Natural Killer Cells Therapy: From in Vitro Amplification to Engineering Modification
DOI:
https://doi.org/10.61173/j13x9317Keywords:
- Natural Killer Cells, Tumor Microenviron-ment, Cellular Immunotherapy, CAR-NK Engineering, Solid TumorsAbstract
In cancer treatment, traditional therapies are limited, and T-cell therapies are faced with challenges such as high costs and toxicity. As a mainstay of innate immunity, natural killer (NK) cells offer distinct advantages, including the ability to kill target cells without antigen sensitization, a low risk of graft-versus-host disease (GVHD), and the potential for "off-the-shelf" application. This review summarizes recent advancements in NK cell-based therapies, focusing on in vitro amplification strategies and genetic engineering modifications. Key findings include: cytokine and feeder layer co-culture systems have been shown to expand NK cells over 500-fold; CD19-targeted chimeric antigen receptor (CAR)-NK cells exhibit a 50%-70% response rate in B-cell lymphoma patients; CRISPR-mediated gene editing enhances cytotoxicity against solid tumors; nanoparticle-based delivery systems improve tumor infiltration of NK cells; and allogeneic NK cell therapy carries a near-zero GVHD risk. Notably, significant challenges persist, such as the immunosuppressive tumor microenvironment, poor in vivo persistence of NK cells, congenital functional defects, potential off-target effects of CAR-NK cells, and the lack of standardized production protocols. While NK cell therapy demonstrates substantial promise in cancer immunotherapy, overcoming these bottlenecks is essential for its broader clinical translation and application.
References
[1] Cliff E. R. S., Kelkar A. H., Russler-Germain D. A., Tessema F. A., Raymakers A. J. N., Feldman W. B., and Kesselheim A. S., “High cost of chimeric antigen receptor T-cells: Challenges and solutions,” Am. Soc. Clin. Oncol. Educ. Book, vol. 43, pp. e397912, Jun. 2023.
[2] Neelapu S. S., Tummala S., Kebriaei P., et al., “Chimeric antigen receptor T-cell therapy—assessment and management of toxicities,” Nat. Rev. Clin. Oncol., vol. 15, no. 1, pp. 47–62, Dean&Francis ISSN 2959-409X 2018.
[3] Chen T., Wang M., Chen Y., and Liu Y., “Current challenges and therapeutic advances of CAR-T cell therapy for solid tumors,” Cancer Cell Int., vol. 24, no. 1, p. 133, Apr. 2024.
[4] Vivier E., Tomasello E., Baratin M., Walzer T., and Ugolini S., “Functions of natural killer cells,” Nat. Immunol., vol. 9, no. 5, pp. 503–510, 2008.
[5] Shapiro R. M., and Young K. A., “Harnessing allogeneic NK cells: improving outcomes with tailored approaches,” J. Clin. Invest., vol. 132, no. 10, p. e160584, 2022.
[6] Myers J. A., and Miller J. S., “Exploring the NK cell platform for cancer immunotherapy,” Nat. Rev. Clin. Oncol., vol. 18, no. 2, pp. 85–100, Feb. 2021.
[7] Liu E., Marin D., Banerjee P., et al., “Use of CAR-transduced natural killer cells in CD19-positive lymphoid tumors,” N. Engl. J. Med., vol. 382, no. 6, pp. 545–553, 2020.
[8] Balsamo M., Manzini C., Pietra G., et al., “Tumor-associated macrophages and neutrophils in the tumor microenvironment,” Front. Immunol., vol. 4, p. 120, 2013.
[9] Zhang C., Oberoi P., Oelsner S., et al., “FcεRIγ-negative NK cells persist in vivo and enhance efficacy of anti-CD19 CAR-NK therapy,” J. Immunother. Cancer, vol. 9, no. 8, p. e002131, 2021.
[10] Terrén I., Orrantia A., Vitallé J., et al., “NK cells and solid tumors: therapeutic potential and persisting challenges,” Mol. Cancer, vol. 21, p. 72, 2022.
[11] Bird L., “Gift of life: APC to T cell telomere transfer,” Nat. Rev. Immunol., vol. 22, no. 11, p. 653, Nov. 2022.
[12] Diskin C., Ryan T. A. J., and O’Neill L. A. J., “Modification of proteins by metabolites in immunity,” Immunity, vol. 54, no. 1, pp. 19–31, Jan. 2021.
[13] Turkalj S., Jakobsen N. A., Groom A., et al., “GTAC enables parallel genotyping of multiple genomic loci with chromatin accessibility profiling in single cells,” Cell Stem Cell, vol. 30, no. 5, pp. 722–740.e11, May 2023.
[14] Hung K. L., Mischel P. S., and Chang H. Y., “Gene regulation on extrachromosomal DNA,” Nat. Struct. Mol. Biol., vol. 29, no. 8, pp. 736–744, Aug. 2022.
[15] Piersma S. J., Bangru S., Yoon J., et al., “NK cell expansion requires HuR and mediates control of solid tumors and long-term virus infection,” J. Exp. Med., vol. 220, no. 11, p. e20231154, Nov. 2023.
[16] Terauchi A., Yee P., Johnson-Venkatesh E. M., et al., “The projection-specific signals that establish functionally segregated dopaminergic synapses,” Cell, vol. 186, no. 18, pp. 3845–3861. e24, Aug. 2023.
[17] Wei J., and Ishizuka J. J., “Going viral: HBV-specific CD8+ tissue-resident memory T cells propagate anti-tumor immunity,” Immunity, vol. 54, no. 8, pp. 1630–1632, Aug. 2021.
[18] Alfaro K., Maza M., Cremer M., et al., “Removing global barriers to cervical cancer prevention and moving towards elimination,” Nat. Rev. Cancer, vol. 21, no. 10, pp. 607–608, Oct. 2021.
[19] Liao J., Guan H., Yu M., et al., “Pulmonary granulomatous inflammation after ceritinib treatment in advanced ALK- rearranged pulmonary adenocarcinoma,” Invest. New Drugs, vol. 40, no. 5, pp. 1141–1145, Oct. 2022.
[20] Gordeuk V. R., “Sickle cell vaso-occlusion: the clot thickens,” Blood, vol. 135, no. 20, pp. 1726–1727, May 2020.
[21] Bourdely P., Anselmi G., Vaivode K., et al., “Transcriptional and functional analysis of CD1c+ human dendritic cells identifies a CD163+ subset priming CD8+CD103+ T cells,” Immunity, vol. 53, no. 2, pp. 335–352.e8, Aug. 2020.
[22] John T. D., Maron G., Abraham A., et al., “Strategic infection prevention after genetically modified hematopoietic stem cell therapies: recommendations from the International Society for Cell & Gene Therapy Stem Cell Engineering Committee,” Cytotherapy, vol. 26, no. 7, pp. 660–671, Jul. 2024.
[23] Fan Y., Dan W., Wang Y., et al., “Itaconate transporter SLC13A3 confers immunotherapy resistance via alkylationmediated stabilization of PD-L1,” Cell Metab., vol. 37, no. 2, pp. 514–526.e5, Feb. 2025.
[24] Matsevich C., Gopalakrishnan P., Chang N., et al., “Gene augmentation therapy attenuates retinal degeneration in a knockout mouse model of Fam161a retinitis pigmentosa,” Mol. Ther., vol. 31, no. 10, pp. 2948–2961, Oct. 2023.
[25] Prieto L. I., Sturmlechner I., Graves S. I., et al., “Senescent alveolar macrophages promote early-stage lung tumorigenesis,” Cancer Cell, vol. 41, no. 7, pp. 1261–1275.e6, Jul. 2023.
[26] Haganes K. L., Silva C. P., Eyjólfsdóttir S. K., et al., “Timerestricted eating and exercise training improve HbA1c and body composition in women with overweight/obesity: A randomized controlled trial,” Cell Metab., vol. 34, no. 10, pp. 1457–1471.e4, Oct. 2022.
[27] Prieto L. I., Sturmlechner I., Graves S. I., et al., “Senescent alveolar macrophages promote early-stage lung tumorigenesis,” Cancer Cell, vol. 41, no. 7, pp. 1261–1275.e6, Jul. 2023.
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