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Advances in CAR-T-cell therapy in T-cell malignancies. ​

Literature Information ​

DOI10.1186/s13045-024-01568-z
PMID38915099
JournalJournal of hematology & oncology
Impact Factor40.4
JCR QuartileQ1
Publication Year2024
Times Cited8
KeywordsCAR-T-cell therapy, Challenges, Research advances, T-cell malignancies, Target antigens
Literature TypeJournal Article, Review, Research Support, Non-U.S. Gov't
ISSN1756-8722
Pages49
Issue17(1)
AuthorsRubing Zheng, Xiaojian Zhu, Yi Xiao

TL;DR ​

This review highlights the challenges and progress of chimeric antigen receptor T (CAR-T) cell therapy for aggressive T-cell malignancies, noting that while advances have been made in treating B-cell malignancies, T-cell therapies face issues like nonspecific targeting and contamination. It discusses strategies to overcome these obstacles and presents novel therapeutic approaches that could enhance CAR-T cell efficacy, emphasizing the importance of these developments for future research and clinical applications.

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CAR-T-cell therapy · Challenges · Research advances · T-cell malignancies · Target antigens

Abstract ​

Significant advances have been made in chimeric antigen receptor T (CAR-T)-cell therapy for the treatment of recurrent or refractory B-cell hematologic malignancies. However, CAR-T-cell therapy has not yet achieved comparable success in the management of aggressive T-cell malignancies. This article reviews the challenges of CAR-T-cell therapy in treating T-cell malignancies and summarizes the progress of preclinical and clinical studies in this area. We present an analysis of clinical trials of CAR-T-cell therapies for the treatment of T-cell malignancies grouped by target antigen classification. Moreover, this review focuses on the major challenges encountered by CAR-T-cell therapies, including the nonspecific killing due to T-cell target antigen sharing and contamination with cell products during preparation. This review discusses strategies to overcome these challenges, presenting novel therapeutic approaches that could enhance the efficacy and applicability of CAR-T-cell therapy in the treatment of T-cell malignancies. These ideas and strategies provide important information for future studies to promote the further development and application of CAR-T-cell therapy in this field.

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Primary Questions Addressed ​

  1. What specific challenges do CAR-T-cell therapies face when targeting T-cell malignancies compared to B-cell malignancies?
  2. How do the mechanisms of action of CAR-T-cell therapies differ between T-cell and B-cell hematologic malignancies?
  3. What novel therapeutic approaches are being explored to enhance the efficacy of CAR-T-cell therapy in T-cell malignancies?
  4. How does the classification of target antigens influence the outcomes of CAR-T-cell therapy in T-cell malignancies?
  5. What are the implications of nonspecific killing in CAR-T-cell therapies for T-cell malignancies on patient safety and treatment outcomes?

Key Findings ​

Background and Objectives ​

Chimeric antigen receptor T-cell (CAR-T) therapy has shown significant promise in treating recurrent or refractory B-cell hematologic malignancies. However, its effectiveness in aggressive T-cell malignancies remains limited. This review aims to analyze the challenges faced in CAR-T therapy for T-cell malignancies and summarize the progress in preclinical and clinical studies, providing insights for future research directions.

Main Methods/Materials/Experimental Design ​

The review categorizes clinical trials of CAR-T therapies targeting T-cell malignancies based on target antigen classification. It highlights the challenges of nonspecific killing due to target antigen sharing and contamination during preparation. Strategies to overcome these challenges include identifying specific antigens for T-cell malignancies and employing innovative therapeutic approaches.

Mermaid diagram

Key Results and Findings ​

  1. Target Antigens: The review identifies several potential targets for CAR-T therapy, including CD5, CD7, CD30, and TRBC. Each target exhibits varying levels of expression in T-cell malignancies and poses different challenges regarding specificity and safety.

  2. Challenges:

    • Nonspecific Killing: Due to the shared expression of antigens on both malignant and normal T cells, CAR-T cells can inadvertently attack healthy cells.
    • Fratricide: The phenomenon where CAR-T cells attack each other during expansion in vitro due to shared target antigens.
    • Product Contamination: The mixing of malignant T cells with CAR-T products during preparation can hinder therapeutic efficacy.

  3. Innovative Strategies:

    • Gene Editing: Techniques like CRISPR-Cas9 are being employed to downregulate target antigens on CAR-T cells to minimize fratricide.
    • Bispecific CAR Designs: These designs require the simultaneous recognition of multiple antigens, enhancing specificity and reducing off-target effects.

Main Conclusions/Significance/Innovation ​

CAR-T therapy for T-cell malignancies faces unique challenges compared to B-cell malignancies, primarily due to the lack of specific antigens and the risk of fratricide. However, ongoing research is identifying new targets and employing advanced techniques to enhance the safety and efficacy of CAR-T therapies. The development of novel strategies and technologies offers hope for improved treatment outcomes in patients with T-cell malignancies.

Research Limitations and Future Directions ​

  1. Limitations: The heterogeneity of T-cell malignancies complicates the identification of universal targets. Many studies are still in the preclinical phase, and clinical trials often involve small sample sizes, limiting the generalizability of findings.

  2. Future Directions:

    • Continued exploration of novel antigens specific to T-cell malignancies.
    • Further development of gene editing technologies to enhance CAR-T cell specificity and reduce the risk of adverse effects.
    • Larger clinical trials to validate the efficacy and safety of emerging CAR-T therapies in diverse patient populations.

Summary Table of Key Targets for CAR-T Therapy ​

Target AntigenPropertiesChallengesResearch Phase
CD5Expressed in T cells; potential for fratricideSelf-targeting, limited efficacyPreclinical and clinical studies
CD7Ubiquitous in T/NK cells; high expression in T-ALLSelf-attack by CAR-T cellsClinical trials ongoing
CD30Highly expressed in specific T-cell lymphomasOff-target effects on healthy cellsClinical studies
TRBCSpecific to T cells; distinguishes between TRBC1/TRBC2Fratricide risksPreclinical studies

This structured summary encapsulates the essential findings and insights from the review on CAR-T-cell therapy advancements in T-cell malignancies, emphasizing the challenges, strategies, and future research directions.

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Literatures Citing This Work ​

  1. Nanomaterial-based cancer immunotherapy: enhancing treatment strategies. - Mengxiang Tian;Xionglin Liu;Haiping Pei - Frontiers in chemistry (2024)
  2. Advances in CAR-T cell therapy for hematologic and solid malignancies: latest updates from 2024 ESMO Congress. - Huageng Huang;Le Yu;Huawei Weng;Wei Zhang;Zhao Wang;Lin Wang;He Huang - Journal of hematology & oncology (2024)
  3. Emerging Multifunctional Biomaterials for Addressing Drug Resistance in Cancer. - Mohamed El-Tanani;Syed Arman Rabbani;Rasha Babiker;Yahia El-Tanani;Shakta Mani Satyam;Thantrira Porntaveetus - Biology (2025)
  4. Human T-Lymphotropic Virus (HTLV): Epidemiology, Genetic, Pathogenesis, and Future Challenges. - Francesco Branda;Chiara Romano;Grazia Pavia;Viola Bilotta;Chiara Locci;Ilenia Azzena;Ilaria Deplano;Noemi Pascale;Maria Perra;Marta Giovanetti;Alessandra Ciccozzi;Andrea De Vito;Angela Quirino;Nadia Marascio;Giovanni Matera;Giordano Madeddu;Marco Casu;Daria Sanna;Giancarlo Ceccarelli;Massimo Ciccozzi;Fabio Scarpa - Viruses (2025)
  5. CAR-T cell therapy clinical trials: global progress, challenges, and future directions from ClinicalTrials.gov insights. - Li-Ya Cao;Yue Zhao;Yang Chen;Pan Ma;Jiang-Chuan Xie;Xin-Mei Pan;Xin Zhang;Yong-Chuan Chen;Qian Wang;Lin-Li Xie - Frontiers in immunology (2025)
  6. Harnessing delta-like ligand 3: bridging biomarker discovery to next-generation immunotherapies in refractory small cell lung cancer. - Kangkang Ji;Lin Guo;Dianbao Zuo;Mingqian Feng;Xin Chen;Zhenggang Zhao;Jing Tang;Guoping Chen - Frontiers in immunology (2025)
  7. T cells in cancer: mechanistic insights and therapeutic advances. - Jingjing Pu;Ting Liu;Yi Zhou;Mengping Chen;Xuehang Fu;Yike Wan;Junying Wang;Binzhen Chen;Amit Sharma;Veronika Lukacs-Kornek;Ingo G H Schmidt-Wolf;Jian Hou - Biomarker research (2025)
  8. CD7 CAR-T therapy: current developments, improvements, and dilemmas. - Linjuan Wang;Shaowei Qiu - Blood science (Baltimore, Md.) (2025)

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