CAR-NK细胞在癌症免疫治疗中的研究进展
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摘要
自然杀伤(NK)细胞是一种重要的肿瘤杀伤性免疫细胞,在细胞免疫治疗中有着良好的应用前景。嵌合抗原受体(CAR)是一种人工修饰的融合蛋白,它可以通过胞外区特异性识别肿瘤并激活胞内区信号域。CAR-T细胞在临床中取得了巨大的成功,而NK细胞比T细胞在CAR其相对于T细胞的优势,并就NK细胞的来源、CAR-NK在临床中的应用及存在的挑战做简要综述。
Natural killer(NK) cells are important effector cells in cell-based cancer immunotherapy. The chimeric antigen receptor(CAR) is an artificially modified fusion protein composed of extracellular antigen recognition domain and intracellular signaling domain. CAR-T cells have demonstrated remarkable success in clinical trials. Compared to T cells, CAR-transduced NK cells(CAR-NK) exhibit several advantages. Herein, we reviewed the advantages of NK cells, source of NK cells, and current obstacles to their clinical use.
Natural killer(NK) cells are important effector cells in cell-based cancer immunotherapy. The chimeric antigen receptor(CAR) is an artificially modified fusion protein composed of extracellular antigen recognition domain and intracellular signaling domain. CAR-T cells have demonstrated remarkable success in clinical trials. Compared to T cells, CAR-transduced NK cells(CAR-NK) exhibit several advantages. Herein, we reviewed the advantages of NK cells, source of NK cells, and current obstacles to their clinical use.
引文
[1] None. First-ever CAR T-cell therapy approved in U.S[J].Cancer Discov, 2017,7(10):OF1.
[2] None. FDA approves second CAR T-cell therapy[J].Cancer Discov, 2018,8(1):5-6.
[3] Olson J A, Levesongower D B, Gill S, et al. NK cells mediate reduction of GVHD by inhibiting activated, alloreactive T cells while retaining GVT effects[J]. Blood,2010,115(21):4293-4301.
[4] Ruggeri L, Mancusi A, Burchielli E, et al. NK cell alloreactivity and allogeneic hematopoietic stem cell transplantation[J]. Blood Cells Mol Dis, 2008,40(1):84-90.
[5] Bhat R, Watzl C. Serial killing of tumor cells by human natural killer cells--enhancement by therapeutic antibodies[J]. PLoS One, 2007,2(3):e326-e333.
[6] Sotillo E, Barrett D M, Black K L, et al. Convergence of acquired mutations and alternative splicing of CD19enables resistance to CART-19 immunotherapy[J]. Cancer Discov, 2015,5(12):1282-1295.
[7] Wilber A, Linehan J L, Tian X, et al. Efficient and stable transgene expression in human embryonic stem cells using transposon-mediated gene transfer[J]. Stem Cells, 2010,25(11):2919-2927.
[8] Ni Z, Knorr D A, Bendzick L, et al. Expression of chimeric receptor CD4ζby natural killer cells derived from human pluripotent stem cells improves in vitro activity but does not enhance suppression of HIV infection in vivo[J]. Stem Cells, 2014,32(4):1021-1031.
[9] Matsuo Y, Drexler H G. Immunoprofiling of cell lines derived from natural killer-cell and natural killer-like Tcell leukemia-lymphoma[J]. Leuk Res, 2003,27(10):935-945.
[10] Montaldo E, Vacca P, Vitale C, et al. Human innate lymphoid cells[J]. Immunol Lett, 2016,179(5):2-8.
[11] Campbell K S, Hasegawa J. Natural killer cell biology:an update and future directions[J]. J Allergy Clin Immunol,2013,132(3):536-544.
[12] Rezvani K, Rouce R H. The application of natural killer cell immunotherapy for the treatment of cancer[J]. Front Immunol, 2015,6(12):578-591.
[13] Zhang J, Chen Z, Smith G N, et al. Natural killer celltriggered vascular transformation:maternal care before birth[J]? Cell Mol Immunol, 2011,8(1):1-11.
[14] Stringaris K, Sekine T, Khoder A, et al. Leukemia-induced phenotypic and functional defects in natural killer cells predict failure to achieve remission in acute myeloid leukemia[J]. Haematologica, 2014,99(5):836-847.
[15] Hermanson D L, Kaufman D S. Utilizing chimeric antigen receptors to direct natural killer cell activity[J]. Front Immunol, 2015,6:195-201.
[16] Granzin M, Soltenborn S, Müller S, et al. Fully automated expansion and activation of clinical-grade natural killer cells for adoptive immunotherapy[J]. Cytotherapy, 2015,17(5):621-632.
[17] Szmania S, Lapteva N, Garg T, et al. Ex vivo expanded natural killer cells demonstrate robust proliferation in vivo in high-risk relapsed multiple myeloma patients[J].J Immunother, 2015,38(1):24-36.
[18] Shah N N, Kristin B, Delbrook C P, et al. Acute GVHD in patients receiving IL-15/4-1BBL activated NK cells following T-cell-depleted stem cell transplantation[J].Blood, 2015,125(5):784-792.
[19] Wagner J, Pfannenstiel V, Waldmann A, et al. A twophase expansion protocol combining interleukin(IL)-15and IL-21 improves natural killer cell proliferation and cytotoxicity against rhabdomyosarcoma[J]. Front Immunol,2017,8(1):676-692.
[20] Oelsner S, Wagner J, Friede M E, et al. Chimeric antigen receptor-engineered cytokine-induced killer cells overcome treatment resistance of pre-B-cell acute lymphoblastic leukemia and enhance survival[J]. Int J Cancer, 2016,139(8):1799-1809.
[21] Li L, Liu L N, Feller S, et al. Expression of chimeric antigen receptors in natural killer cells with a regulatorycompliant non-viral method[J]. Cancer Gene Ther, 2009,17(3):147-154.
[22] Chu Y, Hochberg J, Yahr A, et al. Targeting CD20+aggressive B-cell non-Hodgkin lymphoma by anti-CD20CAR mRNA modified expanded natural killer cells in vitro and in NSG mice[J]. Cancer Immunol Res, 2015,3(4):333-344.
[23] Bianca A, Silke L, Sibylle P, et al. 2B4(CD244)signaling by recombinant antigen-specific chimeric receptors costimulates natural killer cell activation to leukemia and neuroblastoma cells[J]. Clin Cancer Res, 2009,15(15):4857-4866.
[24] Han J, Chu J, Chan W K, et al. CAR-engineered NK cells targeting wild-type EGFR and EGFRvIII enhance killing of glioblastoma and patient-derived glioblastoma stem cells[J]. Sci Rep, 2015,5(11483):11483-11496.
[25] T?pfer K, Cartellieri M, Michen S, et al. DAP12-based activating chimeric antigen receptor for NK cell tumor immunotherapy[J]. J Immunol, 2015,194(7):3201-3212.
[26] Chang Y H, Connolly J, Shimasaki N, et al. A chimeric receptor with NKG2D specificity enhances natural killer cell activation and killing of tumor cells[J]. Cancer Res,2013,73(6):1777-1786.
[27] Romanski A, Uherek C, Bug G, et al. CD19-CAR engineered NK-92 cells are sufficient to overcome NK cell resistance in B-cell malignancies[J]. J Cell Mol Med,2016,20(7):1287-1294.
[28] Chu J, Deng Y, Benson D M, et al. CS1-specific chimeric antigen receptor(CAR)-engineered natural killer cells enhance in vitro and in vivo anti-tumor activity against human multiple myeloma[J]. Leukemia, 2014,28(4):917-927.
[29] Chen X, Han J, Chu J, et al. A combinational therapy of EGFR-CAR NK cells and oncolytic herpes simplex virus 1 for breast cancer brain metastases[J]. Oncotarget,2016,7(19):27764-27777.
[30] Yu M, Luo H, Fan M, et al. Development of GPC3-specific chimeric antigen receptor-engineered natural killer cells for the treatment of hepatocellular carcinoma[J]. Mol Ther, 2017,26(2):366-378.
[31] Zhang C, Burger M C, Jennewein L, et al. Erb B2/HER2-specific NK cells for targeted therapy of glioblastoma[J].J Natl Cancer Institute, 2016,108(5):375-386.
[32] Sahm C, Sch?nfeld K, Wels W S. Expression of IL-15in NK cells results in rapid enrichment and selective cytotoxicity of gene-modified effectors that carry a tumorspecific antigen receptor[J]. Cancer Immunol Immunother,2012,61(9):1451-1461.
[33] Shiozawa M, Chang C H, Huang Y C, et al. Pharmacologically upregulated carcinoembryonic antigen-expression enhances the cytolytic activity of geneticallymodified chimeric antigen receptor NK-92MI against colorectal cancer cells[J]. Bmc Immunol, 2018,19(1):27-39.
[34] Zhang P, Zhao S, Wu C, et al. Effects of CSF1R-targeted chimeric antigen receptor-modified NK92MI&T cells on tumor-associated macrophages[J]. Immunotherapy,2018,10(11):935-949.
[35] Schirrmann T, Pecher G. Specific targeting of CD33+leukemia cells by a natural killer cell line modified with a chimeric receptor[J]. Leuk Res, 2005,29(3):301-306.
[36] Murakami T, Nakazawa T, Natsume A, et al. Novel human NK cell line carrying CAR targeting EGFRvIII induces antitumor effects in glioblastoma cells[J]. Anticancer Res, 2018,38(9):5049-5056.
[37] Liu E, Tong Y, Dotti G, et al. Cord blood NK cells engineered to express IL-15 and a CD19-targeted CAR show long-term persistence and potent anti-tumor activity[J]. Leukemia, 2018,32(2):520-531.
[38] Ye L, Hermanson D L, Moriarity B S, et al. Human i PSC-derived natural killer cells engineered with chimeric antigen receptors enhance anti-tumor activity[J].Cell Stem Cell, 2018,23(2):181-192.
[39] Gong J H, Maki G, Klingemann H G. Characterization of a human cell line(NK-92)with phenotypical and functional characteristics of activated natural killer cells[J].Leukemia, 1994,8(4):652-658.
[40] Maki G, Klingemann H G, Martinson J A, et al. Factors regulating the cytotoxic activity of the human natural killer cell line, NK-92[J]. J Hematother Stem Cell Res,2001,10(3):369-383.
[41] Tonn T, Becker S, Esser R, et al. Cellular immunotherapy of malignancies using the clonal natural killer cell line NK-92[J]. J Hematother Stem Cell Res, 2001,10(4):535-544.
[42] Arai S, Meagher R, Swearingen M, et al. Infusion of the allogeneic cell line NK-92 in patients with advanced renal cell cancer or melanoma:a phase I trial[J]. Cytotherapy, 2008,10(6):625-632.
[43] Tonn T, Schwabe D, Klingemann H G, et al. Treatment of patients with advanced cancer with the natural killer cell line NK-92[J]. Cytotherapy, 2013,15(12):1563-1570.
[44] Boyiadzis M, Agha M, Redner R L, et al. Phase 1clinical trial of adoptive immunotherapy using"off-theshelf"activated natural killer cells in patients with refractory and relapsed acute myeloid leukemia[J]. Cytotherapy, 2017,19(10):1225-1232.
[45] Zhang C, Oberoi P, Oelsner S, et al. 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[J]. Front Immunol, 2017,8(1):533-549.
[46] Pela M, Han-Ching T, Bui V T, et al. Regulation of split anergy in natural killer cells by inhibition of cathepsins C and H and cystatin F[J]. Oncotarget, 2015,6(26):22310-22327.
[47] Rezvani K, Rouce R, Liu E, et al. Engineering natural killer cells for cancer immunotherapy[J]. Mol Ther, 2017,9(6):487-497.
[48] Jean-Hugues D, JoséM, Eric W, et al. Characterization of cord blood natural killer cells:implications for transplantation and neonatal infections[J]. Pediatr Res,2005,57(1):649-655.
[49] Bj?rkstr?m N K, Riese P, Heuts F, et al. Expression patterns of NKG2A, KIR, and CD57 define a process of CD56dim NK-cell differentiation uncoupled from NK-cell education[J]. Blood, 2010,116(19):3853-3864.
[50] Shah N, Martin-Antonio B, Yang H, et al. Antigen presenting cell-mediated expansion of human umbilical cord blood yields log-scale expansion of natural killer cells with anti-myeloma activity[J]. PLo S One,2013,8(10):e76781-e76789.
[51] Saar G, Vasey A E, Alysha D S, et al. Rapid development of exhaustion and down-regulation of eomesodermin limit the antitumor activity of adoptively transferred murine natural killer cells[J]. Blood, 2012,119(24):5758-5768.
[52] Intlekofer A M, Takemoto N, Wherry E J, et al. Effector and memory CD8+T cell fate coupled by T-bet and eomesodermin[J]. Nat Immunol, 2005,6(12):1236-1244.
[53] Valamehr B, Robinson M, Abujarour R, et al. Platform for induction and maintenance of transgene-free hi PSCs resembling ground state pluripotent stem cells[J]. Stem Cell Rep, 2014,2(3):366-381.
[54] Hermanson D L, Bendzick L, Pribyl L, et al. Induced pluripotent stem cell-derived natural killer cells for treatment of ovarian cancer[J]. Stem Cells, 2016,34(1):93-101.
[55] Chihaya I, Shotaro I, Dario C. Genetic modification of primary natural killer cells overcomes inhibitory signals and induces specific killing of leukemic cells[J]. Blood,2005,106(1):376-383.
[56] Carlsten M, Childs R W. Genetic manipulation of NK cells for cancer immunotherapy:techniques and clinical implications[J]. Front Immunol, 2015,6(1):266-274.
[2] None. FDA approves second CAR T-cell therapy[J].Cancer Discov, 2018,8(1):5-6.
[3] Olson J A, Levesongower D B, Gill S, et al. NK cells mediate reduction of GVHD by inhibiting activated, alloreactive T cells while retaining GVT effects[J]. Blood,2010,115(21):4293-4301.
[4] Ruggeri L, Mancusi A, Burchielli E, et al. NK cell alloreactivity and allogeneic hematopoietic stem cell transplantation[J]. Blood Cells Mol Dis, 2008,40(1):84-90.
[5] Bhat R, Watzl C. Serial killing of tumor cells by human natural killer cells--enhancement by therapeutic antibodies[J]. PLoS One, 2007,2(3):e326-e333.
[6] Sotillo E, Barrett D M, Black K L, et al. Convergence of acquired mutations and alternative splicing of CD19enables resistance to CART-19 immunotherapy[J]. Cancer Discov, 2015,5(12):1282-1295.
[7] Wilber A, Linehan J L, Tian X, et al. Efficient and stable transgene expression in human embryonic stem cells using transposon-mediated gene transfer[J]. Stem Cells, 2010,25(11):2919-2927.
[8] Ni Z, Knorr D A, Bendzick L, et al. Expression of chimeric receptor CD4ζby natural killer cells derived from human pluripotent stem cells improves in vitro activity but does not enhance suppression of HIV infection in vivo[J]. Stem Cells, 2014,32(4):1021-1031.
[9] Matsuo Y, Drexler H G. Immunoprofiling of cell lines derived from natural killer-cell and natural killer-like Tcell leukemia-lymphoma[J]. Leuk Res, 2003,27(10):935-945.
[10] Montaldo E, Vacca P, Vitale C, et al. Human innate lymphoid cells[J]. Immunol Lett, 2016,179(5):2-8.
[11] Campbell K S, Hasegawa J. Natural killer cell biology:an update and future directions[J]. J Allergy Clin Immunol,2013,132(3):536-544.
[12] Rezvani K, Rouce R H. The application of natural killer cell immunotherapy for the treatment of cancer[J]. Front Immunol, 2015,6(12):578-591.
[13] Zhang J, Chen Z, Smith G N, et al. Natural killer celltriggered vascular transformation:maternal care before birth[J]? Cell Mol Immunol, 2011,8(1):1-11.
[14] Stringaris K, Sekine T, Khoder A, et al. Leukemia-induced phenotypic and functional defects in natural killer cells predict failure to achieve remission in acute myeloid leukemia[J]. Haematologica, 2014,99(5):836-847.
[15] Hermanson D L, Kaufman D S. Utilizing chimeric antigen receptors to direct natural killer cell activity[J]. Front Immunol, 2015,6:195-201.
[16] Granzin M, Soltenborn S, Müller S, et al. Fully automated expansion and activation of clinical-grade natural killer cells for adoptive immunotherapy[J]. Cytotherapy, 2015,17(5):621-632.
[17] Szmania S, Lapteva N, Garg T, et al. Ex vivo expanded natural killer cells demonstrate robust proliferation in vivo in high-risk relapsed multiple myeloma patients[J].J Immunother, 2015,38(1):24-36.
[18] Shah N N, Kristin B, Delbrook C P, et al. Acute GVHD in patients receiving IL-15/4-1BBL activated NK cells following T-cell-depleted stem cell transplantation[J].Blood, 2015,125(5):784-792.
[19] Wagner J, Pfannenstiel V, Waldmann A, et al. A twophase expansion protocol combining interleukin(IL)-15and IL-21 improves natural killer cell proliferation and cytotoxicity against rhabdomyosarcoma[J]. Front Immunol,2017,8(1):676-692.
[20] Oelsner S, Wagner J, Friede M E, et al. Chimeric antigen receptor-engineered cytokine-induced killer cells overcome treatment resistance of pre-B-cell acute lymphoblastic leukemia and enhance survival[J]. Int J Cancer, 2016,139(8):1799-1809.
[21] Li L, Liu L N, Feller S, et al. Expression of chimeric antigen receptors in natural killer cells with a regulatorycompliant non-viral method[J]. Cancer Gene Ther, 2009,17(3):147-154.
[22] Chu Y, Hochberg J, Yahr A, et al. Targeting CD20+aggressive B-cell non-Hodgkin lymphoma by anti-CD20CAR mRNA modified expanded natural killer cells in vitro and in NSG mice[J]. Cancer Immunol Res, 2015,3(4):333-344.
[23] Bianca A, Silke L, Sibylle P, et al. 2B4(CD244)signaling by recombinant antigen-specific chimeric receptors costimulates natural killer cell activation to leukemia and neuroblastoma cells[J]. Clin Cancer Res, 2009,15(15):4857-4866.
[24] Han J, Chu J, Chan W K, et al. CAR-engineered NK cells targeting wild-type EGFR and EGFRvIII enhance killing of glioblastoma and patient-derived glioblastoma stem cells[J]. Sci Rep, 2015,5(11483):11483-11496.
[25] T?pfer K, Cartellieri M, Michen S, et al. DAP12-based activating chimeric antigen receptor for NK cell tumor immunotherapy[J]. J Immunol, 2015,194(7):3201-3212.
[26] Chang Y H, Connolly J, Shimasaki N, et al. A chimeric receptor with NKG2D specificity enhances natural killer cell activation and killing of tumor cells[J]. Cancer Res,2013,73(6):1777-1786.
[27] Romanski A, Uherek C, Bug G, et al. CD19-CAR engineered NK-92 cells are sufficient to overcome NK cell resistance in B-cell malignancies[J]. J Cell Mol Med,2016,20(7):1287-1294.
[28] Chu J, Deng Y, Benson D M, et al. CS1-specific chimeric antigen receptor(CAR)-engineered natural killer cells enhance in vitro and in vivo anti-tumor activity against human multiple myeloma[J]. Leukemia, 2014,28(4):917-927.
[29] Chen X, Han J, Chu J, et al. A combinational therapy of EGFR-CAR NK cells and oncolytic herpes simplex virus 1 for breast cancer brain metastases[J]. Oncotarget,2016,7(19):27764-27777.
[30] Yu M, Luo H, Fan M, et al. Development of GPC3-specific chimeric antigen receptor-engineered natural killer cells for the treatment of hepatocellular carcinoma[J]. Mol Ther, 2017,26(2):366-378.
[31] Zhang C, Burger M C, Jennewein L, et al. Erb B2/HER2-specific NK cells for targeted therapy of glioblastoma[J].J Natl Cancer Institute, 2016,108(5):375-386.
[32] Sahm C, Sch?nfeld K, Wels W S. Expression of IL-15in NK cells results in rapid enrichment and selective cytotoxicity of gene-modified effectors that carry a tumorspecific antigen receptor[J]. Cancer Immunol Immunother,2012,61(9):1451-1461.
[33] Shiozawa M, Chang C H, Huang Y C, et al. Pharmacologically upregulated carcinoembryonic antigen-expression enhances the cytolytic activity of geneticallymodified chimeric antigen receptor NK-92MI against colorectal cancer cells[J]. Bmc Immunol, 2018,19(1):27-39.
[34] Zhang P, Zhao S, Wu C, et al. Effects of CSF1R-targeted chimeric antigen receptor-modified NK92MI&T cells on tumor-associated macrophages[J]. Immunotherapy,2018,10(11):935-949.
[35] Schirrmann T, Pecher G. Specific targeting of CD33+leukemia cells by a natural killer cell line modified with a chimeric receptor[J]. Leuk Res, 2005,29(3):301-306.
[36] Murakami T, Nakazawa T, Natsume A, et al. Novel human NK cell line carrying CAR targeting EGFRvIII induces antitumor effects in glioblastoma cells[J]. Anticancer Res, 2018,38(9):5049-5056.
[37] Liu E, Tong Y, Dotti G, et al. Cord blood NK cells engineered to express IL-15 and a CD19-targeted CAR show long-term persistence and potent anti-tumor activity[J]. Leukemia, 2018,32(2):520-531.
[38] Ye L, Hermanson D L, Moriarity B S, et al. Human i PSC-derived natural killer cells engineered with chimeric antigen receptors enhance anti-tumor activity[J].Cell Stem Cell, 2018,23(2):181-192.
[39] Gong J H, Maki G, Klingemann H G. Characterization of a human cell line(NK-92)with phenotypical and functional characteristics of activated natural killer cells[J].Leukemia, 1994,8(4):652-658.
[40] Maki G, Klingemann H G, Martinson J A, et al. Factors regulating the cytotoxic activity of the human natural killer cell line, NK-92[J]. J Hematother Stem Cell Res,2001,10(3):369-383.
[41] Tonn T, Becker S, Esser R, et al. Cellular immunotherapy of malignancies using the clonal natural killer cell line NK-92[J]. J Hematother Stem Cell Res, 2001,10(4):535-544.
[42] Arai S, Meagher R, Swearingen M, et al. Infusion of the allogeneic cell line NK-92 in patients with advanced renal cell cancer or melanoma:a phase I trial[J]. Cytotherapy, 2008,10(6):625-632.
[43] Tonn T, Schwabe D, Klingemann H G, et al. Treatment of patients with advanced cancer with the natural killer cell line NK-92[J]. Cytotherapy, 2013,15(12):1563-1570.
[44] Boyiadzis M, Agha M, Redner R L, et al. Phase 1clinical trial of adoptive immunotherapy using"off-theshelf"activated natural killer cells in patients with refractory and relapsed acute myeloid leukemia[J]. Cytotherapy, 2017,19(10):1225-1232.
[45] Zhang C, Oberoi P, Oelsner S, et al. 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[J]. Front Immunol, 2017,8(1):533-549.
[46] Pela M, Han-Ching T, Bui V T, et al. Regulation of split anergy in natural killer cells by inhibition of cathepsins C and H and cystatin F[J]. Oncotarget, 2015,6(26):22310-22327.
[47] Rezvani K, Rouce R, Liu E, et al. Engineering natural killer cells for cancer immunotherapy[J]. Mol Ther, 2017,9(6):487-497.
[48] Jean-Hugues D, JoséM, Eric W, et al. Characterization of cord blood natural killer cells:implications for transplantation and neonatal infections[J]. Pediatr Res,2005,57(1):649-655.
[49] Bj?rkstr?m N K, Riese P, Heuts F, et al. Expression patterns of NKG2A, KIR, and CD57 define a process of CD56dim NK-cell differentiation uncoupled from NK-cell education[J]. Blood, 2010,116(19):3853-3864.
[50] Shah N, Martin-Antonio B, Yang H, et al. Antigen presenting cell-mediated expansion of human umbilical cord blood yields log-scale expansion of natural killer cells with anti-myeloma activity[J]. PLo S One,2013,8(10):e76781-e76789.
[51] Saar G, Vasey A E, Alysha D S, et al. Rapid development of exhaustion and down-regulation of eomesodermin limit the antitumor activity of adoptively transferred murine natural killer cells[J]. Blood, 2012,119(24):5758-5768.
[52] Intlekofer A M, Takemoto N, Wherry E J, et al. Effector and memory CD8+T cell fate coupled by T-bet and eomesodermin[J]. Nat Immunol, 2005,6(12):1236-1244.
[53] Valamehr B, Robinson M, Abujarour R, et al. Platform for induction and maintenance of transgene-free hi PSCs resembling ground state pluripotent stem cells[J]. Stem Cell Rep, 2014,2(3):366-381.
[54] Hermanson D L, Bendzick L, Pribyl L, et al. Induced pluripotent stem cell-derived natural killer cells for treatment of ovarian cancer[J]. Stem Cells, 2016,34(1):93-101.
[55] Chihaya I, Shotaro I, Dario C. Genetic modification of primary natural killer cells overcomes inhibitory signals and induces specific killing of leukemic cells[J]. Blood,2005,106(1):376-383.
[56] Carlsten M, Childs R W. Genetic manipulation of NK cells for cancer immunotherapy:techniques and clinical implications[J]. Front Immunol, 2015,6(1):266-274.