Chimeric antigen receptor natural killer (CAR-NK) cell design and engineering for cancer therapy

Summary

Due to their efficient recognition and lysis of malignant cells, natural killer (NK) cells are considered as specialized immune cells that can be genetically modified to obtain capable effector cells for adoptive cellular treatment of cancer patients. Recent technological advancements, including improved cell expansion techniques, chimeric antigen receptors (CAR), CRISPR/Cas9 gene editing and enhanced viral transduction and electroporation, have endowed comprehensive generation and characterization of genetically modified NK cells. These promising developments assist scientists and physicians to design better applications of NK cells in clinical therapy.

Patients characteristics

Various diseases are targeted, with an anti-CD19 CAR (B cell malignancies) on NK cells initially being compared the same CAR on T cells. Furthermore, different tumor antigens, like HER2, Mucin-1, EpCAM or PMSA, are targeted on a variety of solid and hematological tumors.

Introduction

The use of CAR-NK cell therapies has emerged as a potential alternative to CAR-T cell therapies, due to their ability to overcome therapy-induced side effects. With over 500 CAR-T and 17 CAR-NK cell trials currently underway globally, CAR-immune cell therapies that use precise gene insertion or a dual targeting method with adapter CARs are being investigated. CD19-specific CAR-T cells have shown promise in treating B-cell malignancies, while CAR-NK cells offer an intrinsic tumor killing capacity in addition to their CAR-dependent killing mechanism, potentially impeding tumor immune escape mechanisms.

Introduction

Although in recent years, the first 2 papers showing evidence of clinical successes have been published, many of the investigations are still in early planning or recruiting into clinical trials. Most of these trials are company-driven, with the majority coming from China. In these trials, various diseases are targeted, with an anti-CD19 CAR (B cell malignancies) on NK cells initially being compared to the same CAR on T cells. Furthermore, different tumor antigens, like HER2, Mucin-1, EpCAM or PMSA, are targeted on a variety of solid and hematological tumors. In the clinical studies currently conducted, CAR-NK cells are derived from PBMC the NK-92 cell line or a newly generated uniform cell line NK101. In contrast, Rezvani and colleagues have used expanded umbilical cord NK cells, selected on a KIR mismatch between donor and recipient and promising results were reported. These promising developments assist scientists and physicians to design better applications of NK cells in clinical therapy.

Conclusion

Notably, redirecting NK cells using CARs holds important promise for cancer immunotherapy. Various preclinical and a limited number of clinical studies using CAR-NK cells show promising results: efficient elimination of target cells without side effects, such as cytokine release syndrome and neurotoxicity which are seen in CAR-T therapies. Overcoming the suppressive tumor microenvironment remains an important challenge on the design of CARs before CAR-NK cells, in combination with other therapies, will fulfill their promise.

Article Reference link: Here

Scientific article publishing date: 01/05/2021

Article Identifier: BSC22_424EN

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Chimeric antigen receptor natural killer (CAR-NK) cell design and engineering for cancer therapy

Summary

Patients characteristics

Introduction

Introduction

Conclusion

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