Single-Domain Antibody-Based TCR-Like CAR-T: A Potential Cancer Therapy.

Lichen Zhu,Xiaoqiong Hou,Xiaomei Yang,Huihui Zhou,Shihua Yin,Xiaoling Lu,Xinyue Zhao,Dani Zhong,Wei Shi,Ziqiang Ding,Shenxia Xie,Minlong Zhao,Aiqun Liu,Yangzi Li,Huayao Huayao,Fengzhen Mo

doi:10.1155/2020/2454907

Lichen Zhu, Xiaoqiong Hou + Show 14 more

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https://doi.org/10.1155/2020/2454907

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Abstract

Retargeting the antigen-binding specificity of T cells to intracellular antigens that are degraded and presented on the tumor surface by engineering chimeric antigen receptor (CAR), also named TCR-like antibody CAR-T, remains limited. With the exception of the commercialized CD19 CAR-T for hematological malignancies and other CAR-T therapies aiming mostly at extracellular antigens achieving great success, the rareness and scarcity of TCR-like CAR-T therapies might be due to their current status and limitations. This review provides the probable optimized initiatives for improving TCR-like CAR-T reprogramming and discusses single-domain antibodies administered as an alternative to conventional scFvs and secreted by CAR-T cells, which might be of great value to the development of CAR-T immunotherapies for intracellular antigens.

Highlights

Cancer diseases, setting up barriers to human longevity worldwide, are estimated to be the top cause of death, based on the most recent GLOBOCAN data [1]
Though HLA-A2 is the dominant allele in patients and, together with other HLA alleles, makes up the majority of the worldwide patients’ MHC alleles, the specific peptides of tumor antigens that are relevant to the MHC alleles themselves remain insufficient [10, 29, 30]
It has been reported that the T cell receptor- (TCR-)like nanobody GPA7, recognizing gp100 209–217/HLA-A2, was engineered into GPA7-28z chimeric antigen receptor (CAR) and mediated the effective cytotoxicity against human melanoma cells together with HLAA2 following GPA7-28z CAR transduction into T cells [69]

Summary

Introduction

Cancer diseases, setting up barriers to human longevity worldwide, are estimated to be the top cause of death, based on the most recent GLOBOCAN data [1]. Journal of Immunology Research the market are almost all directed towards extracellular antigens, not intracellular ones To target these antigens, a specific group of antibodies called T cell receptor- (TCR-) like/mimic antibodies has been developed in the preclinical process. To improve the TCR-like antibodies with therapeutic potential, the TCR-like antibodies associated with CAR-T therapy were initially developed in 2001 They functioned to recognize the MHC/peptide complexes and subsequently triggered T cell activation and proliferation under the potent costimulation signals [18, 19]. There is much potential to be explored In this perspective article, we elaborate on the current status and limitations of the small number of TCR-like CAR-T therapies for intracellular antigens and imagine the alternative improvements in CAR-T engineering, with special emphasis on the single-domain antibodies (nanobodies), and provide discussion of possible initiatives in the future

Current Situations and Limitations with

Probable Optimized Initiatives in Improving TCR-Like CAR-T Engineering

Findings

Conclusion