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

Frontiers in Immunology

Volumn 8, Issue MAY, 2017, Pages

  Zhang, Congcong ^a,b   Oberoi, Pranav ^a   Oelsner, Sarah ^a   Waldmann, Anja ^a   Lindner, Aline ^a   Tonn, Torsten ^b,c,d   Wels, Winfried S ^a,b  

^a INSTITUTE FOR TUMOR BIOLOGY AND EXPERIMENTAL THERAPY   (Germany)

^b GERMAN CANCER RESEARCH CENTER DKFZ   (Germany)

^c Red Cross Donor Service Sachsen   (Germany)

^d DRESDEN UNIVERSITY OF TECHNOLOGY   (Germany)

Author keywords

Adoptive cancer immunotherapy; Chimeric antigen receptor; Leukemia; Lymphoma; Natural killer cells; NK 92; Solid tumors

Indexed keywords

CD137 ANTIGEN; CD19 ANTIGEN; CD3 ANTIGEN; CD4 ANTIGEN; CHIMERIC ANTIGEN RECEPTOR; EPIDERMAL GROWTH FACTOR RECEPTOR 2;

ADAPTIVE IMMUNITY; ANTINEOPLASTIC ACTIVITY; ARTICLE; CANCER CELL; CELL EXPANSION; CELL LINE; DENDRITIC CELL; GOOD MANUFACTURING PRACTICE; HUMAN; HUMAN CELL; IMMUNOSUPPRESSIVE TREATMENT; INNATE IMMUNITY; NATURAL KILLER CELL; NATURAL KILLER CELL MEDIATED CYTOTOXICITY; NK 92 CELL LINE; PROTEIN EXPRESSION;

EID: 85019997751     PISSN: None     EISSN: 16643224     Source Type: Journal    
DOI: 10.3389/fimmu.2017.00533     Document Type: Article

References (149)

1. Lanier LL. Up on the tightrope: natural killer cell activation and inhibition. Nat Immunol (2008) 9(5):495-502. doi:10.1038/ni1581
2. Koch J, Steinle A, Watzl C, Mandelboim O. Activating natural cytotoxicity receptors of natural killer cells in cancer and infection. Trends Immunol (2013) 34(4):182-91. doi:10.1016/j.it.2013.01.003
3. Smyth MJ, Hayakawa Y, Takeda K, Yagita H. New aspects of natural-killer-cell surveillance and therapy of cancer. Nat Rev Cancer (2002) 2(11):850-61. doi:10.1038/nrc928
4. Vesely MD, Kershaw MH, Schreiber RD, Smyth MJ. Natural innate and adaptive immunity to cancer. Annu Rev Immunol (2011) 29:235-71. doi:10.1146/annurev-immunol-031210-101324
5. Imai K, Matsuyama S, Miyake S, Suga K, Nakachi K. Natural cytotoxic activity of peripheral-blood lymphocytes and cancer incidence: an 11-year follow-up study of a general population. Lancet (2000) 356(9244):1795-9. doi:10.1016/S0140-6736(00)03231-1
6. Carrega P, Morandi B, Costa R, Frumento G, Forte G, Altavilla G, et al. Natural killer cells infiltrating human nonsmall-cell lung cancer are enriched in CD56 bright CD16(-) cells and display an impaired capability to kill tumor cells. Cancer (2008) 112(4):863-75. doi:10.1002/cncr.23239
7. Halama N, Braun M, Kahlert C, Spille A, Quack C, Rahbari N, et al. Natural killer cells are scarce in colorectal carcinoma tissue despite high levels of chemokines and cytokines. Clin Cancer Res (2011) 17(4):678-89. doi:10.1158/1078-0432.CCR-10-2173
8. Eckl J, Buchner A, Prinz PU, Riesenberg R, Siegert SI, Kammerer R, et al. Transcript signature predicts tissue NK cell content and defines renal cell carcinoma subgroups independent of TNM staging. J Mol Med (Berl) (2012) 90(1):55-66. doi:10.1007/s00109-011-0806-7
9. Kochan G, Escors D, Breckpot K, Guerrero-Setas D. Role of non-classical MHC class I molecules in cancer immunosuppression. Oncoimmunology (2013) 2(11):e26491. doi:10.4161/onci.26491
10. Guerra N, Tan YX, Joncker NT, Choy A, Gallardo F, Xiong N, et al. NKG2D-deficient mice are defective in tumor surveillance in models of spontaneous malignancy. Immunity (2008) 28(4):571-80. doi:10.1016/j.immuni.2008.02.016
11. Elboim M, Gazit R, Gur C, Ghadially H, Betser-Cohen G, Mandelboim O. Tumor immunoediting by NKp46. J Immunol (2010) 184(10):5637-44. doi:10.4049/jimmunol.0901644
12. Reiners KS, Topolar D, Henke A, Simhadri VR, Kessler J, Sauer M, et al. Soluble ligands for NK cell receptors promote evasion of chronic lymphocytic leukemia cells from NK cell anti-tumor activity. Blood (2013) 121(18):3658-65. doi:10.1182/blood-2013-01-476606
13. Schlecker E, Fiegler N, Arnold A, Altevogt P, Rose-John S, Moldenhauer G, et al. Metalloprotease-mediated tumor cell shedding of B7-H6, the ligand of the natural killer cell-activating receptor NKp30. Cancer Res (2014) 74(13):3429-40. doi:10.1158/0008-5472.CAN-13-3017
14. Klöss S, Chambron N, Gardlowski T, Arseniev L, Koch J, Esser R, et al. Increased sMICA and TGFbeta1 levels in HNSCC patients impair NKG2D-dependent functionality of activated NK cells. Oncoimmunology (2015) 4(11):e1055993. doi:10.1080/2162402x.2015.1055993
15. Bruno A, Ferlazzo G, Albini A, Noonan DM. A think tank of TINK/TANKs: tumor-infiltrating/tumor-associated natural killer cells in tumor progression and angiogenesis. J Natl Cancer Inst (2014) 106(8):dju200. doi:10.1093/jnci/dju200
16. Melero I, Rouzaut A, Motz GT, Coukos G. T-cell and NK-cell infiltration into solid tumors: a key limiting factor for efficacious cancer immunotherapy. Cancer Discov (2014) 4(5):522-6. doi:10.1158/2159-8290.CD-13-0985
17. Vitale M, Cantoni C, Pietra G, Mingari MC, Moretta L. Effect of tumor cells and tumor microenvironment on NK-cell function. Eur J Immunol (2014) 44(6):1582-92. doi:10.1002/eji.201344272
18. Velardi A, Ruggeri L, Mancusi A, Aversa F, Christiansen FT. Natural killer cell allorecognition of missing self in allogeneic hematopoietic transplantation: a tool for immunotherapy of leukemia. Curr Opin Immunol (2009) 21(5):525-30. doi:10.1016/j.coi.2009.07.015
19. Davis ZB, Felices M, Verneris MR, Miller JS. Natural killer cell adoptive transfer therapy: exploiting the first line of defense against cancer. Cancer J (2015) 21(6):486-91. doi:10.1097/ppo.0000000000000156
20. Rezvani K, Rouce RH. The application of natural killer cell immunotherapy for the treatment of cancer. Front Immunol (2015) 6:578. doi:10.3389/fimmu.2015.00578
21. Vivier E, Ugolini S, Blaise D, Chabannon C, Brossay L. Targeting natural killer cells and natural killer T cells in cancer. Nat Rev Immunol (2012) 12(4):239-52. doi:10.1038/nri3174
22. Vallera DA, Felices M, McElmurry R, McCullar V, Zhou X, Schmohl JU, et al. IL15 trispecific killer engagers (TriKE) make natural killer cells specific to CD33+ targets while also inducing persistence, in vivo expansion, and enhanced function. Clin Cancer Res (2016) 22(14):3440-50. doi:10.1158/1078-0432.CCR-15-2710
23. Uherek C, Tonn T, Uherek B, Becker S, Schnierle B, Klingemann HG, et al. Retargeting of natural killer-cell cytolytic activity to ErbB2-expressing cancer cells results in efficient and selective tumor cell destruction. Blood (2002) 100(4):1265-73
24. 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. doi:10.1182/blood-2004-12-4797
25. Shimasaki N, Coustan-Smith E, Kamiya T, Campana D. Expanded and armed natural killer cells for cancer treatment. Cytotherapy (2016) 18(11):1422-34. doi:10.1016/j.jcyt.2016.06.013
26. Tran AC, Zhang D, Byrn R, Roberts MR. Chimeric zeta-receptors direct human natural killer (NK) effector function to permit killing of NK-resistant tumor cells and HIV-infected T lymphocytes. J Immunol (1995) 155(2):1000-9
27. Binyamin L, Alpaugh RK, Hughes TL, Lutz CT, Campbell KS, Weiner LM. Blocking NK cell inhibitory self-recognition promotes antibody-dependent cellular cytotoxicity in a model of anti-lymphoma therapy. J Immunol (2008) 180(9):6392-401. doi:10.4049/jimmunol.180.9.6392
28. Sahm C, Schönfeld K, Wels WS. Expression of IL-15 in NK cells results in rapid enrichment and selective cytotoxicity of gene-modified effectors that carry a tumor-specific antigen receptor. Cancer Immunol Immunother (2012) 61(9):1451-61. doi:10.1007/s00262-012-1212-x
29. Oberoi P, Jabulowsky RA, Bähr-Mahmud H, Wels WS. EGFR-targeted granzyme B expressed in NK cells enhances natural cytotoxicity and mediates specific killing of tumor cells. PLoS One (2013) 8(4):e61267. doi:10.1371/journal.pone.0061267
30. Glienke W, Esser R, Priesner C, Suerth JD, Schambach A, Wels WS, et al. Advantages and applications of CAR-expressing natural killer cells. Front Pharmacol (2015) 6:21. doi:10.3389/fphar.2015.00021
31. Tonn T, Becker S, Esser R, Schwabe D, Seifried E. Cellular immunotherapy of malignancies using the clonal natural killer cell line NK-92. J Hematother Stem Cell Res (2001) 10(4):535-44. doi:10.1089/15258160152509145
32. Klingemann H, Boissel L, Toneguzzo F. Natural killer cells for immunotherapy - advantages of the NK-92 cell line over blood NK cells. Front Immunol (2016) 7:91. doi:10.3389/fimmu.2016.00091
33. Gong JH, Maki G, Klingemann HG. Characterization of a human cell line (NK-92) with phenotypical and functional characteristics of activated natural killer cells. Leukemia (1994) 8(4):652-8
34. Maki G, Klingemann HG, Martinson JA, Tam YK. Factors regulating the cytotoxic activity of the human natural killer cell line, NK-92. J Hematother Stem Cell Res (2001) 10(3):369-83. doi:10.1089/152581601750288975
35. 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. doi:10.1080/14653240802301872
36. 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. doi:10.1016/j.jcyt.2013.06.017
37. Eshhar Z, Waks T, Gross G, Schindler DG. Specific activation and targeting of cytotoxic lymphocytes through chimeric single chains consisting of antibody-binding domains and the gamma or zeta subunits of the immunoglobulin and T-cell receptors. Proc Natl Acad Sci U S A (1993) 90(2):720-4. doi:10.1073/pnas.90.2.720
38. Gill S, June CH. Going viral: chimeric antigen receptor T-cell therapy for hematological malignancies. Immunol Rev (2015) 263(1):68-89. doi:10.1111/imr.12243
39. Davila ML, Sadelain M. Biology and clinical application of CAR T cells for B cell malignancies. Int J Hematol (2016) 104(1):6-17. doi:10.1007/s12185-016-2039-6
40. Maus MV, Grupp SA, Porter DL, June CH. Antibody-modified T cells: CARs take the front seat for hematologic malignancies. Blood (2014) 123(17):2625-35. doi:10.1182/blood-2013-11-492231
41. Fesnak AD, June CH, Levine BL. Engineered T cells: the promise and challenges of cancer immunotherapy. Nat Rev Cancer (2016) 16(9):566-81. doi:10.1038/nrc.2016.97
42. Chmielewski M, Hombach AA, Abken H. Of CARs and TRUCKs: chimeric antigen receptor (CAR) T cells engineered with an inducible cytokine to modulate the tumor stroma. Immunol Rev (2014) 257(1):83-90. doi:10.1111/imr.12125
43. Cartellieri M, Feldmann A, Koristka S, Arndt C, LoffS, Ehninger A, et al. Switching CAR T cells on and off: a novel modular platform for retargeting of T cells to AML blasts. Blood Cancer J (2016) 6(8):e458. doi:10.1038/bcj.2016.61
44. Grada Z, Hegde M, Byrd T, Shaffer DR, Ghazi A, Brawley VS, et al. TanCAR: a novel bispecific chimeric antigen receptor for cancer immunotherapy. Mol Ther Nucleic Acids (2013) 2:e105. doi:10.1038/mtna.2013.32
45. Hegde M, Mukherjee M, Grada Z, Pignata A, Landi D, Navai SA, et al. Tandem CAR T cells targeting HER2 and IL13Ralpha2 mitigate tumor antigen escape. J Clin Invest (2016) 126(8):3036-52. doi:10.1172/JCI83416
46. Milone MC, Fish JD, Carpenito C, Carroll RG, Binder GK, Teachey D, et al. Chimeric receptors containing CD137 signal transduction domains mediate enhanced survival of T cells and increased antileukemic efficacy in vivo. Mol Ther (2009) 17(8):1453-64. doi:10.1038/mt.2009.83
47. Kawalekar OU, O'Connor RS, Fraietta JA, Guo L, McGettigan SE, Posey AD Jr, et al. Distinct signaling of coreceptors regulates specific metabolism pathways and impacts memory development in CAR T cells. Immunity (2016) 44(2):380-90. doi:10.1016/j.immuni.2016.01.021
48. Romanski A, Uherek C, Bug G, Müller T, Rössig C, Kampfmann M, et al. Re-targeting of an NK cell line (NK92) with specificity for CD19 efficiently kills human B-precursor leukemia cells. Blood (2004) 104(11):751A-751A
49. Müller 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. doi:10.1007/s00262-007-0383-3
50. Boissel L, Betancur M, Wels WS, Tuncer H, Klingemann H. Transfection with mRNA for CD19 specific chimeric antigen receptor restores NK cell mediated killing of CLL cells. Leuk Res (2009) 33(9):1255-9. doi:10.1016/j.leukres.2008.11.024
51. 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. doi:10.3109/10428194.2011.634048
52. Boissel L, Betancur-Boissel M, Lu W, Krause DS, Van Etten RA, Wels WS, et al. Retargeting NK-92 cells by means of CD19-and CD20-specific chimeric antigen receptors compares favorably with antibody-dependent cellular cytotoxicity. Oncoimmunology (2013) 2(10):e26527. doi:10.4161/onci.26527
53. Romanski A, Uherek C, Bug G, Seifried E, Klingemann H, Wels WS, et al. CD19-CAR engineered NK-92 cells are sufficient to overcome NK cell resistance in B-cell malignancies. J Cell Mol Med (2016) 20(7):1287-94. doi:10.1111/jcmm.12810
54. Jiang H, Zhang W, Shang P, Zhang H, Fu W, Ye F, et al. Transfection of chimeric anti-CD138 gene enhances natural killer cell activation and killing of multiple myeloma cells. Mol Oncol (2014) 8(2):297-310. doi:10.1016/j.molonc.2013.12.001
55. Tavri S, Jha P, Meier R, Henning TD, Müller T, Hostetter D, et al. Optical imaging of cellular immunotherapy against prostate cancer. Mol Imaging (2009) 8(1):15-26. doi:10.2310/7290.2009.00002
56. Esser R, Müller T, Stefes D, Kloess S, Seidel D, Gillies SD, et al. NK cells engineered to express a GD2-specific antigen receptor display built-in ADCC-like activity against tumour cells of neuroectodermal origin. J Cell Mol Med (2012) 16(3):569-81. doi:10.1111/j.1582-4934.2011.01343.x
57. Zhang G, Liu RZ, Zhu XK, Wang L, Ma J, Han HM, et al. Retargeting NK-92 for anti-melanoma activity by a TCR-like single-domain antibody. Immunol Cell Biol (2013) 91(10):615-24. doi:10.1038/icb.2013.45
58. Clemenceau B, Valsesia-Wittmann S, Jallas AC, Vivien R, Rousseau R, Marabelle A, et al. In vitro and in vivo comparison of lymphocytes transduced with a human CD16 or with a chimeric antigen receptor reveals potential off-target interactions due to the IgG2 CH2-CH3 CAR-spacer. J Immunol Res (2015) 2015:482089. doi:10.1155/2015/482089
59. Seidel D, Shibina A, Siebert N, Wels WS, Reynolds CP, Huebener N, et al. Disialoganglioside-specific human natural killer cells are effective against drug-resistant neuroblastoma. Cancer Immunol Immunother (2015) 64(5):621-34. doi:10.1007/s00262-015-1669-5
60. Altvater B, Landmeier S, Pscherer S, Temme J, Schweer K, Kailayangiri S, et al. 2B4 (CD244) signaling by recombinant antigen-specific chimeric receptors costimulates natural killer cell activation to leukemia and neuroblastoma cells. Clin Cancer Res (2009) 15(15):4857-66. doi:10.1158/1078-0432.CCR-08-2810
61. 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. doi:10.1073/pnas.0804788105
62. Chu Y, Hochberg J, Yahr A, Ayello J, van de Ven C, Barth M, et al. Targeting CD20+ aggressive B-cell non-Hodgkin lymphoma by anti-CD20 CAR mRNA-modified expanded natural killer cells in vitro and in NSG mice. Cancer Immunol Res (2015) 3(4):333-44. doi:10.1158/2326-6066.CIR-14-0114
63. Daldrup-Link HE, Meier R, Rudelius M, Piontek G, Piert M, Metz S, et al. In vivo tracking of genetically engineered, anti-HER2/neu directed natural killer cells to HER2/neu positive mammary tumors with magnetic resonance imaging. Eur Radiol (2005) 15(1):4-13. doi:10.1007/s00330-004-2526-7
64. 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. Nucl Med Biol (2008) 35(5):579-88. doi:10.1016/j.nucmedbio.2008.02.006
65. Alkins R, Burgess A, Ganguly M, Francia G, Kerbel R, Wels WS, et al. Focused ultrasound delivers targeted immune cells to metastatic brain tumors. Cancer Res (2013) 73(6):1892-9. doi:10.1158/0008-5472.CAN-12-2609
66. Alkins R, Burgess A, Kerbel R, Wels WS, Hynynen K. Early treatment of HER2-amplified brain tumors with targeted NK-92 cells and focused ultrasound improves survival. Neuro Oncol (2016) 18(7):974-81. doi:10.1093/neuonc/nov318
67. Schönfeld K, Sahm C, Zhang C, Naundorf S, Brendel C, Odendahl M, et al. Selective inhibition of tumor growth by clonal NK cells expressing an ErbB2/HER2-specific chimeric antigen receptor. Mol Ther (2015) 23(2):330-8. doi:10.1038/mt.2014.219
68. Liu H, Yang B, Sun T, Lin L, Hu Y, Deng M, et al. Specific growth inhibition of ErbB2-expressing human breast cancer cells by genetically modified NK92 cells. Oncol Rep (2015) 33(1):95-102. doi:10.3892/or.2014.3548
69. Zhang C, Burger MC, Jennewein L, Genssler S, Schönfeld K, Zeiner P, et al. ErbB2/HER2-specific NK cells for targeted therapy of glioblastoma. J Natl Cancer Inst (2016) 108(5):djv375. doi:10.1093/jnci/djv375
70. Chen X, Han J, Chu J, Zhang L, Zhang J, Chen C, et al. A combinational therapy of EGFR-CAR NK cells and oncolytic herpes simplex virus 1 for breast cancer brain metastases. Oncotarget (2016) 7(19):27764-77. doi:10.18632/oncotarget.8526
71. Genßler S, Burger MC, Zhang C, Oelsner S, Mildenberger I, Wagner M, et al. Dual targeting of glioblastoma with chimeric antigen receptor-engineered natural killer cells overcomes heterogeneity of target antigen expression and enhances antitumor activity and survival. Oncoimmunology (2016) 5(4):e1119354. doi:10.1080/2162402X.2015.1119354
72. Han J, Chu J, Keung Chan W, Zhang J, Wang Y, Cohen JB, et al. CAR-engineered NK cells targeting wild-type EGFR and EGFRvIII enhance killing of glioblastoma and patient-derived glioblastoma stem cells. Sci Rep (2015) 5:11483. doi:10.1038/srep11483
73. Meier R, Golovko D, Tavri S, Henning TD, Knopp C, Piontek G, et al. Depicting adoptive immunotherapy for prostate cancer in an animal model with magnetic resonance imaging. Magn Reson Med (2011) 65(3):756-63. doi:10.1002/mrm.22652
74. Oelsner S, Friede ME, Zhang C, Wagner J, Badura S, Bader P, et al. Continuously expanding CAR NK-92 cells display selective cytotoxicity against B-cell leukemia and lymphoma. Cytotherapy (2017) 19(2):235-49. doi:10.1016/j.jcyt.2016.10.009
75. Chen KH, Wada M, Firor AE, Pinz KG, Jares A, Liu H, et al. Novel anti-CD3 chimeric antigen receptor targeting of aggressive T cell malignancies. Oncotarget (2016) 7(35):56219-32. doi:10.18632/oncotarget.11019
76. Chen KH, Wada M, Pinz KG, Liu H, Lin KW, Jares A, et al. Preclinical targeting of aggressive T-cell malignancies using anti-CD5 chimeric antigen receptor. Leukemia (2017). doi:10.1038/leu.2017.8
77. Chu J, Deng Y, Benson DM, He S, Hughes T, Zhang J, et al. CS1-specific chimeric antigen receptor (CAR)-engineered natural killer cells enhance in vitro and in vivo antitumor activity against human multiple myeloma. Leukemia (2014) 28(4):917-27. doi:10.1038/leu.2013.279
78. Tassev DV, Cheng M, Cheung NKV. Retargeting NK92 cells using an HLA-A2-restricted, EBNA3C-specific chimeric antigen receptor. Cancer Gene Ther (2012) 19(2):84-100. doi:10.1038/cgt.2011.66
79. Zhao Q, Ahmed M, Tassev DV, Hasan A, Kuo TY, Guo HF, et al. Affinity maturation of T-cell receptor-like antibodies for Wilms tumor 1 peptide greatly enhances therapeutic potential. Leukemia (2015) 29(11):2238-47. doi:10.1038/leu.2015.125
80. Klingemann H. Are natural killer cells superior CAR drivers? Oncoimmunology (2014) 3:e28147. doi:10.4161/onci.28147
81. Rafiq S, Purdon TJ, Schultz L, Klingemann H, Brentjens RJ. NK-92 cells engineered with anti-CD33 chimeric antigen receptors (CAR) for the treatment of acute myeloid leukemia (AML). Cytotherapy (2015) 17(6):S23-23. doi:10.1016/j.jcyt.2015.03.384
82. Hombach AA, Schildgen V, Heuser C, Finnern R, Gilham DE, Abken H. T cell activation by antibody-like immunoreceptors: the position of the binding epitope within the target molecule determines the efficiency of activation of redirected T cells. J Immunol (2007) 178(7):4650-7. doi:10.4049/jimmunol.178.7.4650
83. James SE, Greenberg PD, Jensen MC, Lin Y, Wang J, Till BG, et al. Antigen sensitivity of CD22-specific chimeric TCR is modulated by target epitope distance from the cell membrane. J Immunol (2008) 180(10):7028-38. doi:10.4049/jimmunol.180.10.7028
84. Sadelain M, Brentjens R, Riviere I. The basic principles of chimeric antigen receptor design. Cancer Discov (2013) 3(4):388-98. doi:10.1158/2159-8290.CD-12-0548
85. Klingemann H. Challenges of cancer therapy with natural killer cells. Cytotherapy (2015) 17(3):245-9. doi:10.1016/j.jcyt.2014.09.007
86. Vivier E. What is natural in natural killer cells? Immunol Lett (2006) 107(1):1-7. doi:10.1016/j.imlet.2006.07.004
87. Sun JC, Lanier LL. NK cell development, homeostasis and function: parallels with CD8(+) T cells. Nat Rev Immunol (2011) 11(10):645-57. doi:10.1038/nri3044
88. Childs RW, Berg M. Bringing natural killer cells to the clinic: ex vivo manipulation. Hematology Am Soc Hematol Educ Program (2013) 2013:234-46. doi:10.1182/asheducation-2013.1.234
89. Koehl U, Brehm C, Huenecke S, Zimmermann SY, Kloess S, Bremm M, et al. Clinical grade purification and expansion of NK cell products for an optimized manufacturing protocol. Front Oncol (2013) 3:118. doi:10.3389/fonc.2013.00118
90. Suck G, Odendahl M, Nowakowska P, Seidl C, Wels WS, Klingemann HG, et al. NK-92: an 'off-the-shelf therapeutic' for adoptive natural killer cell-based cancer immunotherapy. Cancer Immunol Immunother (2016) 65(4):485-92. doi:10.1007/s00262-015-1761-x
91. Nagashima S, Mailliard R, Kashii Y, Reichert TE, Herberman RB, Robbins P, et al. Stable transduction of the interleukin-2 gene into human natural killer cell lines and their phenotypic and functional characterization in vitro and in vivo. Blood (1998) 91(10):3850-61
92. 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. doi:10.1089/10430349950018030
93. Zhang J, Sun R, Wei H, Zhang J, Tian Z. Characterization of interleukin-15 gene-modified human natural killer cells: implications for adoptive cellular immunotherapy. Haematologica (2004) 89(3):338-47
94. Zhang J, Sun R, Wei H, Zhang J, Tian Z. Characterization of stem cell factor gene-modified human natural killer cell line, NK-92 cells: implication in NK cell-based adoptive cellular immunotherapy. Oncol Rep (2004) 11(5):1097-106. doi:10.3892/or.11.5.1097
95. Waldmann TA, Dubois S, Tagaya Y. Contrasting roles of IL-2 and IL-15 in the life and death of lymphocytes: implications for immunotherapy. Immunity (2001) 14(2):105-10. doi:10.1016/S1074-7613(01)00093-0
96. Konstantinidis KV, Alici E, Aints A, Christensson B, Ljunggren HG, Dilber MS. Targeting IL-2 to the endoplasmic reticulum confines autocrine growth stimulation to NK-92 cells. Exp Hematol (2005) 33(2):159-64. doi:10.1016/j.exphem.2004.11.003
97. Jochems C, Hodge JW, Fantini M, Fujii R, Morillon YM II, Greiner JW, et al. An NK cell line (haNK) expressing high levels of granzyme and engineered to express the high affinity CD16 allele. Oncotarget (2016) 7(52):86359-73. doi:10.18632/oncotarget.13411
98. Lanier LL, Yu G, Phillips JH. Analysis of Fc gamma RIII (CD16) membrane expression and association with CD3 zeta and Fc epsilon RI-gamma by site-directed mutation. J Immunol (1991) 146(5):1571-6
99. Vivier E, Rochet N, Ackerly M, Petrini J, Levine H, Daley J, et al. Signaling function of reconstituted CD16: zeta: gamma receptor complex isoforms. Int Immunol (1992) 4(11):1313-23. doi:10.1093/intimm/4.11.1313
100. Clemenceau B, Vivien R, Pellat C, Foss M, Thibault G, Vie H. The human natural killer cytotoxic cell line NK-92, once armed with a murine CD16 receptor, represents a convenient cellular tool for the screening of mouse mAbs according to their ADCC potential. MAbs (2013) 5(4):587-94. doi:10.4161/mabs.25077
101. Isakov N. Immunoreceptor tyrosine-based activation motif (ITAM), a unique module linking antigen and Fc receptors to their signaling cascades. J Leukoc Biol (1997) 61(1):6-16
102. Fernandez NC, Lozier A, Flament C, Ricciardi-Castagnoli P, Bellet D, Suter M, et al. Dendritic cells directly trigger NK cell functions: cross-talk relevant in innate anti-tumor immune responses in vivo. Nat Med (1999) 5(4):405-11. doi:10.1038/7403
103. Walzer T, Dalod M, Robbins SH, Zitvogel L, Vivier E. Natural-killer cells and dendritic cells: 'l'union fait la force'. Blood (2005) 106(7):2252-8. doi:10.1182/blood-2005-03-1154
104. Van Elssen CH, Oth T, Germeraad WT, Bos GM, Vanderlocht J. Natural killer cells: the secret weapon in dendritic cell vaccination strategies. Clin Cancer Res (2014) 20(5):1095-103. doi:10.1158/1078-0432.CCR-13-2302
105. Gerosa F, Baldani-Guerra B, Nisii C, Marchesini V, Carra G, Trinchieri G. Reciprocal activating interaction between natural killer cells and dendritic cells. J Exp Med (2002) 195(3):327-33. doi:10.1084/jem.20010938
106. Piccioli D, Sbrana S, Melandri E, Valiante NM. Contact-dependent stimulation and inhibition of dendritic cells by natural killer cells. J Exp Med (2002) 195(3):335-41. doi:10.1084/jem.20010934
107. Vitale M, Della Chiesa M, Carlomagno S, Pende D, Arico M, Moretta L, et al. NK-dependent DC maturation is mediated by TNFalpha and IFNgamma released upon engagement of the NKp30 triggering receptor. Blood (2005) 106(2):566-71. doi:10.1182/blood-2004-10-4035
108. Ni J, Miller M, Stojanovic A, Garbi N, Cerwenka A. Sustained effector function of IL-12/15/18-preactivated NK cells against established tumors. J Exp Med (2012) 209(13):2351-65. doi:10.1084/jem.20120944
109. Colonna M, Trinchieri G, Liu YJ. Plasmacytoid dendritic cells in immunity. Nat Immunol (2004) 5(12):1219-26. doi:10.1038/ni1141
110. Ferlazzo G, Tsang ML, Moretta L, Melioli G, Steinman RM, Munz C. Human dendritic cells activate resting natural killer (NK) cells and are recognized via the NKp30 receptor by activated NK cells. J Exp Med (2002) 195(3):343-51. doi:10.1084/jem.20011149
111. Jinushi M, Takehara T, Kanto T, Tatsumi T, Groh V, Spies T, et al. Critical role of MHC class I-related chain A and B expression on IFN-alpha-stimulated dendritic cells in NK cell activation: impairment in chronic hepatitis C virus infection. J Immunol (2003) 170(3):1249-56. doi:10.4049/jimmunol.170.3.1249
112. Draghi M, Pashine A, Sanjanwala B, Gendzekhadze K, Cantoni C, Cosman D, et al. NKp46 and NKG2D recognition of infected dendritic cells is necessary for NK cell activation in the human response to influenza infection. J Immunol (2007) 178(5):2688-98. doi:10.4049/jimmunol.178.5.2688
113. Wai LE, Garcia JA, Martinez OM, Krams SM. Distinct roles for the NK cell-activating receptors in mediating interactions with dendritic cells and tumor cells. J Immunol (2011) 186(1):222-9. doi:10.4049/jimmunol.1002597
114. Della Chiesa M, Vitale M, Carlomagno S, Ferlazzo G, Moretta L, Moretta A. The natural killer cell-mediated killing of autologous dendritic cells is confined to a cell subset expressing CD94/NKG2A, but lacking inhibitory killer Ig-like receptors. Eur J Immunol (2003) 33(6):1657-66. doi:10.1002/eji.200323986
115. Castriconi R, Cantoni C, Della Chiesa M, Vitale M, Marcenaro E, Conte R, et al. Transforming growth factor beta 1 inhibits expression of NKp30 and NKG2D receptors: consequences for the NK-mediated killing of dendritic cells. Proc Natl Acad Sci U S A (2003) 100(7):4120-5. doi:10.1073/pnas.0730640100
116. Fauriat C, Moretta A, Olive D, Costello RT. Defective killing of dendritic cells by autologous natural killer cells from acute myeloid leukemia patients. Blood (2005) 106(6):2186-8. doi:10.1182/blood-2005-03-1270
117. Ferlazzo G, Morandi B, D'Agostino A, Meazza R, Melioli G, Moretta A, et al. The interaction between NK cells and dendritic cells in bacterial infections results in rapid induction of NK cell activation and in the lysis of uninfected dendritic cells. Eur J Immunol (2003) 33(2):306-13. doi:10.1002/immu.200310004
118. Martin-Fontecha A, Thomsen LL, Brett S, Gerard C, Lipp M, Lanzavecchia A, et al. Induced recruitment of NK cells to lymph nodes provides IFN-gamma for T(H)1 priming. Nat Immunol (2004) 5(12):1260-5. doi:10.1038/ni1138
119. Sutlu T, Alici E. Natural killer cell-based immunotherapy in cancer: current insights and future prospects. J Intern Med (2009) 266(2):154-81. doi:10.1111/j.1365-2796.2009.02121.x
120. Baginska J, Viry E, Paggetti J, Medves S, Berchem G, Moussay E, et al. The critical role of the tumor microenvironment in shaping natural killer cell-mediated anti-tumor immunity. Front Immunol (2013) 4:490. doi:10.3389/fimmu.2013.00490
121. Favier B, Lemaoult J, Lesport E, Carosella ED. ILT2/HLA-G interaction impairs NK-cell functions through the inhibition of the late but not the early events of the NK-cell activating synapse. FASEB J (2010) 24(3):689-99. doi:10.1096/fj.09-135194
122. Narai S, Watanabe M, Hasegawa H, Nishibori H, Endo T, Kubota T, et al. Significance of transforming growth factor beta1 as a new tumor marker for colorectal cancer. Int J Cancer (2002) 97(4):508-11. doi:10.1002/ijc.1631
123. Kirwan SE, Burshtyn DN. Killer cell Ig-like receptor-dependent signaling by Ig-like transcript 2 (ILT2/CD85j/LILRB1/LIR-1). J Immunol (2005) 175(8):5006-15. doi:10.4049/jimmunol.175.8.5006
124. Yan Y, Steinherz P, Klingemann HG, Dennig D, Childs BH, McGuirk J, et al. Antileukemia activity of a natural killer cell line against human leukemias. Clin Cancer Res (1998) 4(11):2859-68
125. Tam YK, Miyagawa B, Ho VC, Klingemann HG. Immunotherapy of malignant melanoma in a SCID mouse model using the highly cytotoxic natural killer cell line NK-92. J Hematother (1999) 8(3):281-90. doi:10.1089/106161299320316
126. Boissel L, Klingemann H, Khan J, Soon-Shiong P. Intra-tumor injection of CAR-engineered NK cells induces tumor regression and protection against tumor re-challenge. Blood (2016) 128(22):466
127. Green JD, Terrell TG. Utilization of homologous proteins to evaluate the safety of recombinant human proteins - case study: recombinant human interferon-gamma (rhIFN-γ). Toxicol Lett (1992) 6(4-65):321-7. doi:10.1016/0378-4274(92)90204-W
128. Schroder K, Hertzog PJ, Ravasi T, Hume DA. Interferon-gamma: an overview of signals, mechanisms and functions. J Leukoc Biol (2004) 75(2):163-89. doi:10.1189/jlb.0603252
129. Schnurr M, Scholz C, Rothenfusser S, Galambos P, Dauer M, Robe J, et al. Apoptotic pancreatic tumor cells are superior to cell lysates in promoting cross-priming of cytotoxic T cells and activate NK and gammadelta T cells. Cancer Res (2002) 62(8):2347-52
130. Kokhaei P, Choudhury A, Mahdian R, Lundin J, Moshfegh A, Osterborg A, et al. Apoptotic tumor cells are superior to tumor cell lysate, and tumor cell RNA in induction of autologous T cell response in B-CLL. Leukemia (2004) 18(11):1810-5. doi:10.1038/sj.leu.2403517
131. Jacoby E, Yang Y, Qin H, Chien CD, Kochenderfer JN, Fry TJ. Murine allogeneic CD19 CAR T cells harbor potent antileukemic activity but have the potential to mediate lethal GVHD. Blood (2016) 127(10):1361-70. doi:10.1182/blood-2015-08-664250
132. Shah NN, Baird K, Delbrook CP, Fleisher TA, Kohler ME, Rampertaap S, et al. Acute GVHD in patients receiving IL-15/4-1BBL activated NK cells following T-cell-depleted stem cell transplantation. Blood (2015) 125(5):784-92. doi:10.1182/blood-2014-07-592881
133. Burger MC, Mildenberger I, Zhang C, Ihrig K, Wagner M, Mittelbronn M, et al. The CAR2BRAIN study: a monocentric phase I trial with ErbB2-specific NK-92/5.28.z cells in recurrent glioblastoma. Neuro Oncol (2016) 18:24-5. doi:10.1093/neuonc/now188.083
134. Teachey DT, Lacey SF, Shaw PA, Melenhorst JJ, Maude SL, Frey N, et al. Identification of predictive biomarkers for cytokine release syndrome after chimeric antigen receptor T-cell therapy for acute lymphoblastic leukemia. Cancer Discov (2016) 6(6):664-79. doi:10.1158/2159-8290.CD-16-0040
135. Lee DW, Gardner R, Porter DL, Louis CU, Ahmed N, Jensen M, et al. Current concepts in the diagnosis and management of cytokine release syndrome. Blood (2014) 124(2):188-95. doi:10.1182/blood-2014-05-552729
136. Maude SL, Barrett D, Teachey DT, Grupp SA. Managing cytokine release syndrome associated with novel T cell-engaging therapies. Cancer J (2014) 20(2):119-22. doi:10.1097/ppo.0000000000000035
137. Morgan RA, Yang JC, Kitano M, Dudley ME, Laurencot CM, Rosenberg SA. Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing ERBB2. Mol Ther (2010) 18(4):843-51. doi:10.1038/mt.2010.24
138. Liu X, Jiang S, Fang C, Yang S, Olalere D, Pequignot EC, et al. Affinity-tuned ErbB2 or EGFR chimeric antigen receptor T cells exhibit an increased therapeutic index against tumors in mice. Cancer Res (2015) 75(17):3596-607. doi:10.1158/0008-5472.can-15-0159
139. Cho HS, Mason K, Ramyar KX, Stanley AM, Gabelli SB, Denney DW Jr, et al. Structure of the extracellular region of HER2 alone and in complex with the Herceptin Fab. Nature (2003) 421(6924):756-60. doi:10.1038/nature01392
140. Gerstmayer B, Altenschmidt U, Hoffmann M, Wels W. Costimulation of T cell proliferation by a chimeric B7-2 antibody fusion protein specifically targeted to cells expressing the erbB2 proto-oncogene. J Immunol (1997) 158(10):4584-90
141. Ahmed N, Brawley VS, Hegde M, Robertson C, Ghazi A, Gerken C, et al. Human epidermal growth factor receptor 2 (HER2)-specific chimeric antigen receptor-modified T cells for the immunotherapy of HER2-positive sarcoma. J Clin Oncol (2015) 33(15):1688-96. doi:10.1200/jco.2014.58.0225
142. Di Stasi A, Tey SK, Dotti G, Fujita Y, Kennedy-Nasser A, Martinez C, et al. Inducible apoptosis as a safety switch for adoptive cell therapy. N Engl J Med (2011) 365(18):1673-83. doi:10.1056/NEJMoa1106152
143. Oberoi P, Wels WS. Arming NK cells with enhanced antitumor activity: CARs and beyond. Oncoimmunology (2013) 2(8):e25220. doi:10.4161/onci.25220
144. Wendel M, Galani IE, Suri-Payer E, Cerwenka A. Natural killer cell accumulation in tumors is dependent on IFN-gamma and CXCR3 ligands. Cancer Res (2008) 68(20):8437-45. doi:10.1158/0008-5472.CAN-08-1440
145. Pachynski RK, Zabel BA, Kohrt HE, Tejeda NM, Monnier J, Swanson CD, et al. The chemoattractant chemerin suppresses melanoma by recruiting natural killer cell antitumor defenses. J Exp Med (2012) 209(8):1427-35. doi:10.1084/jem.20112124
146. Müller N, Michen S, Tietze S, Topfer K, Schulte A, Lamszus K, et al. Engineering NK cells modified with an EGFRvIII-specific chimeric antigen receptor to overexpress CXCR4 improves immunotherapy of CXCL12/SDF-1alpha-secreting glioblastoma. J Immunother (2015) 38(5):197-210. doi:10.1097/cji.0000000000000082
147. Torikai H, Reik A, Liu PQ, Zhou Y, Zhang L, Maiti S, et al. A foundation for universal T-cell based immunotherapy: T cells engineered to express a CD19-specific chimeric-antigen-receptor and eliminate expression of endogenous TCR. Blood (2012) 119(24):5697-705. doi:10.1182/blood-2012-01-405365
148. Ren J, Liu X, Fang C, Jiang S, June CH, Zhao Y. Multiplex genome editing to generate universal CAR T cells resistant to PD1 inhibition. Clin Cancer Res (2016). doi:10.1158/1078-0432.ccr-16-1300
149. Qasim W, Zhan H, Samarasinghe S, Adams S, Amrolia P, Stafford S, et al. Molecular remission of infant B-ALL after infusion of universal TALEN gene-edited CAR T cells. Sci Transl Med (2017) 9(374):eaaj2013. doi:10.1126/scitranslmed.aaj2013