCM] and central memory [TCM]T cells), which are long-lived and possess high self-renewal ability, exhibit long-term persistence and superior antitumor response in vivo.17,18,19”
From Point-of-care manufacturing of anti-CD19 CAR-T cells using a closed production platform: Experiences of an academic in Thailand (2024) · cites this paper as [18]
In “The stage of CAR T cells differentiation” (page not provided), the review says CAR T-cell products rich in naïve, stem cell memory, and central memory T cells have superior antitumor responses and long-term persistence in vivo. It does not state that all three subsets are long-lived and have high self-renewal ability, and its outcome statement concerns CAR T-cell products rich in those subsets rather than each subset individually. (LLM, conf=0.85)
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Glioblastoma-targeted CD4+ CAR T cells mediate superior antitumor activity
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Donor CD19 CAR T cells exert potent graft-versus-lymphoma activity with diminished graft-versus-host activity
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The Loss of TET2 Promotes CD8+ T Cell Memory Differentiation
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Co-stimulatory signaling determines tumor antigen sensitivity and persistence of CAR T cells targeting PSCA+ metastatic prostate cancer
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4-1BB enhancement of CAR T function requires NF-κB and TRAFs
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Low interleukin-2 concentration favors generation of early memory T cells over effector phenotypes during chimeric antigen receptor T-cell expansion
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Toll-like receptor 2 costimulation potentiates the antitumor efficacy of CAR T Cells
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Co-Expression of IL-7 Improves NKG2D-Based CAR T Cell Therapy on Prostate Cancer by Enhancing the Expansion and Inhibiting the Apoptosis and Exhaustion
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Decitabine-Mediated Epigenetic Reprograming Enhances Anti-leukemia Efficacy of CD123-Targeted Chimeric Antigen Receptor T-Cells
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Combination strategies to maximize the benefits of cancer immunotherapy
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Authors: Zhang, H., Zhao, P., & Huang, H.
Affiliations: Ruian People's Hospital (CN)
First Affiliated Hospital Zhejiang University (CN)
Corresponding author: Huang, He
ORCID: Zhang, Hao
Zhao, Pu
Huang, He
Venue: Experimental Hematology & Oncology
Publisher: Springer Science and Business Media LLC
Published: 2020-12
Volume: 9
Issue: 1
Pages: 34-34
ISSN: 2162-3619 (ISSN-L)
DOI: 10.1186/s40164-020-00190-2
PMC: PMC7709221
OpenAlex: W3108012933
Cited by: 93
References: 136
Citations by year: 2026: 2 · 2025: 11 · 2024: 17 · 2023: 22 · 2022: 27 · 2021: 14
FWCI: 1.72
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by
creativecommons.org/licenses/by/4.0/ (tdm)
creativecommons.org/licenses/by/4.0/ (vor, 1 d)
Locations: Experimental Hematology and Oncology (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders: National Natural Science Foundation of China (81730008)
Topics: Health Sciences › Medicine › Oncology › CAR-T cell therapy research
Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
Keywords: chimeric antigen receptor T cells, CD19, CAR T cell persistence, relapse, B-cell malignancies, CAR signaling, T cell receptor stimulation, T cell differentiation, T cell exhaustion, epigenetic regulation, tumor microenvironment, in vitro culture, gene transduction

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Engineering better chimeric antigen receptor T cells

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