Efficacy and safety of autologous NK cells for the treatment of malignant tumors: a systematic review_Chinese Journal of Evidence-Based Medicine

Authors：

HUANG Guoxin ^1,2 , CAO Qilong ³ , LIANG Shaoshuai ³ , ZHANG Dongdong ⁴ , QU Gaojing ^1,2 ,  PEI Bin ^1,2

1. Department of Evidence-Based Medicine Center, Xiangyang No.1 People’s Hospital, Hubei University of Medicine, Xiangyang 441000, P. R. China;
2. Department of Cell Therapy Centre, Xiangyang No.1 People’s Hospital, Hubei University of Medicine, Xiangyang 441000, P. R. China;
3. Qingdao Haier Biotechnology Co., Ltd., Qingdao 266000, P. R. China;
4. Department of Tumor, Xiangyang No.1 People’s Hospital, Hubei University of Medicine, Xiangyang 441000, P. R. China;

Corresponding author：

PEI Bin, Email: xyxzyxzx@163.com

Keywords：

Autologous natural killer cells; Malignant tumors; Systematic review

DOI：

10.7507/1672-2531.202312158

Video：

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Objective To systematically evaluate the efficacy and safety of autologous natural killer cells (NK) cells for the treatment of malignant tumors. Methods The PubMed, Web of Science, and Embase databases were electronically searched to collect clinical studies on autologous NK cells for the treatment of malignant tumors from inception to July 1, 2023. Two reviewers independently screened literature, extracted data and assessed the risk of bias of the included studies. Descriptive analysis of the results were conducted. Results A total of 15 studies were included. The most common tumor type was non-small cell lung cancer. The dose of NK cell injections usually ranged from 7.0×10⁷ to 7.0×10⁹ cell counts, with a treatment interval of 14-21 days and a frequency of 3-6 injections. The overall response rate for NK cell therapy was 0% to 77.78%. The main adverse effects were fever (3.98%), fatigue (1.99%), rash (0.4%), and dizziness (1.20%). Conclusion Current evidence shows that autologous NK cell therapy is safe for malignant tumors, and some studies have shown that NK cell therapy has a relieving effect. However, due to limitations in the number and quality of studies included, the above conclusions come from a qualitative synthesis of individual studies and need to be validated by more high-quality studies.

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2.	Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 2021, 71(3): 209-249.
3.	Roy PS, Saikia BJ. Cancer and cure: a critical analysis. Indian J Cancer, 2016, 53(3): 441-442.
4.	Wang JJ, Lei KF, Han F. Tumor microenvironment: recent advances in various cancer treatments. Eur Rev Med Pharmacol Sci, 2018, 22(12): 3855-3864.
5.	Ribas A, Butterfield LH, Glaspy JA, et al. Current developments in cancer vaccines and cellular immunotherapy. J Clin Oncol, 2003, 21(12): 2415-2432.
6.	Wang S, Wang X, Zhou X, et al. DC-CIK as a widely applicable cancer immunotherapy. Expert Opin Biol Ther, 2020, 20(6): 601-607.
7.	Becker PS, Suck G, Nowakowska P, et al. Selection and expansion of natural killer cells for NK cell-based immunotherapy. Cancer Immunol Immunother, 2016, 65(4): 477-484.
8.	Liu S, Galat V, Galat Y, et al. NK cell-based cancer immunotherapy: from basic biology to clinical development. J Hematol Oncol, 2021, 14(1): 7.
9.	Rosenberg SA, Lotze MT, Muul LM, et al. Observations on the systemic administration of autologous lymphokine-activated killer cells and recombinant interleukin-2 to patients with metastatic cancer. N Engl J Med, 1985, 313(23): 1485-1492.
10.	刘洪秀, 韩艳秋. CAR-NK细胞治疗血液肿瘤的研究进展. 临床血液学杂志, 2023, 36(1): 76-80.
11.	史聪丽, 沈涯, 徐志国, 等. NK细胞抗肿瘤机制及肿瘤免疫治疗的研究进展. 右江医学, 2023, 51(4): 366-369.
12.	李翠翠, 陈梦梦, 邹伟, 等. 基于NK细胞的免疫疗法在癌症治疗中的应用及其研究进展. 生物学通报, 2021, 56(12): 1-4.
13.	Bae WK, Lee BC, Kim HJ, et al. A phase Ⅰ study of locoregional high-dose autologous natural killer cell therapy with hepatic arterial infusion chemotherapy in patients with locally advanced hepatocellular carcinoma. Front Immunol, 2022, 13: 879452.
14.	Yang YJ, Park JC, Kim HK, et al. A trial of autologous ex vivo-expanded NK cell-enriched lymphocytes with docetaxel in patients with advanced non-small cell lung cancer as second- or third-line treatment: phase Ⅱa study. Anticancer Res, 2013, 33(5): 2115-2122.
15.	Li L, Li W, Wang C, et al. Adoptive transfer of natural killer cells in combination with chemotherapy improves outcomes of patients with locally advanced colon carcinoma. Cytotherapy, 2018, 20(1): 134-148.
16.	Ishikawa E, Tsuboi K, Saijo K, et al. Autologous natural killer cell therapy for human recurrent malignant glioma. Anticancer Res, 2004, 24(3b): 1861-1871.
17.	Hong G, Chen X, Sun X, et al. Effect of autologous NK cell immunotherapy on advanced lung adenocarcinoma with EGFR mutations. Precis Clin Med, 2019, 2(4): 235-245.
18.	Nagai K, Harada Y, Harada H, et al. Highly activated ex vivo-expanded natural killer cells in patients with solid tumors in a phase Ⅰ/Ⅱa clinical study. Anticancer Res, 2020, 40(10): 5687-5700.
19.	Leivas A, Perez-Martinez A, Blanchard MJ, et al. Novel treatment strategy with autologous activated and expanded natural killer cells plus anti-myeloma drugs for multiple myeloma. Oncoimmunology, 2016, 5(12): e1250051.
20.	Sakamoto N, Ishikawa T, Kokura S, et al. Phase Ⅰ clinical trial of autologous NK cell therapy using novel expansion method in patients with advanced digestive cancer. J Transl Med, 2015, 13: 277.
21.	Tanaka J, Tanaka N, Wang YH, et al. Phase Ⅰ study of cellular therapy using ex vivo expanded natural killer cells from autologous peripheral blood mononuclear cells combined with rituximab-containing chemotherapy for relapsed CD20-positive malignant lymphoma patients. Haematologica, 2020, 105(4): e190-e193.
22.	Lim CM, Liou A, Poon M, et al. Phase Ⅰ study of expanded natural killer cells in combination with cetuximab for recurrent/metastatic nasopharyngeal carcinoma. Cancer Immunol Immunother, 2022, 71(9): 2277-2286.
23.	Lee SC, Shimasaki N, Lim JSJ, et al. Phase I trial of expanded, activated autologous NK-cell infusions with trastuzumab in patients with HER2-positive cancers. Clin Cancer Res, 2020, 26(17): 4494-4502.
24.	Jia L, Chen N, Chen X, et al. Sintilimab plus autologous NK cells as second-line treatment for advanced non-small-cell lung cancer previous treated with platinum-containing chemotherapy. Front Immunol, 2022, 13: 1074906.
25.	Multhoff G, Seier S, Stangl S, et al. Targeted natural killer cell-based adoptive immunotherapy for the treatment of patients with NSCLC after radiochemotherapy: a randomized phase Ⅱ clinical trial. Clin Cancer Res, 2020, 26(20): 5368-5379.
26.	Park HJ, Kim YM, Jung JS, et al. Two-year efficacy of SNK01 plus pembrolizumab for non-small cell lung cancer: expanded observations from a phase Ⅰ/Ⅱa randomized controlled trial. Thorac Cancer, 2022, 13(14): 2050-2056.
27.	Xie S, Wu Z, Niu L, et al. Preparation of highly activated natural killer cells for advanced lung cancer therapy. Onco Targets Ther, 2019, 12: 5077-5086.
28.	Goldstraw P, Chansky K, Crowley J, et al. The IASLC lung cancer staging project: proposals for revision of the TNM stage groupings in the forthcoming (eighth) edition of the TNM classification for lung cancer. J Thorac Oncol, 2016, 11(1): 39-51.
29.	Wang X, Romero-Gutierrez CW, Kothari J, et al. Prediagnosis smoking cessation and overall survival among patients with non-small cell lung cancer. JAMA Netw Open, 2023, 6(5): e2311966.
30.	张虹, 高晨燕, 陈晓媛, 等. 关于采用单臂临床试验数据用于支持进口药品注册的考虑. 中国新药杂志, 2013, 22(18): 2126-2129.
31.	李戈, 孙凤. 设置外对照的单臂试验研究现状及其偏倚风险评估案例分析. 中国药物评价, 2022, 39(5): 363-369.

1. Hausman DM. What is cancer. Perspect Biol Med, 2019, 62(4): 778-784.
2. Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 2021, 71(3): 209-249.
3. Roy PS, Saikia BJ. Cancer and cure: a critical analysis. Indian J Cancer, 2016, 53(3): 441-442.
4. Wang JJ, Lei KF, Han F. Tumor microenvironment: recent advances in various cancer treatments. Eur Rev Med Pharmacol Sci, 2018, 22(12): 3855-3864.
5. Ribas A, Butterfield LH, Glaspy JA, et al. Current developments in cancer vaccines and cellular immunotherapy. J Clin Oncol, 2003, 21(12): 2415-2432.
6. Wang S, Wang X, Zhou X, et al. DC-CIK as a widely applicable cancer immunotherapy. Expert Opin Biol Ther, 2020, 20(6): 601-607.
7. Becker PS, Suck G, Nowakowska P, et al. Selection and expansion of natural killer cells for NK cell-based immunotherapy. Cancer Immunol Immunother, 2016, 65(4): 477-484.
8. Liu S, Galat V, Galat Y, et al. NK cell-based cancer immunotherapy: from basic biology to clinical development. J Hematol Oncol, 2021, 14(1): 7.
9. Rosenberg SA, Lotze MT, Muul LM, et al. Observations on the systemic administration of autologous lymphokine-activated killer cells and recombinant interleukin-2 to patients with metastatic cancer. N Engl J Med, 1985, 313(23): 1485-1492.
10. 刘洪秀, 韩艳秋. CAR-NK细胞治疗血液肿瘤的研究进展. 临床血液学杂志, 2023, 36(1): 76-80.
11. 史聪丽, 沈涯, 徐志国, 等. NK细胞抗肿瘤机制及肿瘤免疫治疗的研究进展. 右江医学, 2023, 51(4): 366-369.
12. 李翠翠, 陈梦梦, 邹伟, 等. 基于NK细胞的免疫疗法在癌症治疗中的应用及其研究进展. 生物学通报, 2021, 56(12): 1-4.
13. Bae WK, Lee BC, Kim HJ, et al. A phase Ⅰ study of locoregional high-dose autologous natural killer cell therapy with hepatic arterial infusion chemotherapy in patients with locally advanced hepatocellular carcinoma. Front Immunol, 2022, 13: 879452.
14. Yang YJ, Park JC, Kim HK, et al. A trial of autologous ex vivo-expanded NK cell-enriched lymphocytes with docetaxel in patients with advanced non-small cell lung cancer as second- or third-line treatment: phase Ⅱa study. Anticancer Res, 2013, 33(5): 2115-2122.
15. Li L, Li W, Wang C, et al. Adoptive transfer of natural killer cells in combination with chemotherapy improves outcomes of patients with locally advanced colon carcinoma. Cytotherapy, 2018, 20(1): 134-148.
16. Ishikawa E, Tsuboi K, Saijo K, et al. Autologous natural killer cell therapy for human recurrent malignant glioma. Anticancer Res, 2004, 24(3b): 1861-1871.
17. Hong G, Chen X, Sun X, et al. Effect of autologous NK cell immunotherapy on advanced lung adenocarcinoma with EGFR mutations. Precis Clin Med, 2019, 2(4): 235-245.
18. Nagai K, Harada Y, Harada H, et al. Highly activated ex vivo-expanded natural killer cells in patients with solid tumors in a phase Ⅰ/Ⅱa clinical study. Anticancer Res, 2020, 40(10): 5687-5700.
19. Leivas A, Perez-Martinez A, Blanchard MJ, et al. Novel treatment strategy with autologous activated and expanded natural killer cells plus anti-myeloma drugs for multiple myeloma. Oncoimmunology, 2016, 5(12): e1250051.
20. Sakamoto N, Ishikawa T, Kokura S, et al. Phase Ⅰ clinical trial of autologous NK cell therapy using novel expansion method in patients with advanced digestive cancer. J Transl Med, 2015, 13: 277.
21. Tanaka J, Tanaka N, Wang YH, et al. Phase Ⅰ study of cellular therapy using ex vivo expanded natural killer cells from autologous peripheral blood mononuclear cells combined with rituximab-containing chemotherapy for relapsed CD20-positive malignant lymphoma patients. Haematologica, 2020, 105(4): e190-e193.
22. Lim CM, Liou A, Poon M, et al. Phase Ⅰ study of expanded natural killer cells in combination with cetuximab for recurrent/metastatic nasopharyngeal carcinoma. Cancer Immunol Immunother, 2022, 71(9): 2277-2286.
23. Lee SC, Shimasaki N, Lim JSJ, et al. Phase I trial of expanded, activated autologous NK-cell infusions with trastuzumab in patients with HER2-positive cancers. Clin Cancer Res, 2020, 26(17): 4494-4502.
24. Jia L, Chen N, Chen X, et al. Sintilimab plus autologous NK cells as second-line treatment for advanced non-small-cell lung cancer previous treated with platinum-containing chemotherapy. Front Immunol, 2022, 13: 1074906.
25. Multhoff G, Seier S, Stangl S, et al. Targeted natural killer cell-based adoptive immunotherapy for the treatment of patients with NSCLC after radiochemotherapy: a randomized phase Ⅱ clinical trial. Clin Cancer Res, 2020, 26(20): 5368-5379.
26. Park HJ, Kim YM, Jung JS, et al. Two-year efficacy of SNK01 plus pembrolizumab for non-small cell lung cancer: expanded observations from a phase Ⅰ/Ⅱa randomized controlled trial. Thorac Cancer, 2022, 13(14): 2050-2056.
27. Xie S, Wu Z, Niu L, et al. Preparation of highly activated natural killer cells for advanced lung cancer therapy. Onco Targets Ther, 2019, 12: 5077-5086.
28. Goldstraw P, Chansky K, Crowley J, et al. The IASLC lung cancer staging project: proposals for revision of the TNM stage groupings in the forthcoming (eighth) edition of the TNM classification for lung cancer. J Thorac Oncol, 2016, 11(1): 39-51.
29. Wang X, Romero-Gutierrez CW, Kothari J, et al. Prediagnosis smoking cessation and overall survival among patients with non-small cell lung cancer. JAMA Netw Open, 2023, 6(5): e2311966.
30. 张虹, 高晨燕, 陈晓媛, 等. 关于采用单臂临床试验数据用于支持进口药品注册的考虑. 中国新药杂志, 2013, 22(18): 2126-2129.
31. 李戈, 孙凤. 设置外对照的单臂试验研究现状及其偏倚风险评估案例分析. 中国药物评价, 2022, 39(5): 363-369.

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