Abstract: With the rapid development of immunology, molecular biology, and associated technologies such as next-generation sequencing, cellular immunotherapy has recently become the fourth major cancer treatment. Immunotherapies based on T cells, natural killer cells, and dendritic cells play key roles in cancer immunotherapy. However, their application in clinical practice raises several ethical issues. Thus, studies should focus on proper adherence to basic ethical principles that can effectively guide and solve related clinical problems in the course of treatment, improve treatment effects, and protect the rights and interests of patients. In this review, we discuss cellular immunotherapy-related ethical issues and highlight the ethical practices and current status of cellular immunotherapy in China. These considerations may supplement existing ethical standards in cancer immunotherapy.

肿瘤细胞免疫治疗相关伦理学探讨

[1]Adachi K, Kano Y, Nagai T, et al., 2018. IL-7 and CCL19 expression in CAR-T cells improves immune cell infiltration and CAR-T cell survival in the tumor. Nat Biotechnol, 36(4):346-351.

[2]Anderson AC, Joller N, Kuchroo VK, 2016. Lag-3, Tim-3, and TIGIT: co-inhibitory receptors with specialized functions in immune regulation. Immunity, 44(5):989-1004.

[3]Anguille S, Smits EL, Lion E, et al., 2014. Clinical use of dendritic cells for cancer therapy. Lancet Oncol, 15(7):e257-e267.

[4]Benson DM Jr, Bakan CE, Mishra A, et al., 2010. The PD-1/PD-L1 axis modulates the natural killer cell versus multiple myeloma effect: a therapeutic target for CT-011, a novel monoclonal anti-PD-1 antibody. Blood, 116(13):2286-2294.

[5]Cheng M, Chen YY, Xiao WH, et al., 2013. NK cell-based immunotherapy for malignant diseases. Cell Mol Immunol, 10(3):230-252.

[6]Childs RW, Carlsten M, 2015. Therapeutic approaches to enhance natural killer cell cytotoxicity against cancer: the force awakens. Nat Rev Drug Discov, 14(7):487-498.

[7]Couzin-Frankel J, 2013. Cancer immunotherapy. Science, 342(6165):1432-1433.

[8]Fukuda K, Funakoshi T, Sakurai T, et al., 2017. Peptide-pulsed dendritic cell vaccine in combination with carboplatin and paclitaxel chemotherapy for stage IV melanoma. Melanoma Res, 27(4):326-334.

[9]Glienke W, Esser R, Priesner C, et al., 2015. Advantages and applications of CAR-expressing natural killer cells. Front Pharmacol, 6:21.

[10]Gross G, Waks T, Eshhar Z, 1989. Expression of immunoglobulin-T-cell receptor chimeric molecules as functional receptors with antibody-type specificity. Proc Natl Acad Sci USA, 86(24):10024-10028.

[11]Gubin MM, Artyomov MN, Mardis ER, et al., 2015. Tumor neoantigens: building a framework for personalized cancer immunotherapy. J Clin Invest, 125(9):3413-3421.

[12]Hansen M, Hjortø GM, Donia M, et al., 2013. Comparison of clinical grade type 1 polarized and standard matured dendritic cells for cancer immunotherapy. Vaccine, 31(4):639-646.

[13]Helmby H, 2009. Gastrointestinal nematode infection exacerbates malaria-induced liver pathology. J Immunol, 182(9):5663-5671.

[14]Hermanson DL, Kaufman DS, 2015. Utilizing chimeric antigen receptors to direct natural killer cell activity. Front Immunol, 6:195.

[15]Hsu FJ, Benike C, Fagnoni F, et al., 1996. Vaccination of patients with B-cell lymphoma using autologous antigen-pulsed dendritic cells. Nat Med, 2(1):52-58.

[16]Jackson HJ, Rafiq S, Brentjens RJ, 2016. Driving CAR T-cells forward. Nat Rev Clin Oncol, 13(6):370-383.

[17]Kochenderfer JN, Dudley ME, Kassim SH, et al., 2015. Chemotherapy-refractory diffuse large B-cell lymphoma and indolent B-cell malignancies can be effectively treated with autologous T cells expressing an anti-CD19 chimeric antigen receptor. J Clin Oncol, 33(6):540-549.

[18]Mao QX, Li LF, Zhang CJ, et al., 2015. Clinical effects of immunotherapy of DC-CIK combined with chemotherapy in treating patients with metastatic breast cancer. Pak J Pharm Sci, 28(S3):1055-1058.

[19]Maude SL, Frey N, Shaw PA, et al., 2014. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med, 371(16):1507-1517.

[20]Miller JS, Soignier Y, Panoskaltsis-Mortari A, et al., 2005. Successful adoptive transfer and in vivo expansion of human haploidentical NK cells in patients with cancer. Blood, 105(8):3051-3057.

[21]Morgan RA, Dudley ME, Wunderlich JR, et al., 2006. Cancer regression in patients after transfer of genetically engineered lymphocytes. Science, 314(5796):126-129.

[22]Muul LM, Spiess PJ, Director EP, et al., 1987. Identification of specific cytolytic immune responses against autologous tumor in humans bearing malignant melanoma. J Immunol, 138(3):989-995.

[23]Robinson MW, Harmon C, O'Farrelly C, 2016. Liver immunology and its role in inflammation and homeostasis. Cell Mol Immunol, 13(3):267-276.

[24]Rosenberg SA, Packard BS, Aebersold PM, et al., 1988. Use of tumor-infiltrating lymphocytes and interleukin-2 in the immunotherapy of patients with metastatic melanoma. N Engl J Med, 319(25):1676-1680.

[25]Ruggeri L, Capanni M, Urbani E, et al., 2002. Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Science, 295(5562):2097-2100.

[26]Ruggeri L, Urbani E, André P, et al., 2016. Effects of anti-NKG2A antibody administration on leukemia and normal hematopoietic cells. Haematologica, 101(5):626-633.

[27]Shimodaira S, Sano K, Hirabayashi K, et al., 2015. Dendritic cell-based adjuvant vaccination targeting Wilms’ tumor 1 in patients with advanced colorectal Cancer. Vaccines (Basel), 3(4):1004-1018.

[28]Sims RB, 2012. Development of sipuleucel-T: autologous cellular immunotherapy for the treatment of metastatic castrate resistant prostate cancer. Vaccine, 30(29):4394-4397.

[29]Strønen E, Toebes M, Kelderman S, et al., 2016. Targeting of cancer neoantigens with donor-derived T cell receptor repertoires. Science, 352(6291):1337-1341.

[30]Su J, Han YH, 2016. Ethical reflection on “Wei Zexi incident”. J Kunming Univ Sci Technol, 16(4):17-21 (in Chinese).

[31]Verdegaal EME, de Miranda NFCC, Visser M, et al., 2016. Neoantigen landscape dynamics during human melanoma-T cell interactions. Nature, 536(7614):91-95.

[32]World Medical Association, 2013. World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA, 310(20):2191-2194. http://doi.org/10.1001/jama.2013.281053

[33]Yang Y, Lu Q, Liu YF, et al., 2016. Investigating the gray zone in ethical review of medical new technology: innovative treatment vs. experimental care. Med Philos, 37(8):94-97 (in Chinese).

[34]Ying KM, Ding Y, Chen YQ, et al., 2012. The ethical principles of clinical studies of DC-CIK cellular biotherapy technology. Hosp Admin J Chin PLA, 19(6):513-514 (in Chinese).

[35]Yu H, Qu P, Liu LB, 2005. Ethical issues and progress in clinical study of dendritic cell tumor vaccine. Chin Med Ethics, 40(4):60-62 (in Chinese).

[36]Zhang CC, Oberoi P, Oelsner S, et al., 2017. Chimeric antigen receptor-engineered NK-92 cells: an off-the-shelf cellular therapeutic for targeted elimination of cancer cells and induction of protective antitumor immunity. Front Immunol, 8:533.