1932
0

Annual Review of Cancer Biology

Volume 7, 2023

CAR NK Cells: The Future Is Now

  • Martin J. Raftery1, Alexander Sebastian Franzén1 and Gabriele Pecher1
  • Competence Center of Immuno-Oncology and Translational Cell Therapy, Department of Hematology, Oncology and Tumor Immunology CCM, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Germany; email: [email protected]
  • Vol. 7:229-246 (Volume publication date April 2023)
  • First published as a Review in Advance on January 17, 2023
  • Copyright © 2023 by the author(s).
    This work is licensed under a Creative Commons Attribution 4.0 International License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. See credit lines of images or other third-party material in this article for license information

Abstract

Chimeric antigen receptor (CAR) T cell therapy has been a great success in CD19+ hematological diseases. Natural killer (NK) CAR cells offer an alternative to CAR T cells with an intrinsic potential for universal off-the-shelf cell therapeutics. The choice of cell type and the choice of CAR are both relevant for the feasibility, effectivity, engraftment, persistence, side effects, and safety of the cell therapy. Until recently CAR NK cells have proven difficult to develop into therapeutic products. Here, we give an overview of the source of CAR NK cells, gene transfer methods, and the manufacture of CAR NK cells for clinical application. We discuss improvements, as well as future options and problems that need to be addressed.

Keyword(s): cancer, CAR, cell therapy, chimeric antigen receptor, immunotherapy, NK cells, off-the-shelf product
Loading

Article metrics loading...

/content/journals/10.1146/annurev-cancerbio-061521-082320
2023-04-11
2025-06-21
Loading full text...

Full text loading...

/deliver/fulltext/cancerbio/7/1/annurev-cancerbio-061521-082320.html?itemId=/content/journals/10.1146/annurev-cancerbio-061521-082320&mimeType=html&fmt=ahah

Literature Cited

  1. Agresta L, Hoebe KHN, Janssen EM. 2018. The emerging role of CD244 signaling in immune cells of the tumor microenvironment. Front. Immunol. 9:2809
     [Google Scholar]
  2. Albinger N, Pfeifer R, Nitsche M, Mertlitz S, Campe J et al. 2022. Primary CD33-targeting CAR-NK cells for the treatment of acute myeloid leukemia. Blood Cancer J. 12:61
     [Google Scholar]
  3. Altvater B, Landmeier S, Pscherer S, Temme J, Schweer K et al. 2009. 2B4 (CD244) signaling by recombinant antigen-specific chimeric receptors costimulates natural killer cell activation to leukemia and neuroblastoma cells. Clin. Cancer Res. 15:4857–66
     [Google Scholar]
  4. Arias J, Yu J, Varshney M, Inzunza J, Nalvarte I. 2021. Hematopoietic stem cell- and induced pluripotent stem cell-derived CAR-NK cells as reliable cell-based therapy solutions. Stem Cells Transl. Med. 10:987–95
     [Google Scholar]
  5. Asai O, Longo DL, Tian ZG, Hornung RL, Taub DD et al. 1998. Suppression of graft-versus-host disease and amplification of graft-versus-tumor effects by activated natural killer cells after allogeneic bone marrow transplantation. J. Clin. Investig. 101:1835–42
     [Google Scholar]
  6. Bari R, Granzin M, Tsang KS, Roy A, Krueger W et al. 2019. A distinct subset of highly proliferative and lentiviral vector (LV)-transducible NK cells define a readily engineered subset for adoptive cellular therapy. Front. Immunol. 10:2001
     [Google Scholar]
  7. Benson DM Jr., Bakan CE, Mishra A, Hofmeister CC, Efebera Y 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 116:2286–94
     [Google Scholar]
  8. Bhat R, Watzl C. 2007. Serial killing of tumor cells by human natural killer cells–enhancement by therapeutic antibodies. PLOS ONE 2:e326
     [Google Scholar]
  9. Boissel L, Betancur M, Wels WS, Tuncer H, Klingemann H. 2009. Transfection with mRNA for CD19 specific chimeric antigen receptor restores NK cell mediated killing of CLL cells. Leuk. Res. 33:1255–59
     [Google Scholar]
  10. Boissel L, Betancur-Boissel M, Lu W, Krause DS, Van Etten RA et al. 2013. Retargeting NK-92 cells by means of CD19- and CD20-specific chimeric antigen receptors compares favorably with antibody-dependent cellular cytotoxicity. Oncoimmunology 2:e26527
     [Google Scholar]
  11. Braendstrup P, Levine BL, Ruella M 2020. The long road to the first FDA-approved gene therapy: chimeric antigen receptor T cells targeting CD19. Cytotherapy 22:57–69
     [Google Scholar]
  12. Burger MC, Zhang C, Harter PN, Romanski A, Strassheimer F et al. 2019. CAR-engineered NK cells for the treatment of glioblastoma: turning innate effectors into precision tools for cancer immunotherapy. Front. Immunol. 10:2683
     [Google Scholar]
  13. Chang YH, Connolly J, Shimasaki N, Mimura K, Kono K, Campana D. 2013. A chimeric receptor with NKG2D specificity enhances natural killer cell activation and killing of tumor cells. Cancer Res. 73:1777–86
     [Google Scholar]
  14. Chockley P, Patil SL, Gottschalk S. 2021. Transient blockade of TBK1/IKKε allows efficient transduction of primary human natural killer cells with vesicular stomatitis virus G-pseudotyped lentiviral vectors. Cytotherapy 23:787–92
     [Google Scholar]
  15. Christodoulou I, Ho WJ, Marple A, Ravich JW, Tam A et al. 2021a. Engineering CAR-NK cells to secrete IL-15 sustains their anti-AML functionality but is associated with systemic toxicities. J. Immunother. Cancer 9:e003894
     [Google Scholar]
  16. Christodoulou I, Rahnama R, Ravich JW, Seo J, Zolov SN et al. 2021b. Glycoprotein targeted CAR-NK cells for the treatment of SARS-CoV-2 infection. Front. Immunol. 12:763460
     [Google Scholar]
  17. Chu J, Deng Y, Benson DM, He S, Hughes T et al. 2014. CS1-specific chimeric antigen receptor (CAR)-engineered natural killer cells enhance in vitro and in vivo antitumor activity against human multiple myeloma. Leukemia 28:917–27
     [Google Scholar]
  18. Chu Y, Yahr A, Huang B, Ayello J, Barth M, Cairo MS 2017. Romidepsin alone or in combination with anti-CD20 chimeric antigen receptor expanded natural killer cells targeting Burkitt lymphoma in vitro and in immunodeficient mice. Oncoimmunology 6:e1341031
     [Google Scholar]
  19. Cichocki F, Bjordahl R, Gaidarova S, Mahmood S, Abujarour R et al. 2020. iPSC-derived NK cells maintain high cytotoxicity and enhance in vivo tumor control in concert with T cells and anti-PD-1 therapy. Sci. Transl. Med. 12:eaaz5618
     [Google Scholar]
  20. Cichocki F, Goodridge J, Bjordahl R, Mahmood S, Davis ZB et al. 2022. Dual-antigen targeted off-the-shelf NK cells show durable response and prevent antigen escape in lymphoma and leukemia. Blood 140:232451–62
     [Google Scholar]
  21. Clemenceau B, Valsesia-Wittmann S, Jallas AC, Vivien R, Rousseau R et al. 2015. 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. 2015:482089
     [Google Scholar]
  22. Colamartino ABL, Lemieux W, Bifsha P, Nicoletti S, Chakravarti N et al. 2019. Efficient and robust NK-cell transduction with Baboon envelope pseudotyped lentivector. Front. Immunol. 10:2873
     [Google Scholar]
  23. Conde E, Vercher E, Soria-Castellano M, Suarez-Olmos J, Mancheno U et al. 2021. Epitope spreading driven by the joint action of CART cells and pharmacological STING stimulation counteracts tumor escape via antigen-loss variants. J. Immunother. Cancer 9:e003351
     [Google Scholar]
  24. Crespo J, Vatan L, Maj T, Liu R, Kryczek I, Zou W. 2017. Phenotype and tissue distribution of CD28H+ immune cell subsets. Oncoimmunology 6:e1362529
     [Google Scholar]
  25. Crinier A, Dumas PY, Escaliere B, Piperoglou C, Gil L et al. 2021. Single-cell profiling reveals the trajectories of natural killer cell differentiation in bone marrow and a stress signature induced by acute myeloid leukemia. Cell Mol. Immunol. 18:1290–304
     [Google Scholar]
  26. Da Y, Liu Y, Hu Y, Liu W, Ma J et al. 2022. STING agonist cGAMP enhances anti-tumor activity of CAR-NK cells against pancreatic cancer. Oncoimmunology 11:2054105
     [Google Scholar]
  27. Daher M, Basar R, Gokdemir E, Baran N, Uprety N et al. 2021. Targeting a cytokine checkpoint enhances the fitness of armored cord blood CAR-NK cells. Blood 137:624–36
     [Google Scholar]
  28. Dehbashi M, Hojati Z, Motovali-Bashi M, Ganjalikhany MR, Cho WC et al. 2021. A novel CAR expressing NK cell targeting CD25 with the prospect of overcoming immune escape mechanism in cancers. Front. Oncol. 11:649710
     [Google Scholar]
  29. Denman CJ, Senyukov VV, Somanchi SS, Phatarpekar PV, Kopp LM et al. 2012. Membrane-bound IL-21 promotes sustained ex vivo proliferation of human natural killer cells. PLOS ONE 7:e30264
     [Google Scholar]
  30. Deuse T, Hu X, Gravina A, Wang D, Tediashvili G et al. 2019. Hypoimmunogenic derivatives of induced pluripotent stem cells evade immune rejection in fully immunocompetent allogeneic recipients. Nat. Biotechnol. 37:252–58
     [Google Scholar]
  31. Dong H, Ham JD, Hu G, Xie G, Vergara J et al. 2022. Memory-like NK cells armed with a neoepitope-specific CAR exhibit potent activity against NPM1 mutated acute myeloid leukemia. PNAS 119:e2122379119
     [Google Scholar]
  32. Du Z, Ng YY, Zha S, Wang S 2021. piggyBac system to co-express NKG2D CAR and IL-15 to augment the in vivo persistence and anti-AML activity of human peripheral blood NK cells. Mol. Ther. Methods Clin. Dev. 23:582–96
     [Google Scholar]
  33. Euchner J, Sprissler J, Cathomen T, Furst D, Schrezenmeier H et al. 2021. Natural killer cells generated from human induced pluripotent stem cells mature to CD56brightCD16+NKp80+/−in-vitro and express KIR2DL2/DL3 and KIR3DL1. Front. Immunol. 12:640672
     [Google Scholar]
  34. Fabian KP, Padget MR, Donahue RN, Solocinski K, Robbins Y et al. 2020. PD-L1 targeting high-affinity NK (t-haNK) cells induce direct antitumor effects and target suppressive MDSC populations. J. Immunother. Cancer 8:e000450
     [Google Scholar]
  35. Fraietta JA, Lacey SF, Orlando EJ, Pruteanu-Malinici I, Gohil M et al. 2018. Determinants of response and resistance to CD19 chimeric antigen receptor (CAR) T cell therapy of chronic lymphocytic leukemia. Nat. Med. 24:563–71
     [Google Scholar]
  36. Freeman AJ, Vervoort SJ, Ramsbottom KM, Kelly MJ, Michie J et al. 2019. Natural killer cells suppress T cell-associated tumor immune evasion. Cell Rep. 28:2784–94.e5
     [Google Scholar]
  37. Gang M, Marin ND, Wong P, Neal CC, Marsala L et al. 2020. CAR-modified memory-like NK cells exhibit potent responses to NK-resistant lymphomas. Blood 136:2308–18
     [Google Scholar]
  38. Georg P, Astaburuaga-Garcia R, Bonaguro L, Brumhard S, Michalick L et al. 2022. Complement activation induces excessive T cell cytotoxicity in severe COVID-19. Cell 185:493–512.e25
     [Google Scholar]
  39. Goldenson BH, Hor P, Kaufman DS. 2022. iPSC-derived natural killer cell therapies—expansion and targeting. Front. Immunol. 13:841107
     [Google Scholar]
  40. Granzin M, Soltenborn S, Müller S, Kollet J, Berg M et al. 2015. Fully automated expansion and activation of clinical-grade natural killer cells for adoptive immunotherapy. Cytotherapy 17:621–32
     [Google Scholar]
  41. Gross G, Waks T, Eshhar Z. 1989. Expression of immunoglobulin-T-cell receptor chimeric molecules as functional receptors with antibody-type specificity. PNAS 86:10024–28
     [Google Scholar]
  42. Han J, Chu J, Keung Chan W, Zhang J, Wang Y et al. 2015. CAR-engineered NK cells targeting wild-type EGFR and EGFRvIII enhance killing of glioblastoma and patient-derived glioblastoma stem cells. Sci. Rep. 5:11483
     [Google Scholar]
  43. Han X, Wang M, Duan S, Franco PJ, Kenty JH et al. 2019. Generation of hypoimmunogenic human pluripotent stem cells. PNAS 116:10441–46
     [Google Scholar]
  44. Herberman RB, Nunn ME, Holden HT, Lavrin DH. 1975. Natural cytotoxic reactivity of mouse lymphoid cells against syngeneic and allogeneic tumors. II. Characterization of effector cells. Int. J. Cancer 16:230–39
     [Google Scholar]
  45. Hermanson DL, Bendzick L, Pribyl L, McCullar V, Vogel RI et al. 2016. Induced pluripotent stem cell-derived natural killer cells for treatment of ovarian cancer. Stem Cells 34:93–101
     [Google Scholar]
  46. Hoerster K, Uhrberg M, Wiek C, Horn PA, Hanenberg H, Heinrichs S. 2020. HLA class I knockout converts allogeneic primary NK cells into suitable effectors for “off-the-shelf” immunotherapy. Front. Immunol. 11:586168
     [Google Scholar]
  47. Huang R-S, Lai M-C, Shih H-A, Lin S 2021. A robust platform for expansion and genome editing of primary human natural killer cells. J. Exp. Med. 218:e20201529
     [Google Scholar]
  48. Imai C, Iwamoto S, Campana D. 2005. Genetic modification of primary natural killer cells overcomes inhibitory signals and induces specific killing of leukemic cells. Blood 106:376–83
     [Google Scholar]
  49. Imai K, Matsuyama S, Miyake S, Suga K, Nakachi K. 2000. Natural cytotoxic activity of peripheral-blood lymphocytes and cancer incidence: an 11-year follow-up study of a general population. Lancet 356:1795–99
     [Google Scholar]
  50. Ingegnere T, Mariotti FR, Pelosi A, Quintarelli C, De Angelis B et al. 2019. Human CAR NK cells: a new non-viral method allowing high efficient transfection and strong tumor cell killing. Front. Immunol. 10:957
     [Google Scholar]
  51. Jacobson CA, Hunter BD, Redd R, Rodig SJ, Chen PH et al. 2020. Axicabtagene ciloleucel in the non-trial setting: outcomes and correlates of response, resistance, and toxicity. J. Clin. Oncol. 38:3095–106
     [Google Scholar]
  52. Jamali A, Hadjati J, Madjd Z, Mirzaei HR, Thalheimer FB et al. 2020. Highly efficient generation of transgenically augmented CAR NK cells overexpressing CXCR4. Front. Immunol. 11:2028
     [Google Scholar]
  53. Jamieson AM, Isnard P, Dorfman JR, Coles MC, Raulet DH. 2004. Turnover and proliferation of NK cells in steady state and lymphopenic conditions. J. Immunol. 172:864–70
     [Google Scholar]
  54. Johnson CDL, Zale NE, Frary ED, Lomakin JA. 2022. Feeder-cell-free and serum-free expansion of natural killer cells using Cloudz microspheres, G-Rex6M, and human platelet lysate. Front. Immunol. 13:803380
     [Google Scholar]
  55. Kärre K, Ljunggren HG, Piontek G, Kiessling R. 1986. Selective rejection of H–2-deficient lymphoma variants suggests alternative immune defence strategy. Nature 319:675–78
     [Google Scholar]
  56. Kiekens L, Van Loocke W, Taveirne S, Wahlen S, Persyn E et al. 2021. T-BET and EOMES accelerate and enhance functional differentiation of human natural killer cells. Front. Immunol. 12:732511
     [Google Scholar]
  57. Kiessling R, Klein E, Wigzell H. 1975.. “ Natural” killer cells in the mouse. I. Cytotoxic cells with specificity for mouse Moloney leukemia cells. Specificity and distribution according to genotype. Eur. J. Immunol. 5:112–17
     [Google Scholar]
  58. Klöß S, Oberschmidt O, Morgan M, Dahlke J, Arseniev L et al. 2017. Optimization of human NK cell manufacturing: fully automated separation, improved ex vivo expansion using IL-21 with autologous feeder cells, and generation of anti-CD123-CAR-expressing effector cells. Hum. Gene Ther. 28:897–913
     [Google Scholar]
  59. Knelson EH, Ivanova EV, Tarannum M, Campisi M, Lizotte PH et al. 2022. Activation of tumor-cell STING primes NK-cell therapy. Cancer Immunol. Res. 10:947–61
     [Google Scholar]
  60. Knorr DA, Ni Z, Hermanson D, Hexum MK, Bendzick L et al. 2013. Clinical-scale derivation of natural killer cells from human pluripotent stem cells for cancer therapy. Stem Cells Transl. Med. 2:274–83
     [Google Scholar]
  61. Kruschinski A, Moosmann A, Poschke I, Norell H, Chmielewski M et al. 2008. Engineering antigen-specific primary human NK cells against HER-2 positive carcinomas. PNAS 105:17481–86
     [Google Scholar]
  62. Kulemzin SV, Matvienko DA, Sabirov AH, Sokratyan AM, Chernikova DS et al. 2019. Design and analysis of stably integrated reporters for inducible transgene expression in human T cells and CAR NK-cell lines. BMC Med. Genom. 12:44
     [Google Scholar]
  63. Kuwana Y, Asakura Y, Utsunomiya N, Nakanishi M, Arata Y et al. 1987. Expression of chimeric receptor composed of immunoglobulin-derived V regions and T-cell receptor-derived C regions. Biochem. Biophys. Res. Commun. 149:960–68
     [Google Scholar]
  64. Lanier LL. 2005. NK cell recognition. Annu. Rev. Immunol. 23:225–74
     [Google Scholar]
  65. Lee DA. 2016. Regulatory considerations for NK cells used in human immunotherapy applications. Natural Killer Cells: Methods and Protocols SS Somanchi 347–61. New York: Springer
     [Google Scholar]
  66. Leivas A, Valeri A, Córdoba L, García-Ortiz A, Ortiz A et al. 2021. NKG2D-CAR-transduced natural killer cells efficiently target multiple myeloma. Blood Cancer J. 11:8146
     [Google Scholar]
  67. Li X, He C, Liu C, Ma J, Ma P et al. 2015. Expansion of NK cells from PBMCs using immobilized 4-1BBL and interleukin-21. Int. J. Oncol. 47:335–42
     [Google Scholar]
  68. Li Y, Basar R, Wang G, Liu E, Moyes JS et al. 2022. KIR-based inhibitory CARs overcome CAR-NK cell trogocytosis-mediated fratricide and tumor escape. Nat. Med. 28:2133–44
     [Google Scholar]
  69. Li Y, Hermanson DL, Moriarity BS, Kaufman DS. 2018. Human iPSC-derived natural killer cells engineered with chimeric antigen receptors enhance anti-tumor activity. Cell Stem Cell 23:181–92.e5
     [Google Scholar]
  70. Lisovsky I, Isitman G, Bruneau J, Bernard NF. 2015. Functional analysis of NK cell subsets activated by 721.221 and K562 HLA-null cells. J. Leukoc. Biol. 97:761–67
     [Google Scholar]
  71. Liu E, Marin D, Banerjee P, Macapinlac HA, Thompson P et al. 2020. Use of CAR-transduced natural killer cells in CD19-positive lymphoid tumors. New Engl. J. Med. 382:545–53
     [Google Scholar]
  72. Liu E, Tong Y, Dotti G, Shaim H, Savoldo B et al. 2018. Cord blood NK cells engineered to express IL-15 and a CD19-targeted CAR show long-term persistence and potent antitumor activity. Leukemia 32:520–31
     [Google Scholar]
  73. Liu S, Galat V, Galat Y, Lee YKA, Wainwright D, Wu J. 2021. NK cell-based cancer immunotherapy: from basic biology to clinical development. J. Hematol. Oncol. 14:7
     [Google Scholar]
  74. Liu WN, So WY, Harden SL, Fong SY, Wong MXY et al. 2022. Successful targeting of PD-1/PD-L1 with chimeric antigen receptor-natural killer cells and nivolumab in a humanized mouse cancer model. Sci. Adv. 8:eadd1187
     [Google Scholar]
  75. Long AH, Haso WM, Shern JF, Wanhainen KM, Murgai M et al. 2015. 4-1BB costimulation ameliorates T cell exhaustion induced by tonic signaling of chimeric antigen receptors. Nat. Med. 21:581–90
     [Google Scholar]
  76. Lopez-Soto A, Gonzalez S, Smyth MJ, Galluzzi L. 2017. Control of metastasis by NK cells. Cancer Cell 32:135–54
     [Google Scholar]
  77. Lopez-Verges S, Milush JM, Schwartz BS, Pando MJ, Jarjoura J et al. 2011. Expansion of a unique CD57+NKG2Chi natural killer cell subset during acute human cytomegalovirus infection. PNAS 108:14725–32
     [Google Scholar]
  78. Lowe E, Truscott LC, De Oliveira SN. 2016. In vitro generation of human NK cells expressing chimeric antigen receptor through differentiation of gene-modified hematopoietic stem cells. Methods Mol. Biol. 1441:241–51
     [Google Scholar]
  79. Lu T, Ma R, Dong W, Teng KY, Kollath DS et al. 2022. Off-the-shelf CAR natural killer cells secreting IL-15 target spike in treating COVID-19. Nat. Commun. 13:2576
     [Google Scholar]
  80. Ma M, Badeti S, Chen CH, Pinter A, Jiang Q et al. 2021. CAR-NK cells effectively target the D614 and G614 SARS-CoV-2-infected cells. bioRxiv 2021.01.14.426742. https://doi.org/10.1101/2021.01.14.426742
  81. Marin V, Kakuda H, Dander E, Imai C, Campana D et al. 2007. Enhancement of the anti-leukemic activity of cytokine induced killer cells with an anti-CD19 chimeric receptor delivering a 4-1BB-ζ activating signal. Exp. Hematol. 35:1388–97
     [Google Scholar]
  82. Miller JS, Soignier Y, Panoskaltsis-Mortari A, McNearney SA, Yun GH et al. 2005. Successful adoptive transfer and in vivo expansion of human haploidentical NK cells in patients with cancer. Blood 105:3051–57
     [Google Scholar]
  83. Miller SC 1982. Production and renewal of murine natural killer cells in the spleen and bone marrow. J. Immunol. 129:2282–86
     [Google Scholar]
  84. Min B, Choi H, Her JH, Jung MY, Kim H-J et al. 2018. Optimization of large-scale expansion and cryopreservation of human natural killer cells for anti-tumor therapy. Immune Netw. 18:e31
     [Google Scholar]
  85. Muller N, Michen S, Tietze S, Topfer K, Schulte A et al. 2015. Engineering NK cells modified with an EGFRvIII-specific chimeric antigen receptor to overexpress CXCR4 improves immunotherapy of CXCL12/SDF-1α-secreting glioblastoma. J. Immunother. 38:197–210
     [Google Scholar]
  86. Muller S, Bexte T, Gebel V, Kalensee F, Stolzenberg E et al. 2019. High cytotoxic efficiency of lentivirally and alpharetrovirally engineered CD19-specific chimeric antigen receptor natural killer cells against acute lymphoblastic leukemia. Front. Immunol. 10:3123
     [Google Scholar]
  87. Muller YD, Nguyen DP, Ferreira LMR, Ho P, Raffin C et al. 2021. The CD28-transmembrane domain mediates chimeric antigen receptor heterodimerization with CD28. Front. Immunol. 12:639818
     [Google Scholar]
  88. Naeimi Kararoudi M, Likhite S, Elmas E, Yamamoto K, Schwartz M et al. 2022. Optimization and validation of CAR transduction into human primary NK cells using CRISPR and AAV. Cell Rep. Methods 2:100236
     [Google Scholar]
  89. Ng YY, Du Z, Zhang X, Chng WJ, Wang S 2022. CXCR4 and anti-BCMA CAR co-modified natural killer cells suppress multiple myeloma progression in a xenograft mouse model. Cancer Gene Ther. 29:475–83
     [Google Scholar]
  90. Ng YY, Tay JCK, Wang S 2020. CXCR1 expression to improve anti-cancer efficacy of intravenously injected CAR-NK cells in mice with peritoneal xenografts. Mol. Ther. Oncolytics 16:75–85
     [Google Scholar]
  91. Nowakowska P, Romanski A, Miller N, Odendahl M, Bonig H et al. 2018. Clinical grade manufacturing of genetically modified, CAR-expressing NK-92 cells for the treatment of ErbB2-positive malignancies. Cancer Immunol. Immunother. 67:25–38
     [Google Scholar]
  92. Oberschmidt O, Morgan M, Huppert V, Kessler J, Gardlowski T et al. 2019. Development of automated separation, expansion, and quality control protocols for clinical-scale manufacturing of primary human NK cells and alpharetroviral chimeric antigen receptor engineering. Hum. Gene Ther. Methods 30:102–20
     [Google Scholar]
  93. Oei VYS, Siernicka M, Graczyk-Jarzynka A, Hoel HJ, Yang W et al. 2018. Intrinsic functional potential of NK-cell subsets constrains retargeting driven by chimeric antigen receptors. Cancer Immunol. Res. 6:467–80
     [Google Scholar]
  94. Ojo EO, Sharma AA, Liu R, Moreton S, Checkley-Luttge M-A et al. 2019. Membrane bound IL-21 based NK cell feeder cells drive robust expansion and metabolic activation of NK cells. Sci. Rep. 9:14916
     [Google Scholar]
  95. Olson JA, Leveson-Gower DB, Gill S, Baker J, Beilhack A, Negrin RS. 2010. NK cells mediate reduction of GVHD by inhibiting activated, alloreactive T cells while retaining GVT effects. Blood 115:4293–301
     [Google Scholar]
  96. Oren R, Hod-Marco M, Haus-Cohen M, Thomas S, Blat D et al. 2014. Functional comparison of engineered T cells carrying a native TCR versus TCR-like antibody-based chimeric antigen receptors indicates affinity/avidity thresholds. J. Immunol. 193:5733–43
     [Google Scholar]
  97. Oyer JL, Igarashi RY, Kulikowski AR, Colosimo DA, Solh MM et al. 2015. Generation of highly cytotoxic natural killer cells for treatment of acute myelogenous leukemia using a feeder-free, particle-based approach. Biol. Blood Marrow Transplant. 21:632–39
     [Google Scholar]
  98. Parkhurst MR, Riley JP, Dudley ME, Rosenberg SA. 2011. Adoptive transfer of autologous natural killer cells leads to high levels of circulating natural killer cells but does not mediate tumor regression. Clin. Cancer Res. 17:6287–97
     [Google Scholar]
  99. Porter DL, Levine BL, Kalos M, Bagg A, June CH. 2011. Chimeric antigen receptor–modified T cells in chronic lymphoid leukemia. N. Engl. J. Med. 365:725–33
     [Google Scholar]
  100. Prager I, Watzl C. 2019. Mechanisms of natural killer cell-mediated cellular cytotoxicity. J. Leukoc. Biol. 105:1319–29
     [Google Scholar]
  101. Quintarelli C, Sivori S, Caruso S, Carlomagno S, Boffa I et al. 2018. CD19 redirected CAR NK cells are equally effective but less toxic than CAR T cells. Blood 132:3491
     [Google Scholar]
  102. Quintarelli C, Sivori S, Caruso S, Carlomagno S, Falco M et al. 2020. Efficacy of third-party chimeric antigen receptor modified peripheral blood natural killer cells for adoptive cell therapy of B-cell precursor acute lymphoblastic leukemia. Leukemia 34:1102–15
     [Google Scholar]
  103. Rasid O, Chevalier C, Camarasa TM, Fitting C, Cavaillon JM, Hamon MA. 2019. H3K4me1 supports memory-like NK cells induced by systemic inflammation. Cell Rep. 29:3933–45.e3
     [Google Scholar]
  104. Reisner Y, Kapoor N, Kirkpatrick D, Pollack MS, Cunningham-Rundles S et al. 1983. Transplantation for severe combined immunodeficiency with HLA-A,B,D,DR incompatible parental marrow cells fractionated by soybean agglutinin and sheep red blood cells. Blood 61:341–48
     [Google Scholar]
  105. Roex G, Campillo-Davo D, Flumens D, Shaw PAG, Krekelbergh L et al. 2022. Two for one: targeting BCMA and CD19 in B-cell malignancies with off-the-shelf dual-CAR NK-92 cells. J. Transl. Med. 20:124
     [Google Scholar]
  106. Romee R, Rosario M, Berrien-Elliott MM, Wagner JA, Jewell BA et al. 2016. Cytokine-induced memory-like natural killer cells exhibit enhanced responses against myeloid leukemia. Sci. Transl. Med. 8:357ra123
     [Google Scholar]
  107. Rosenberg SA, Aebersold P, Cornetta K, Kasid A, Morgan RA et al. 1990. Gene transfer into humans–immunotherapy of patients with advanced melanoma, using tumor-infiltrating lymphocytes modified by retroviral gene transduction. N. Engl. J. Med. 323:570–78
     [Google Scholar]
  108. Roychowdhury S, May KF Jr., Tzou KS, Lin T, Bhatt D et al. 2004. Failed adoptive immunotherapy with tumor-specific T cells: reversal with low-dose interleukin 15 but not low-dose interleukin 2. Cancer Res. 64:8062–67
     [Google Scholar]
  109. Rubnitz JE, Inaba H, Ribeiro RC, Pounds S, Rooney B et al. 2010. NKAML: a pilot study to determine the safety and feasibility of haploidentical natural killer cell transplantation in childhood acute myeloid leukemia. J. Clin. Oncol. 28:955–59
     [Google Scholar]
  110. Ruggeri L, Capanni M, Urbani E, Perruccio K, Shlomchik WD et al. 2002. Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Science 295:2097–100
     [Google Scholar]
  111. Sahm C, Schonfeld K, Wels WS. 2012. 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. 61:1451–61
     [Google Scholar]
  112. Sakamoto N, Ishikawa T, Kokura S, Okayama T, Oka K et al. 2015. Phase I clinical trial of autologous NK cell therapy using novel expansion method in patients with advanced digestive cancer. J. Transl. Med. 13:277
     [Google Scholar]
  113. Schirrmann T, Pecher G. 2002. Human natural killer cell line modified with a chimeric immunoglobulin T-cell receptor gene leads to tumor growth inhibition in vivo. Cancer Gene Ther. 9:390–98
     [Google Scholar]
  114. Shaffer BC, Le Luduec JB, Forlenza C, Jakubowski AA, Perales MA et al. 2016. Phase II study of haploidentical natural killer cell infusion for treatment of relapsed or persistent myeloid malignancies following allogeneic hematopoietic cell transplantation. Biol. Blood Marrow Transplant. 22:705–9
     [Google Scholar]
  115. Smith SL, Kennedy PR, Stacey KB, Worboys JD, Yarwood A et al. 2020. Diversity of peripheral blood human NK cells identified by single-cell RNA sequencing. Blood Adv. 4:1388–406
     [Google Scholar]
  116. Soldierer M, Bister A, Haist C, Thivakaran A, Cengiz SC et al. 2022. Genetic engineering and enrichment of human NK cells for CAR-enhanced immunotherapy of hematological malignancies. Front. Immunol. 13:847008
     [Google Scholar]
  117. Spits H, Cupedo T. 2012. Innate lymphoid cells: emerging insights in development, lineage relationships, and function. Annu. Rev. Immunol. 30:647–75
     [Google Scholar]
  118. Stikvoort A, van der Schans J, Sarkar S, Poels R, Ruiter R et al. 2021. CD38-specific chimeric antigen receptor expressing natural killer KHYG-1 cells: a proof of concept for an “off the shelf” therapy for multiple myeloma. Hemasphere 5:e596
     [Google Scholar]
  119. Suerth JD, Morgan MA, Kloess S, Heckl D, Neudorfl C et al. 2016. Efficient generation of gene-modified human natural killer cells via alpharetroviral vectors. J. Mol. Med. 94:83–93
     [Google Scholar]
  120. Sun JC, Beilke JN, Lanier LL. 2009. Adaptive immune features of natural killer cells. Nature 457:557–61
     [Google Scholar]
  121. Sutlu T, Stellan B, Gilljam M, Concha H, Nahi H et al. 2010. Clinical-grade, large-scale, feeder-free expansion of highly active human natural killer cells for adoptive immunotherapy using an automated bioreactor. Cytotherapy 12:1044–55
     [Google Scholar]
  122. Taks EJM, Moorlag S, Netea MG, van der Meer JWM. 2022. Shifting the immune memory paradigm: trained immunity in viral infections. Annu. Rev. Virol. 9:469–89
     [Google Scholar]
  123. Tang X, Yang L, Li Z, Nalin AP, Dai H et al. 2018. First-in-man clinical trial of CAR NK-92 cells: safety test of CD33-CAR NK-92 cells in patients with relapsed and refractory acute myeloid leukemia. Am. J. Cancer Res. 8:1083–89
     [Google Scholar]
  124. Thakkar A, Igarashi RY, Lee DA. 2019. Automated closed-system large-scale expansion of clinical-grade natural killer cells. Cytotherapy 21:S31–32
     [Google Scholar]
  125. Tran AC, Zhang D, Byrn R, Roberts MR. 1995. 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. 155:1000–9
     [Google Scholar]
  126. Tremblay-McLean A, Coenraads S, Kiani Z, Dupuy FP, Bernard NF. 2019. Expression of ligands for activating natural killer cell receptors on cell lines commonly used to assess natural killer cell function. BMC Immunol. 20:8
     [Google Scholar]
  127. Ueda T, Kumagai A, Iriguchi S, Yasui Y, Miyasaka T et al. 2020. Non–clinical efficacy, safety and stable clinical cell processing of induced pluripotent stem cell-derived anti–glypican-3 chimeric antigen receptor-expressing natural killer/innate lymphoid cells. Cancer Sci. 111:1478–90
     [Google Scholar]
  128. Vanherberghen B, Olofsson PE, Forslund E, Sternberg-Simon M, Khorshidi MA et al. 2013. Classification of human natural killer cells based on migration behavior and cytotoxic response. Blood 121:1326–34
     [Google Scholar]
  129. Waldmann TA. 2006. The biology of interleukin-2 and interleukin-15: implications for cancer therapy and vaccine design. Nat. Rev. Immunol. 6:595–601
     [Google Scholar]
  130. Walseng E, Koksal H, Sektioglu IM, Fane A, Skorstad G et al. 2017. A TCR-based chimeric antigen receptor. Sci. Rep. 7:10713
     [Google Scholar]
  131. Wang X, Martin AD, Negri KR, McElvain ME, Oh J et al. 2021. Extensive functional comparisons between chimeric antigen receptors and T cell receptors highlight fundamental similarities. Mol. Immunol. 138:137–49
     [Google Scholar]
  132. Woan KV, Kim H, Bjordahl R, Davis ZB, Gaidarova S et al. 2021. Harnessing features of adaptive NK cells to generate iPSC-derived NK cells for enhanced immunotherapy. Cell Stem Cell 28:2062–75.e5
     [Google Scholar]
  133. Xiao L, Cen D, Gan H, Sun Y, Huang N et al. 2019. Adoptive transfer of NKG2D CAR mRNA-engineered natural killer cells in colorectal cancer patients. Mol. Ther. 27:1114–25
     [Google Scholar]
  134. Xu H, Wang B, Ono M, Kagita A, Fujii K et al. 2019. Targeted disruption of HLA genes via CRISPR-Cas9 generates iPSCs with enhanced immune compatibility. Cell Stem Cell 24:566–78.e7
     [Google Scholar]
  135. Xue X, Huang X, Nodland SE, Mates L, Ma L et al. 2009. Stable gene transfer and expression in cord blood-derived CD34+ hematopoietic stem and progenitor cells by a hyperactive Sleeping Beauty transposon system. Blood 114:1319–30
     [Google Scholar]
  136. Yang Y, Badeti S, Tseng HC, Ma MT, Liu T et al. 2020. Superior expansion and cytotoxicity of human primary NK and CAR-NK cells from various sources via enriched metabolic pathways. Mol. Ther. Methods Clin. Dev. 18:428–45
     [Google Scholar]
  137. Yang Y, Lim O, Kim TM, Ahn Y-O, Choi H et al. 2016. Phase I study of random healthy donor–derived allogeneic natural killer cell therapy in patients with malignant lymphoma or advanced solid tumors. Cancer Immunol. Res. 4:215–24
     [Google Scholar]
  138. Yoon SR, Lee YS, Yang SH, Ahn KH, Lee JH et al. 2010. Generation of donor natural killer cells from CD34+ progenitor cells and subsequent infusion after HLA-mismatched allogeneic hematopoietic cell transplantation: a feasibility study. Bone Marrow Transplant. 45:1038–46
     [Google Scholar]
  139. Zhang S, Liu W, Hu B, Wang P, Lv X et al. 2020. Prognostic significance of tumor-infiltrating natural killer cells in solid tumors: a systematic review and meta-analysis. Front. Immunol. 11:1242
     [Google Scholar]
  140. Zhang X, Guo Y, Ji Y, Gao Y, Zhang M et al. 2022. Cytokine release syndrome after modified CAR-NK therapy in an advanced non-small cell lung cancer patient: a case report. Cell Transplant. 31:9636897221094244
     [Google Scholar]
  141. Zhang Y, Wallace DL, de Lara CM, Ghattas H, Asquith B et al. 2007. In vivo kinetics of human natural killer cells: the effects of ageing and acute and chronic viral infection. Immunology 121:258–65
     [Google Scholar]
  142. Zhuang X, Long EO. 2019. CD28 homolog is a strong activator of natural killer cells for lysis of B7H7+ tumor cells. Cancer Immunol. Res. 7:939–51
     [Google Scholar]
/content/journals/10.1146/annurev-cancerbio-061521-082320
Loading
CAR NK Cells: The Future Is Now
Annual Review of Cancer Biology 7, 229 (2023); https://doi.org/10.1146/annurev-cancerbio-061521-082320
/content/journals/10.1146/annurev-cancerbio-061521-082320
/content/journals/10.1146/annurev-cancerbio-061521-082320
Loading

Data & Media loading...

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error