CDTM uses natural killer cells to develop next-generation cellular immunotherapies

Cellular immunotherapy harnesses the body's own immune system to fight cancer
by engineering T cells, macrophages, or natural killer (NK) cells.
Compared with chimeric antigen receptor T (CAR-T) cells, which are commonly used to treat hematologic malignancies, chimeric antigen receptor NK (CAR-NK) cells exhibit significant therapeutic efficacy while demonstrating enhanced safety, reduced risk of graft-versus-host disease, fewer side effects, and enhanced anti-tumor efficacy
.
Yubin Zhou's team from the Department of Translational Medicine at Texas A&M University School of Medicine introduced the design principles of CAR-NK cells, highlighted the latest advances in preclinical trials and clinical trials of CAR-NK cells, briefly explored the main barriers to CAR-NK treatment, and discussed potential solutions
to overcome these challenges.

For decades, cancer treatment has focused on
surgery, radiation and chemotherapy.
However, in the past 5 years, cellular immunotherapy has increasingly become the fourth pillar
of cancer treatment.
The most prominent example is chimeric antigen receptor T (CAR-T) cell therapy, which utilizes the body's immune system to specifically participate in and eliminate cancer cells, but their widespread use is limited by some non-negligible side effects or inherent defects, and CAR-NK cells are able to overcome these obstacles because they have an advantage over CAR-T cells and fewer
side effects in killing malignant cells after transplantation.
Therefore, CAR-NK cells can be used as an alternative treatment option
.
Over the past 10 years, CAR-NK cell-centric research has steadily increased (Figure 1).

Figure 1: (A) Number of
articles related to CAR-NK cells from 2012 to 2021.
(B) Number
of CAR-NK clinical trials registered for the specified cancer type.

Autologous CAR-NK cell transfusion is the safest method of adoptive cell therapy because it relies on the patient's own blood as a cell source and does not require immunosuppressive pretreatment
of the patient.
However, the reduced risk of variant reactivity inherent in NK cells allows CAR-NK cells to be generated from a variety of allogeneic sources (Figure 2), including PBMCs, hematopoietic progenitor cells (HPCs), cord blood (UCB), NK-92 cell lines, and induced pluripotent stem cells (iPSCs).

This flexibility allows CAR-NK cell generation to be produced without the individualized, patient-specific production
typically required for CAR-T cell therapy.
Therefore, CAR-NK cells are expected to be produced in "off-the-shelf" products that significantly reduce costs for on-demand and universal use
in cancer patients.

Figure 2 Schematic diagram of the source and manufacturing process of CAR-NK cells

With the great clinical success of CAR-T therapy, CAR-NK cell-based therapies have been increasingly tested and optimized
in various mouse tumor models and clinical trials.
Due to limited progress in clinical trials, the biosafety and efficacy of CAR-NK cells in humans have not been rigorously tested
in a clinical setting.
The researchers present representative preclinical results
using different CAR-NK cell sources in hematologic malignancies and solid tumors.
Despite encouraging progress, the barriers that exist must be addressed to accelerate the clinical translation
of NK cell-based therapies.
Recent research has focused on reprogramming and modifying NK cells to maximize expansion and increase persistence, facilitate their transport or penetration, and combat the immunosuppressed tumor microenvironment
.

Figure 3 Summary of CAR-NK clinical trial (partial)

In summary, compared with T cells, NK cells are important innate immune cells in the human body, which can kill tumor cells without pre-sensitization, and CAR-NK is expected to become one of the most anticipated engineered cell therapies after the success of CAR-T cell therapy.

Overall, as a relatively new supplement to cellular immunotherapy, CAR-NK is expected to become a first-line strategy for cancer treatment and has high translational value in the clinic, which can directly benefit cancer patients
.

References

Liu, S, Nguyen, K, Park, D, Wong, N, Wang, A, Zhou, Y.
Harnessing natural killer cells todevelop next-generation cellular immunotherapy.
Chronic Dis Transl Med.
2022; 8: 245- 255.
doi:10.
1002/cdt3.
40

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Journal introduction

Chronic diseases have become a major challenge
to human health worldwide.
Chronic Diseases and Translational Medicine aims to provide an international perspective communication platform for clinicians and basic researchers in mature and emerging disciplines related to chronic diseases, so as to promote the prevention, diagnosis and treatment
of chronic diseases.
At present, the journal has been indexed
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The CiteScore 2021 score is 3.
6, and the Medicine-General Medicine classification Q1 area (163/826).

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Content | Chen Jingwen

Proofreading | CDTM Editorial Office

Typesetting | Zhou Kaiyao