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Curated Papers > High-impact authoritative literature on "CAR-T therapy"

The Application of Nanobody in CAR-T Therapy. ​

Literature Information ​

DOI10.3390/biom11020238
PMID33567640
JournalBiomolecules
Impact Factor4.8
JCR QuartileQ1
Publication Year2021
Times Cited56
KeywordsBCMA, CAR-T, VHH, nanobody
Literature TypeJournal Article, Research Support, Non-U.S. Gov't, Review
ISSN2218-273X
Issue11(2)
AuthorsChaolemeng Bao, Quanli Gao, Lin-Lin Li, Lu Han, Bingxiang Zhang, Yijin Ding, Zongpei Song, Ruining Zhang, Jishuai Zhang, Xian-Hui Wu

TL;DR ​

This study highlights the effectiveness of nanobodies as antigen binding domains in chimeric antigen receptor (CAR) T therapy, demonstrating their ability to produce CAR-T and CAR-NK cells with significant anti-tumor effects across various cancer targets. The findings underscore the potential of nanobody-based CAR constructs to enhance CAR-T therapy's clinical efficacy, offering a promising avenue for tackling complex malignancies.

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BCMA · CAR-T · VHH · nanobody

Abstract ​

Chimeric antigen receptor (CAR) T therapy represents a form of immune cellular therapy with clinical efficacy and a specific target. A typical chimeric antigen receptor (CAR) construct consists of an antigen binding domain, a transmembrane domain, and a cytoplasmic domain. Nanobodies have been widely applied as the antigen binding domain of CAR-T due to their small size, optimal stability, high affinity, and manufacturing feasibility. The nanobody-based CAR structure has shown a proven function in more than ten different tumor-specific targets. After being transduced in Jurkat cells, natural killer cells, or primary T cells, the resulting nanobody-based CAR-T or CAR-NK cells demonstrate anti-tumor effects both in vitro and in vivo. Interestingly, anti-BCMA CAR-T modulated by a single nanobody or bi-valent nanobody displays comparable clinical effects with that of single-chain variable fragment (scFv)-modulated CAR-T. The application of nanobodies in CAR-T therapy has been well demonstrated from bench to bedside and displays great potential in forming advanced CAR-T for more challenging tasks.

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Primary Questions Addressed ​

  1. What are the specific advantages of using nanobodies over traditional scFv in CAR-T therapy?
  2. How do the anti-tumor effects of nanobody-based CAR-T cells compare to those of other CAR-T cell types in clinical settings?
  3. What challenges remain in the manufacturing and application of nanobody-based CAR-T therapies for different types of cancers?
  4. Can the use of bi-valent nanobodies in CAR-T therapy lead to improved efficacy in treating complex tumors, and if so, how?
  5. What are the potential side effects or limitations associated with the use of nanobody-modulated CAR-T therapies in patients?

Key Findings ​

Research Background and Purpose ​

Chimeric antigen receptor (CAR) T cell therapy is a prominent form of immunotherapy with proven efficacy against various hematological malignancies. However, its application in solid tumors remains limited due to challenges such as tumor microenvironment and T cell exhaustion. This review explores the application of nanobodies as antigen-binding domains in CAR-T therapy, highlighting their advantages over traditional single-chain variable fragments (scFv) in improving therapeutic outcomes.

Main Methods/Materials/Experimental Design ​

The review discusses various methodologies employed in developing nanobody-based CAR-T constructs. The primary steps include:

  1. Nanobody Selection: Identification of nanobodies against specific tumor antigens through immunization and phage display.
  2. CAR Construction: Incorporation of selected nanobodies into CAR constructs, which typically consist of:
    • Antigen binding domain (nanobody)
    • Transmembrane domain
    • Costimulatory and signaling domains (e.g., CD28, 4-1BB, CD3ζ)

The following flowchart summarizes the key processes involved in the development of nanobody-based CAR-T therapies:

Mermaid diagram

Key Results and Findings ​

  1. Efficacy: Nanobody-based CAR-T cells demonstrate comparable or superior anti-tumor effects to scFv-based CAR-T cells across multiple tumor targets, including BCMA, HER2, and PSMA.
  2. Advantages of Nanobodies:
    • Smaller size enhances tissue penetration and reduces immunogenicity.
    • Higher stability and solubility compared to scFv, leading to improved CAR expression and function.
    • Ability to reach epitopes that are inaccessible to conventional antibodies.

Main Conclusions/Significance/Innovation ​

The integration of nanobodies into CAR-T therapy represents a significant advancement in the field of immuno-oncology. Their unique properties enhance the efficacy and safety of CAR-T cells, making them a promising alternative to traditional scFv-based constructs. This innovation could lead to improved outcomes in both hematological and solid tumors, paving the way for broader applications of CAR-T therapies.

Research Limitations and Future Directions ​

While the review highlights the potential of nanobody-based CAR-T therapies, several limitations and future research directions are noted:

  • Clinical Validation: More clinical trials are needed to validate the safety and efficacy of nanobody-based CAR-T therapies in diverse patient populations.
  • Manufacturing Challenges: Streamlining the production process for nanobody-based CAR constructs to ensure consistent quality and scalability.
  • Mechanisms of Resistance: Further investigation into tumor microenvironment interactions and potential resistance mechanisms to enhance CAR-T efficacy in solid tumors.

In conclusion, the application of nanobodies in CAR-T therapy not only offers a novel approach to enhance therapeutic effectiveness but also addresses some of the existing challenges in the field, indicating a promising future for cancer immunotherapy.

References ​

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  3. A phase 1, open-label study of LCAR-B38M, a chimeric antigen receptor T cell therapy directed against B cell maturation antigen, in patients with relapsed or refractory multiple myeloma. - Wan-Hong Zhao;Jie Liu;Bai-Yan Wang;Yin-Xia Chen;Xing-Mei Cao;Yun Yang;Yi-Lin Zhang;Fang-Xia Wang;Peng-Yu Zhang;Bo Lei;Liu-Fang Gu;Jian-Li Wang;Nan Yang;Ru Zhang;Hui Zhang;Ying Shen;Ju Bai;Yan Xu;Xu-Geng Wang;Rui-Li Zhang;Li-Li Wei;Zong-Fang Li;Zhen-Zhen Li;Yan Geng;Qian He;Qiu-Chuan Zhuang;Xiao-Hu Fan;Ai-Li He;Wang-Gang Zhang - Journal of hematology & oncology (2018)
  4. CAR T Cells for Solid Tumors: New Strategies for Finding, Infiltrating, and Surviving in the Tumor Microenvironment. - Marina Martinez;Edmund Kyung Moon - Frontiers in immunology (2019)
  5. 4-1BB costimulation ameliorates T cell exhaustion induced by tonic signaling of chimeric antigen receptors. - Adrienne H Long;Waleed M Haso;Jack F Shern;Kelsey M Wanhainen;Meera Murgai;Maria Ingaramo;Jillian P Smith;Alec J Walker;M Eric Kohler;Vikas R Venkateshwara;Rosandra N Kaplan;George H Patterson;Terry J Fry;Rimas J Orentas;Crystal L Mackall - Nature medicine (2015)
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  7. Armored Inducible Expression of IL-12 Enhances Antitumor Activity of Glypican-3-Targeted Chimeric Antigen Receptor-Engineered T Cells in Hepatocellular Carcinoma. - Ying Liu;Shengmeng Di;Bizhi Shi;Honghong Zhang;Yi Wang;Xiuqi Wu;Hong Luo;Huamao Wang;Zonghai Li;Hua Jiang - Journal of immunology (Baltimore, Md. : 1950) (2019)
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Literatures Citing This Work ​

  1. Nanobody-armed T cells endow CAR-T cells with cytotoxicity against lymphoma cells. - Hongxia Wang;Liyan Wang;Yanning Li;Guangqi Li;Xiaochun Zhang;Dan Jiang;Yanting Zhang;Liyuan Liu;Yuankui Chu;Guangxian Xu - Cancer cell international (2021)
  2. Transportation of Single-Domain Antibodies through the Blood-Brain Barrier. - Eduardo Ruiz-López;Alberto J Schuhmacher - Biomolecules (2021)
  3. INDI-integrated nanobody database for immunoinformatics. - Piotr Deszyński;Jakub Młokosiewicz;Adam Volanakis;Igor Jaszczyszyn;Natalie Castellana;Stefano Bonissone;Rajkumar Ganesan;Konrad Krawczyk - Nucleic acids research (2022)
  4. A comprehensive comparison between camelid nanobodies and single chain variable fragments. - Yasaman Asaadi;Fatemeh Fazlollahi Jouneghani;Sara Janani;Fatemeh Rahbarizadeh - Biomarker research (2021)
  5. Engineered NK Cells Against Cancer and Their Potential Applications Beyond. - Maria Karvouni;Marcos Vidal-Manrique;Andreas Lundqvist;Evren Alici - Frontiers in immunology (2022)
  6. Development and comparison of three 89Zr-labeled anti-CLDN18.2 antibodies to noninvasively evaluate CLDN18.2 expression in gastric cancer: a preclinical study. - Guilan Hu;Wenjia Zhu;Yu Liu;Yuan Wang;Zheng Zhang;Shikun Zhu;Wenwen Duan;Peipei Zhou;Chao Fu;Fang Li;Li Huo - European journal of nuclear medicine and molecular imaging (2022)
  7. VHH Structural Modelling Approaches: A Critical Review. - Poonam Vishwakarma;Akhila Melarkode Vattekatte;Nicolas Shinada;Julien Diharce;Carla Martins;Frédéric Cadet;Fabrice Gardebien;Catherine Etchebest;Aravindan Arun Nadaradjane;Alexandre G de Brevern - International journal of molecular sciences (2022)
  8. Revolution of CAR Engineering For Next-Generation Immunotherapy In Solid Tumors. - Tao Yu;Shao-Kun Yu;Yan Xiang;Kai-Hua Lu;Ming Sun - Frontiers in immunology (2022)
  9. Therapeutic targets and biomarkers of tumor immunotherapy: response versus non-response. - Dong-Rui Wang;Xian-Lin Wu;Ying-Li Sun - Signal transduction and targeted therapy (2022)
  10. CAR-T cell potency: from structural elements to vector backbone components. - Marzieh Mazinani;Fatemeh Rahbarizadeh - Biomarker research (2022)

... (46 more literatures)

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