PRACA PRZEGLĄDOWA
Możliwości wykorzystania komórek NK w immunoterapii nowotworów
Więcej
Ukryj
1
Zakład Hematoonkologii Doświadczalnej, Uniwersytet Medyczny, Lublin, Polska
2
Zakład Biologii Medycznej, Instytut Medycyny Wsi, Lublin, Polska
3
Zakład Biologii Medycznej, Instytut Medycyny Wsi, Lublin, Polska; Katedra Anatomii Funkcjonalnej i Cytobiologii, Uniwersytet Marii Curie-Skłodowskiej, Lublin, Polska
Autor do korespondencji
Marta Kinga Lemieszek
Zakład Biologii Medycznej, Instytut Medycyny Wsi, Lublin, Polska, Jaczewskiego 2, 20-090, Lublin, Polska
Med Og Nauk Zdr. 2020;26(1):8-16
SŁOWA KLUCZOWE
DZIEDZINY
STRESZCZENIE
Pomimo postępu, jaki w ostatnich latach dokonał się w onkologii, wciąż wzrasta liczba zachorowań na nowotwory, co
wymusza poszukiwanie nowych, skuteczniejszych, a przede wszystkim bezpieczniejszych strategii terapeutycznych. W trend ten doskonale wpisuje się immunoterapia, u podłoża której leży mobilizacja i wzmacnianie własnych mechanizmów obronnych organizmu. Jest to istotne, gdyż komórki nowotworowe często „wymykają się” spod nadzoru immunologicznego i w ten sposób zdobywają możliwość niekontrolowanego wzrostu i rozprzestrzeniania się po organizmie. Wzmocnienie i usprawnienie odpowiedzi immunologicznej w kierunku rozpoznawania/wykrywania a jednocześnie niszczenia komórek nowotworowych w dużej mierze bazuje na modyfikacjach komórek immunokompetentnych bezpośrednio zaangażowanych w odpowiedź przeciwnowotworową.
Z uwagi na fakt, że pierwszą linię obrony organizmu przed nowotworami stanowią komórki NK (ang. natural killer – naturalni zabójcy), to w nich pokładane są nadzieje na przełom w leczeniu nowotworów. Badania nad biologią komórek NK pozwoliły lepiej zrozumieć ich ogromny potencjał terapeutyczny, a zdobycze współczesnej medycyny umożliwiły ich efektywne wykorzystanie w immunoterapii nowotworów. W niniejszej pracy przedstawiono aktualny stan wiedzy na temat możliwości wykorzystania komórek NK w immunoterapii nowotworowej, przede wszystkim zaś omówiono terapię adoptowaną z wykorzystaniem komórek NK, cytotoksyczność komórkową zależną od przeciwciał oraz strategie opierające się na stymulacji komórek NK cytokinami lub blokowaniu ich receptorów hamujących.
Despite the progress that has been made in oncology in recent years, the increasing number of cases of cancer forces the search for new, more effective, and above all, safer therapeutic strategies. Immunotherapy, which is based on the mobilization and strengthening of the body‘s own defence mechanisms, perfectly fits this trend. This is important because cancer cells often ‘sneak out’ of immune surveillance and thus gain the possibility of uncontrolled growth and spread throughout the body. Strengthening and improving the immune response towards recognition/detection, and at the same time, destroying cancer cells is largely based on the modification
of immunocompetent cells directly involved in the anti-cancer response. Because of the fact that lymphocytes NK (natural killer cells) are the first line of the body‘s defence against cancertransformed cells, hope is placed in them for a breakthrough in cancer treatment. Research on NK cells biology has allowed a better understanding of their huge therapeutic potential, and the achievements of modern medicine have enabled their effective use in cancer immunotherapy. This paper presents the current state of knowledge about the possibilities of using NK cells in cancer immunotherapy, in particular, adopted therapy using NK cells, antibody-dependent cellular cytotoxicity, strategies based on NK cell stimulation with cytokines, or blocking their inhibitory receptors.
REFERENCJE (76)
1.
Wojciechowska U, Czderny K, Ciuba A, Olasek P, Didkowska J. Nowotwory złośliwe w Polsce w 2016 roku. Krajowy Rejestr Nowotworów; 2018.
2.
Bodduluru LN, Kasala ER, Madhana RM, Sriram CS. Natural killer cells: The journey from puzzles in biology to treatment of cancer. CancerLett. 2015; 357(2): 454–67.
https://doi.org/10.1016/j.canl....
3.
Geller MA, Miller JS. Use of allogeneic NK cells for cancer immunotherapy. Immunotherapy. 2011; 2(12): 1445–59.
https://doi.org/10.2217/ imt.11.131.
4.
Cooper MA, Fehniger TA, Caligiuri MA. Biology of human natural killer cell subsets. TrendsImmunol. 2001; 22(11): 633–40.
6.
Gołąb J, Jakóbisiak M, Lasek W, Stokłosa T. Immunologia. Jakóbisiak M, Lasek W. Populacje i subpopulacje limfocytów. Immunologia nowotworów, wyd. Warszawa: Wydawnictwo Naukowe PWN; 2014: 137–173, 450–467.
7.
Dohring C, Scheidegger D, Samaridis J, Cella M, Colonna M. A human killer inhibitory receptor specific for HLA-A1,2. J Immunol. 1996; 156(9): 3098–101.
8.
Litwin V, Gumperz J, Parham P, Phillips JH, Lanier LL. NKB1: a natural killer cell receptor involved in the recognition of polymorphic HLA-B molecules. J Exp Med. 1994; 180(2): 537–43.
https://doi.org/10.1084/ jem.180.2.537.
9.
Moretta A, Bottino C, Pende D et al. Identification of four subsets of human CD3−CD16+ natural killer (NK) cells by the expression of clonally distributed functional surface molecules: correlation between subset assignment of NK clones and ability to mediate specific alloantigen recognition. J Exp Med. 1990; 172(6): 1589–98.
https://doi. org/10.1084/jem.172.6.1589.
10.
Vales-Gomez M, Reyburn HT, Mandelboim M, Strominger JL. Kinetics of interaction of HLA-C ligands with natural killer cell inhibitory receptors. Immunity. 1998; 9(3): 337–44.
11.
Borrego F, Ulbrecht M, Weiss EH, Coligan JE, Brooks AG. Recognition of human histocompatibility leukocyte antigen (HLA)-E complexed with HLA class I signal sequence-derived peptides by CD94/NKG2 confers protection from natural killer cell-mediated lysis. J Exp Med. 1998; 187(5): 813–8.
https://doi.org/10.1084/jem.18....
12.
Lanier LL, Ruitenberg JJ, Phillips JH. Functional and biochemical analysis of CD16 antigen on natural killer cells and granulocytes. J Immunol. 1988; 141(10): 3478–85.
13.
Ames E, Murphy WJ. Advantages and clinical applications of natural killer cells in cancer immunotherapy. Cancer Immunol Immunother. 2014; 63(1): 21–
https://doi.org/10.1007/s00262....
14.
Levy EM, Roberti MP, Mordoh J. Natural killer cells in human cancer: from biological functions to clinical applications. J BiomedBiotechnol. 2011: 676198.
https://doi.org/10.1155/2011/6....
15.
Gómez VR, Murray RJC, Weiner LM. Antibody-Dependent Cellular Cytotoxicity (ADCC). AntibodyFc. LinkingAdaptive and InnateImmunity. 2014; 1–27.
16.
Bryceson YT, March ME, Ljunggren HG, Long EO. Activation, coactivation, and costimulation of resting human natural killer cells. ImmunolRev. 2006; 214: 73–91.
https://doi.org/10.1111/j.1600....
17.
Awasthi A, Ayello J, Van de Ven C, Elmacken M, Sabulski A, Barth MJ et al. Obinutuzumab (GA101) compared to rituximab significantly enhances cell death and antibody-dependent cytotoxicity and improves overall survival against CD20(+) rituximab-sensitive/-resistant Burkitt lymphoma (BL) and precursor B-acute lymphoblastic leukaemia (pre- -B-ALL): potential targeted therapy in patients with poor risk CD20(+) BL and pre-B-ALL. Br J Haematol. 2015; 171(5): 763–75.
https://doi. org/10.1111/bjh.13764.
18.
Trivedi S, Srivastava RM, Concha-Benavente F, Ferrone S, Garcia-Bates TM, Li J et al. Anti-EGFR targeted monoclonal antibody isotype influences antitumor cellular immunity in head and neck cancer patients. ClinCancer Res. 2016; 22(21): 5229–37.
https://doi.org/10.1158/1078- 0432.CCR-15-2971.
19.
Arnould L, Gelly M, Penault-Llorca F, Benoit L, Bonnetain F, Migeon C et al. Trastuzumab-based treatment of HER2-positive breast cancer: an antibody-dependent cellular cytotoxicity mechanism? Br J Cancer. 2006; 94(2): 259–67.
https://doi.org/10.1038/sj.bjc....
20.
Romee R, Foley B, Lenvik T, Wang Y, Zhang B, Ankarlo D, et al. NK cell CD16 surface expression and function is regulated by a disintegrin and metalloprotease-17 (ADAM17). Blood. 2013; 121(18): 3599–608. https:// doi.org/10.1182/blood-2012-04-425397.
21.
Varchetta S, Gibelli N, Oliviero B, Nardini E, Gennari R, Gatti G et al. Elements related to heterogeneity of antibody-dependent cell cytotoxicity in patients under trastuzumab therapy for primary operable breast cancer overexpressing Her2. Cancer Res. 2007; 67(24): 11991–9. https:// doi.org/10.1158/0008-5472.CAN-07-2068.
22.
Kohrt HE, Houot R, Weiskopf K, Goldstein MJ, Scheeren F, Czerwinski D et al. Stimulation of natural killer cells with a CD137-specific antibody enhances trastuzumab efficacy in xenotransplant models of breast cancer. J Clin Invest. 2012; 122(3): 1066–75.
https://doi.org/10.1172/ JCI61226.
23.
Kohrt HE, Colevas AD, Houot R, Weiskopf K, Goldstein MJ, Lund P et al. Targeting CD137 enhances the efficacy of cetuximab. J Clin Invest. 2014; 124(6): 2668–82.
https://doi.org/10.1172/JCI730....
24.
Kohrt HE, Houot R, Goldstein MJ, Weiskopf K, Alizadeh AA, Brody J, et al. CD137 stimulation enhances the antilymphoma activity of anti- -CD20 antibodies. Blood. 2011; 117(8): 2423–32.
https://doi.org/10.1182/ blood-2010-08-301945.
25.
Muntasell A, Ochoa MC, Cordeiro L, Berraondo P, López-Díaz de Cerio A, Cabo M et al. Targeting NK-cell checkpoints for cancer immunotherapy. CurrOpin Immunol. 2017; 45: 73–81.
https://doi.org/10.1016/j. coi.2017.01.003.
26.
Shifrin N, Raulet DH, Ardolino M. NK cell self tolerance, responsiveness and missing self recognition. Semin Immunol. 2014; 26(2): 138–44.
https://doi.org/10.1016/j.smim....
27.
Vahlne G, Lindholm K, Meier A, Wickström S, Lakshmikanth T, Brennan F et al. In vivo tumor cell rejection induced by NK cell inhibitory receptor blockade: maintained tolerance to normal cells even in the presence of IL-2. Eur J Immunol. 2010; 40(3): 813–23.
https://doi. org/10.1002/eji.200939755.
28.
Romagne F, Andre P, Spee P, Zahn S, Anfossi N, Gauthier L et al. Preclinical characterization of 1–7F9, a novel human anti-KIR receptor therapeutic antibody that augments natural killer-mediated killing of tumor cells. Blood. 2009; 114(13): 2667–77.
https://doi.org/10.1182/ blood-2009-02-206532.
29.
Vey N, Karlin L, Sadot-Lebouvier S, Broussais F, Berton-Rigaud D, Rey J et al. A phase 1 study of lirilumab (antibody against killer immunoglobulin-like receptor antibody KIR2D; IPH2102) in patients with solid tumors and hematologic malignancies. Oncotarget. 2018; 9(25): 17675–88.
https://doi.org/10.18632/oncot....
30.
Chen Z, Yang Y, Liu LL, Lundqvist A. Strategies to Augment Natural Killer (NK) Cell Activity against Solid Tumors. Cancers (Basel). 2019; 11(7). pii: E1040.
https://doi.org/10.3390/cancer....
31.
Zaghi E, Calvi M, Marcenaro E, Mavilio D, Di Vito C. Targeting NKG2A to elucidate natural killer cell ontogenesis and to develop novel immune-therapeutic strategies in cancer therapy. J Leukoc Biol. 2019; 105(6): 1243–51.
https://doi.org/10.1002/JLB.MR....
32.
Bottino C, Castriconi R, Pende D, Rivera P, Nanni M, Carnemolla B et al. Identification of PVR (CD155) and Nectin-2 (CD112) as cell surface ligands for the human DNAM-1 (CD226) activating molecule. J Exp Med. 2003; 198(4): 557–67.
https://doi.org/10.1084/jem.20....
33.
Martinet L, Smyth MJ. Balancing natural killer cell activation through paired receptors. Nat RevImmunol. 2015; 15(4): 243–54.
https://doi. org/10.1038/nri3799.
34.
Bernhardt G. TACTILE becomes tangible: CD96 discloses its inhibitory peculiarities. Nat Immunol. 2014; 15(5): 406–8.
https://doi.org/10.1038/ ni.2855.
35.
Chan CJ, Martinet L, Gilfillan S, Souza-Fonseca-Guimaraes F, Chow MT, Town L et al. The receptors CD96 and CD226 oppose each other in the regulation of natural killer cell functions. Nat Immunol. 2014, 15(5): 431–8.
https://doi.org/10.1038/ni.285....
36.
Blake SJ, Stannard K, Liu J, Allen S, Yong MC, Mittal D et al. Suppression of metastases using a new lymphocyte checkpoint target for cancer immunotherapy. CancerDiscov. 2016, 6(4): 446–59.
https://doi. org/10.1158/2159-8290.
37.
Sarhan D, Cichocki F, Zhang B, Yingst A, Spellman SR, Cooley S et al. Adaptive NK cells with low TIGIT expression are inherently resistant to myeloid-derived suppressor cells. Cancer Res. 2016; 76(19): 5696–706.
https://doi.org/10.1158/0008-5....
38.
Pesce S, Greppi M, Tabellini G, Rampinelli F, Parolini S, Olive D et al. Identification of a subset of human natural killer cells expressing high levels of programmed death 1: a phenotypic and functional characterization. J Allergy Clin Immunol. 2017; 139(1): 335–346.e3.
https://doi. org/10.1016/j.jaci.2016.04.025.
39.
Benson DM Jr, Bakan CE, Mishra A, Hofmeister CC, Efebera Y, Becknell B et al. 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. 2010; 116(13): 2286–94. https:// doi.org/10.1182/blood-2010-02-271874.
40.
Pesce S, Greppi M, Grossi F, Zotto GD, Moretta L, Sivori S et al. PD/1--PD-Ls Checkpoint: Insight on the Potential Role of NK Cells. Front Immunol. 2019; 10: 1242.
https://doi.org/10.3389/fimmu.....
41.
Antonia SJ, Villegas A, Daniel D, Vicente D, Murakami S, Hui R et al. Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC. N Engl J Med. 2018; 379(24): 2342–50.
https://doi.org/10.1056/ NEJMoa1809697.
42.
Simsek M, Tekin SB, Bilici M. Immunological agents used in cancer treatment. Eurasian J Med. 2019; 51(1): 90–4.
https://doi.org/10.5152/ eurasianjmed.2018.18194.
43.
Melero I, Johnston JV, Shufford WW, Mittler RS, Chen L. NK1.1 cells express 4-1BB (CDw137) costimulatory molecule and are required for tumor immunity elicited by anti-4-1BB monoclonal antibodies. Cell Immunol. 1998; 190(2): 167–72.
https://doi.org/10.1006/cimm.1....
44.
Baessler T, Charton JE, Schmiedel BJ, Grunebach F, Krusch M, Wacker A, et al. CD137 ligand mediates opposite effects in human and mouse NK cells and impairs NK-cell reactivity against human acute myeloid leukemia cells. Blood. 2010; 115(15): 3058–69.
https://doi.org/10.1182/ blood-2009-06-227934.
45.
Waldmann TA. The shared and contrasting roles of IL2 and IL15 in the life and death of normal and neoplastic lymphocytes: implications for cancer therapy. Cancer Immunol Res. 2015; 3(3): 219–27.
https://doi. org/10.1158/2326-6066.CIR-15-0009.
46.
Able AA, Burrell JA, Stephens JM. STAT5-Interacting Proteins: A Synopsis of Proteins that Regulate STAT5 Activity. Biology (Basel). 2017; 6(1): 20.
https://doi.org/10.3390/biolog....
47.
Delconte RB, Kolesnik TB, Dagley LF, Rautela J, Shi W, Putz EM, et al. CIS is a potent checkpoint in NK cell-mediated tumor immunity. Nat Immunol. 2016; 17(7): 816–24.
https://doi.org/10.1038/ni.347....
48.
Tonn T, Schwabe D, Klingemann HG, Becker S, Esser R, Koehl U et al. Treatment of patients with advanced cancer with the natural killer cell line NK-92. Cytotherapy. 2013; 15(12): 1563–70.
https://doi.org/10.1016/j. jcyt.2013.06.017.
49.
Atkins MB, Regan M, McDermott D. Update on the role of interleukin 2 and other cytokines in the treatment of patients with stage IV renal carcinoma. Clin Cancer Res. 2004; 10(18 Pt 2): 6342S–6S.
https://doi. org/10.1158/1078-0432.CCR-040029.
50.
Ardolino M, Azimi CS, Iannello A, Trevino TN, Horan L, Zhang L et al. Cytokine therapy reverses NK cell anergy in MHC-deficient tumors. J Clin Invest. 2014; 124(11): 4781–94.
https://doi.org/10.1172/JCI743....
51.
Sim GC, Liu C, Wang E, Liu H, Creasy C, Dai Z, et al. IL-2 variant circumvents ICOS+ regulatory T cell expansion and promotes NK cell activation. CancerImmunol Res. 2016; 4(11): 983–94.
https://doi. org/10.1158/2326-6066.CIR-15-0195.
52.
García-Martínez E, Smith M, Buqué A, Aranda F, de la Peña FA, Ivars A et al. Trial Watch: Immunostimulation with recombinant cytokines for cancer therapy. Oncoimmunology. 2018; 7(6):e1433982.
https://doi. org/10.1080/2162402X.2018.1433982.
53.
Conlon KC, Lugli E, Welles HC, Rosenberg SA, Fojo AT, Morris JC et al. Redistribution, hyperproliferation, activation of natural killer cells and CD8 T cells, and cytokine production during first-in-human clinical trial of recombinant human interleukin-15 in patients with cancer. J ClinOncol. 2015; 33(1): 74–82.
https://doi.org/10.1200/JCO.20....
54.
Cheng M, Chen Y, Xiao W, Sun R, Tian Z. NK cell-based immunotherapy for malignant diseases. Cell Mol Immunol. 2013; 10(3): 230–52.
https://doi.org/10.1038/cmi.20....
55.
Luevano M, Madrigal A, Saudemont A. Generation of natural killer cells from hematopoietic stem cells in vitro for immunotherapy. Cell Mol Immunol. 2012; 9(4): 310–20.
https://doi.org/10.1038/cmi.20....
56.
Sutlu T, Alici E. Natural killer cell-based immunotherapy in cancer: current insights and future prospects. J Intern Med. 2009; 266(2): 154–81.
https://doi.org/10.1111/j.1365....
57.
Tam YK, Maki G, Miyagawa B, Hennemann B, Tonn T, Klingemann HG. Characterization of genetically altered, interleukin 2-independent natural killer cell lines suitable for adoptive cellular immunotherapy. Hum Gene Ther. 1999; 10(8): 1359–73.
https://doi. org/10.1089/10430349950018030.
58.
Zhang J, Sun R, Wei H, Tian Z. Characterization of interleukin-15 gene- -modified human natural killer cells: implications for adoptive cellular immunotherapy. Haematologica. 2004; 89(3): 338–47.
59.
Porter DL, Levine BL, Kalos M, Bagg A, June CH. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med. 2011; 365(8): 755–63.
https://doi.org/10.1056/NEJMoa....
60.
Schirrmann T, Pecher G. Human natural killer cell line modified with a chimeric immunoglobulin T-cell receptor gene leads to tumor growth inhibition in vivo. CancerGeneTher. 2002; 9(4): 390–8.
https://doi. org/10.1038/sj.cgt.7700453.
61.
Schirrmann T, Pecher G. Specific targeting of CD33+ leukemia cells by a natural killer cell line modified with a chimeric receptor. Leuk Res. 2005; 29(3): 301–6.
https://doi.org/10.1016/j.leuk....
62.
Muller T, Uherek C, Maki G, Chow KU, Schimpf A, Klingemann HG et al. Expression of a CD20-specific chimeric antigen receptor enhances cytotoxic activity of NK cells and overcomes NK-resistance of lymphoma and leukemia cells. Cancer Immunol Immunother. 2008; 57(3): 411–23.
https://doi.org/10.1007/s00262....
63.
Imai C, Iwamoto S, Campana D. Genetic modification of primary natural killer cells overcomes inhibitory signals and induces specific killing of leukemic cells. Blood. 2005; 106(1): 376–83.
https://doi.org/10.1182/ blood-2004-12-4797.
64.
Kruschinski A, Moosmann A, Poschke I, Norell H, Chmielewski M, Seliger B, et al. Engineering antigen-specific primary human NK cells against HER-2 positive carcinomas. Proc Natl Acad Sci U.S.A. 2008; 105(45): 17481–6.
https://doi.org/10.1073/pnas.0....
65.
Meier R, Piert M, Piontek G, Rudelius M, Oostendorp RA, Senekowitsch-Schmidtke R, et al. Tracking of [18F] FDG-labeled natural killer cells to HER2/neu-positive tumors. NuclMed Biol. 2008; 35(5): 79–588.
https://doi.org/10.1016/j.nucm....
66.
Pegram HJ, Jackson JT, Smyth MJ, Kershaw MH, Darcy PK. Adoptive transfer of gene-modified primary NK cells can specifically inhibit tumor progression in vivo. J Immunol. 2008; 181(5); 3449–55. https:// doi.org/10.4049/jimmunol.181.5.3449.
68.
Ghiringhelli F, Menard C, Terme M, Flament C, Taieb J, Chaput N et al. CD4+ CD25+ regulatory T cells inhibit natural killer cell functions in a transforming growth factor-beta-dependent manner. J Exp Med. 2005; 202(8): 1075–85.
https://doi.org/10.1084/jem.20....
69.
Caligiuri MA, Murray C, Robertson MJ, Wang E, Cochran K, Cameron C et al. Selective modulation of human natural killer cells in vivo after prolonged infusion of low dose recombinant interleukin 2. J Clin Invest. 1993; 91(1): 123–32.
https://doi.org/10.1172/JCI116....
70.
Raulet DH, Held W. Natural killer cell receptors: the offs and ons of NK cell recognition. Cell. 1995; 82(5): 697–700.
https://doi.org/10.1016/0092- 8674(95)90466-2.
71.
Ruggeri L, Capanni M, Urbani E, Perruccio K, Shlomchik WD, Tosti A et al. Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Science. 2002; 295(5562): 2097–100.
https://doi.org/10.1126/scienc....
72.
Cheng M, Zhang J, Jiang W, Chen Y, Tian Z. Natural killer cell lines in tumor immunotherapy. Front Med. 2012; 6(1): 56–66.
https://doi. org/10.1007/s11684-012-0177-7.
73.
Tonn T, Becker S, Esser R, Schwabe D, Seifried E. Cellular immunotherapy of malignancies using the clonal natural killer cell line NK-92. J HematotherStem Cell Res. 2001; 10(4): 535–44.
https://doi. org/10.1089/15258160152509145.
74.
Maki G, Klingemann HG, Martinson JA, Tam YK. Factors regulating the cytotoxic activity of the human natural killer cell line, NK92. J Hematother Stem Cell Res. 2001; 10(3): 369–83.
https://doi. org/10.1089/152581601750288975.
75.
Boissel L, Betancur M, Lu W, Wels WS, Marino T, Van Etten RA et al. Comparison of mRNA and lentiviral based transfection of natural killer cells with chimeric antigen receptors recognizing lymphoid antigens. Leuk Lymphoma. 2012; 53(5): 958–65.
https://doi.org/10.3109/104281 94.2011.634048.
76.
Arai S, Meagher R, Swearingen M, Myint H, Rich E, Martinson J et al. Infusion of the allogeneic cell line NK-92 in patients with advanced renal cell cancer or melanoma: a phase I trial. Cytotherapy. 2008; 10(6): 625–32.
https://doi.org/10.1080/146532....