Abstract
In recent years, chimeric antigen receptor (CAR) T-cell therapy has become popular in immunotherapy, particularly after its tremendous success in the treatment of lineage-restricted hematologic cancers. However, the application of CAR T-cell therapy for solid tumors has not reached its full potential because of the lack of specific tumor antigens and inhibitory factors in suppressive tumor microenvironment (TME) (e.g., programmed death ligand-1, myeloid-derived suppressor cells, and transforming growth factor-β). In this review, we include some limitations in CAR design, such as tumor heterogeneity, indefinite spatial distance between CAR T-cell and its target cell, and suppressive TME. We also summarize some new approaches to overcome these hurdles, including targeting neoantigens and/or multiple antigens at once and depleting some inhibitory factors.
Highlights
Chimeric antigen receptor (CAR) design is based on the signal transduction of T-cell activation [1]
T-cell receptor (TCR) binding to the major histocompatibility complex (MHC)–antigen peptide complex induces a cascade of intracellular events as follows: phosphorylated TCR recruits intracellular second messengers to provide the first signal, and costimulatory molecules (CD28, CD27, CD134, CD137, or ICOS) at the T-cell surface bind to their corresponding receptors (CD80, CD86, CD137L, or ICOSL) on antigen-presenting cells (APCs), which further provides the second signal [3]
This study demonstrated that MUC1–chimeric antigen receptor (CAR) T-cell exhibited no cytotoxicity against normal human primary cells [37]
Summary
Chimeric antigen receptor (CAR) design is based on the signal transduction of T-cell activation [1]. CARs comprise three domains: an extracellular single-chain antibody fragment (scFv), which serves as a target moiety that redirects T-cells to tumor cells by binding to tumor-associated antigens (TAAs); a transmembrane domain and an endodomain, which is often the signal transduction domain comprising a CD3ζ chain and costimulatory factors such as CD28 and 4-1BB (CD137) [5, 6]. They used a secondgeneration CAR with 4-1BB as a costimulatory molecule, and the binding domain was the scFv region of the high-affinity antibody (5E5) targeting truncated O-glycopeptide epitopes presented on tumor tissues.
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