Abstract
The clinical success stories of chimeric antigen receptor (CAR)-T cell therapy against B-cell malignancies have contributed to immunotherapy being at the forefront of cancer therapy today. Their success has fueled interest in improving CAR constructs, identifying additional antigens to target, and clinically evaluating them across a wide range of malignancies. However, along with the exciting potential of CAR-T therapy comes the real possibility of serious side effects. While the FDA has approved commercialized CAR-T cell therapy, challenges associated with manufacturing, costs, and related toxicities have resulted in increased attention being paid to implementing CAR technology in innate cytotoxic natural killer (NK) cells. Here, we review the current landscape of the CAR-NK field, from successful clinical implementation to outstanding challenges which remain to be addressed to deliver the full potential of this therapy to more patients.
Highlights
Background of Chimeric Antigen ReceptorsIn 1986, Steven Rosenberg harnessed the potential of tumor-specific T cells to treat melanoma patients, starting a new chapter of cell-based therapy for cancer patients [1]
While CD8α and CD28 are most commonly used to date, the choice of transmembrane domain (TM) domain has been shown to affect the functionality of the chimeric antigen receptor (CAR) construct mediated through the degree of cell activation
The evolution of the CAR construct has primarily focused on optimizing the intracellular signaling domains, with the first three generations of CAR constructs referring to the number of activating and co-stimulatory molecules making up the endodomain
Summary
In 1986, Steven Rosenberg harnessed the potential of tumor-specific T cells to treat melanoma patients, starting a new chapter of cell-based therapy for cancer patients [1]. An alternative to TIL-based therapy is to genetically engineer the T cell receptor (TCR) to confer specificity to a particular tumor target, aptly named a chimeric antigen receptor (CAR). The of the fragments, variable fragments, wellof asthe the linker, length have of thebeen linker, have to been shown to affectbinding the antigen binding stability of length shown affect the antigen affinity and affinity stabilityand of the construct Both the epitope location and abundancy need to be considered when designing the scFv [8]. Amino acid sequences from CD28 or CD8α are commonly used, as well as CH2 and CH3 domains from IgG1, 2, or 4 While both CH2 and CH3 domains can be utilized to detect CAR expression on the cell’s surface, binding between CH2 domains and Fcγ receptors has been observed and can lead to off-target activation [8,11]
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