Skip to main content

Advertisement

SpringerLink
Log in

Chimeric antigen receptor-natural killer cells: a promising sword against insidious tumor cells

  • Review Article
  • Published:
Human Cell Aims and scope Submit manuscript

Abstract

Natural killer (NK) cells are a critical component of innate immunity, particularly in initial cancer recognition and inhibition of additional tumor growth or metastasis propagation. NK cells recognize transformed cells without prior sensitization via stimulatory receptors and rapidly eradicate them. However, the protective tumor microenvironment facilitates tumor escaping via induction of an exhaustion state in immune cells, including NK cells. Hence, genetic manipulation of NK cells for specific identification of tumor-associated antigens or a more robust response against tumor cells is a promising strategy for NK cells’ tumoricidal augmentation. Regarding the remarkable achievement of engineered CAR-T cells in treating hematologic malignancies, there is evolving interest in CAR-NK cell recruitment in cancer immunotherapy. Innate functionality of NK cells, higher safety, superior in vivo maintenance, and the off-the-shelf potential move CAR-NK-based therapy superior to CAR-T cells treatment. In this review, we have comprehensively discussed the recent genetic manipulations of CAR-NK cell manufacturing regarding different domains of CAR constructs and their following delivery systems into diverse sources of NK cells. Then highlight the preclinical and clinical investigations of CAR-NK cells and examine the current challenges and prospects as an optimistic remedy in cancer immunotherapy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Weber EW, Maus MV, Mackall CL. The emerging landscape of immune cell therapies. Cell. 2020;181(1):46–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Azad M, et al. Short view of leukemia diagnosis and treatment in Iran. Int J Hematol-Oncol Stem Cell Res. 2015;9(2):88.

    PubMed  PubMed Central  Google Scholar 

  3. Hartmann J, et al. Clinical development of CAR T cells—challenges and opportunities in translating innovative treatment concepts. EMBO Mol Med. 2017;9(9):1183–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Stoiber S, et al. Limitations in the design of chimeric antigen receptors for cancer therapy. Cells. 2019;8(5):472.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Burger MC, et al. CAR-engineered NK cells for the treatment of glioblastoma: turning innate effectors into precision tools for cancer immunotherapy. Front Immunol. 2019;10:2683.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Hernández-López A, et al. Chimeric antigen receptor-T cells: a pharmaceutical scope. Front Pharmacol. 2021;12:720692.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Bouchkouj N, et al. FDA approval summary: axicabtagene ciloleucel for relapsed or refractory follicular lymphoma. Oncologist. 2022;27:587–94.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Albinger N, Hartmann J, Ullrich E. Current status and perspective of CAR-T and CAR-NK cell therapy trials in Germany. Gene Ther. 2021;28(9):513–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Wire B. US Food and Drug Administration approves Bristol Myers Squibb’s and Bluebird Bio’s Abecma (idecabtagene vicleucel), the first anti-Bcma car T cell therapy for relapsed or refractory multiple myeloma. Abecma is a first-in-class BCMA-directed personalized immune cell therapy delivered as a one-time infusion for triple-class exposed patients with multiple survival. 2021;5:11–2.

    Google Scholar 

  10. Seipel K, et al. sBCMA plasma level dynamics and anti-BCMA CAR-T-Cell treatment in relapsed multiple myeloma. Curr Issues Mol Biol. 2022;44(4):1463–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Tyagarajan S, Spencer T, Smith J. Optimizing CAR-T cell manufacturing processes during pivotal clinical trials. Mol Ther-Methods Clin Dev. 2020;16:136–44.

    Article  CAS  PubMed  Google Scholar 

  12. Chou CK, Turtle CJ. Assessment and management of cytokine release syndrome and neurotoxicity following CD19 CAR-T cell therapy. Expert Opin Biol Ther. 2020;20(6):653–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Hu Y, Tian Z, Zhang C. Natural killer cell-based immunotherapy for cancer: advances and prospects. Engineering. 2019;5(1):106–14.

    Article  CAS  Google Scholar 

  14. Hilton HG, Parham P. Missing or altered self: human NK cell receptors that recognize HLA-C. Immunogenetics. 2017;69(8):567–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Martinet L, Smyth MJ. Balancing natural killer cell activation through paired receptors. Nat Rev Immunol. 2015;15(4):243–54.

    Article  CAS  PubMed  Google Scholar 

  16. Raulet DH, et al. Specificity, tolerance and developmental regulation of natural killer cells defined by expression of class I-specific Ly49 receptors. Immunol Rev. 1997;155(1):41–52.

    Article  CAS  PubMed  Google Scholar 

  17. Bix M, et al. Rejection of class I MHC-deficient haemopoietic cells by irradiated MHC-matched mice. Nature. 1991;349(6307):329–31.

    Article  CAS  PubMed  Google Scholar 

  18. Miller JS, et al. Successful adoptive transfer and in vivo expansion of human haploidentical NK cells in patients with cancer. Blood. 2005;105(8):3051–7.

    Article  CAS  PubMed  Google Scholar 

  19. Orr MT, Lanier LL. Natural killer cell education and tolerance. Cell. 2010;142(6):847–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Wang X, Zhao X-Y. Transcription factors associated with IL-15 cytokine signaling during NK cell development. Front Immunol. 2021;12:610789.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Peng Y-P, et al. Comprehensive analysis of the percentage of surface receptors and cytotoxic granules positive natural killer cells in patients with pancreatic cancer, gastric cancer, and colorectal cancer. J Transl Med. 2013;11(1):1–10.

    Article  Google Scholar 

  22. Coca S, et al. The prognostic significance of intratumoral natural killer cells in patients with colorectal carcinoma. Cancer Interdiscip Int J Am Cancer Soc. 1997;79(12):2320–8.

    CAS  Google Scholar 

  23. Villegas FR, et al. Prognostic significance of tumor infiltrating natural killer cells subset CD57 in patients with squamous cell lung cancer. Lung Cancer. 2002;35(1):23–8.

    Article  PubMed  Google Scholar 

  24. Okada K, et al. The number of natural killer cells in the largest diameter lymph nodes is associated with the number of retrieved lymph nodes and lymph node size, and is an independent prognostic factor in patients with stage II colon cancer. Oncology. 2018;95(5):288–96.

    Article  CAS  PubMed  Google Scholar 

  25. Xie M-Z, et al. Percentage of Natural Killer (NK) cells in peripheral blood is associated with prognosis in patients with gastric cancer: a retrospective study from a single center. Med Sci Monit. 2021;27:e927464–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Cho F-N, et al. Enhanced cytotoxicity of natural killer cells following the acquisition of chimeric antigen receptors through trogocytosis. PLoS ONE. 2014;9(10):e109352.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Paust S, Blish CA, Reeves RK. Redefining memory: building the case for adaptive NK cells. J Virol. 2017;91(20):e00169-17.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Mao Y, et al. Inhibition of tumor-derived prostaglandin-E2 blocks the induction of myeloid-derived suppressor cells and recovers natural killer cell activityrescue of nk cells by blocking the induction of MDSCs. Clin Cancer Res. 2014;20(15):4096–106.

    Article  CAS  PubMed  Google Scholar 

  29. Cekic C, et al. Myeloid expression of adenosine A2A receptor suppresses T and NK cell responses in the solid tumor microenvironmentmyeloid adenosine receptors control cytotoxic lymphocytes. Can Res. 2014;74(24):7250–9.

    Article  CAS  Google Scholar 

  30. Chiesa MD, et al. The tryptophan catabolite l-kynurenine inhibits the surface expression of NKp46-and NKG2D-activating receptors and regulates NK-cell function. Blood. 2006;108(13):4118–25.

    Article  PubMed  Google Scholar 

  31. Liu E, et al. Use of CAR-transduced natural killer cells in CD19-positive lymphoid tumors. N Engl J Med. 2020;382(6):545–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Marofi F, et al. CAR-NK cell: a new paradigm in tumor immunotherapy. Front Oncol. 2021;11:2078.

    Article  Google Scholar 

  33. Shah NN, et al. Acute GVHD in patients receiving IL-15/4-1BBL activated NK cells following T-cell–depleted stem cell transplantation. Blood J Am Soc Hematol. 2015;125(5):784–92.

    CAS  Google Scholar 

  34. Shimasaki N, Jain A, Campana D. NK cells for cancer immunotherapy. Nat Rev Drug Discov. 2020;19(3):200–18.

    Article  CAS  PubMed  Google Scholar 

  35. Eguizabal C, et al. Natural killer cells for cancer immunotherapy: pluripotent stem cells-derived NK cells as an immunotherapeutic perspective. Front Immunol. 2014;5:439.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Lapteva N, et al. Large-scale ex vivo expansion and characterization of natural killer cells for clinical applications. Cytotherapy. 2012;14(9):1131–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Romee R, et al. Cytokine-induced memory-like natural killer cells exhibit enhanced responses against myeloid leukemia. Sci Transl Med. 2016;8(357):357ra123.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Gang M, et al. CAR-modified memory-like NK cells exhibit potent responses to NK-resistant lymphomas. Blood. 2020;136(20):2308–18.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Gong Y, et al. Chimeric antigen receptor natural killer (CAR-NK) cell design and engineering for cancer therapy. J Hematol Oncol. 2021;14(1):1–35.

    Article  CAS  Google Scholar 

  40. Gong J-H, 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.

    CAS  PubMed  Google Scholar 

  41. Zhang J, Zheng H, Diao Y. Natural killer cells and current applications of chimeric antigen receptor-modified NK-92 cells in tumor immunotherapy. Int J Mol Sci. 2019;20(2):317.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Snyder KM, et al. Expression of a recombinant high affinity IgG Fc receptor by engineered NK cells as a docking platform for therapeutic mAbs to target cancer cells. Front Immunol. 2018;9:2873.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Tam Y, et al. Characterization of genetically altered, interleukin 2-independent natural killer cell lines suitable for adoptive cellular immunotherapy. Hum Gene Ther. 1999;10(8):1359–73.

    Article  CAS  PubMed  Google Scholar 

  44. Suck G, 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.

    Article  CAS  PubMed  Google Scholar 

  45. Maki G, et al. Factors regulating the cytotoxic activity of the human natural killer cell line, NK-92. J Hematother Stem Cell Res. 2001;10(3):369–83.

    Article  CAS  PubMed  Google Scholar 

  46. MacLeod RA, et al. Multicolor-FISH analysis of a natural killer cell line (NK-92). Leuk Res. 2002;26(11):1027–33.

    Article  CAS  PubMed  Google Scholar 

  47. Burga RA, et al. Improving efficacy of cancer immunotherapy by genetic modification of natural killer cells. Cytotherapy. 2016;18(11):1410–21.

    Article  CAS  PubMed  Google Scholar 

  48. Liu D, et al. Chimeric antigen receptor (CAR)-modified natural killer cell-based immunotherapy and immunological synapse formation in cancer and HIV. Protein Cell. 2017;8(12):861–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Woll PS, et al. Human embryonic stem cell-derived NK cells acquire functional receptors and cytolytic activity. J Immunol. 2005;175(8):5095–103.

    Article  CAS  PubMed  Google Scholar 

  51. Ni Z, et al. Human pluripotent stem cells produce natural killer cells that mediate anti-HIV-1 activity by utilizing diverse cellular mechanisms. J Virol. 2011;85(1):43–50.

    Article  CAS  PubMed  Google Scholar 

  52. Maali A, et al. Induced pluripotent stem cell technology: trends in molecular biology, from genetics to epigenetics. Epigenomics. 2021;13(8):631–47.

    Article  CAS  PubMed  Google Scholar 

  53. Meyer-Monard S, et al. Clinical-grade purification of natural killer cells in haploidentical hematopoietic stem cell transplantation. Transfusion. 2009;49(2):362–71.

    Article  PubMed  Google Scholar 

  54. Van der Meer JM, et al. CD34+ progenitor-derived NK cell and gemcitabine combination therapy increases killing of ovarian cancer cells in NOD/SCID/IL2Rgnull mice. Oncoimmunology. 2021;10(1):1981049.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Woll PS, et al. Human embryonic stem cells differentiate into a homogeneous population of natural killer cells with potent in vivo antitumor activity. Blood J Am Soc Hematol. 2009;113(24):6094–101.

    CAS  Google Scholar 

  57. Li Y, et al. human iPSC-derived natural killer cells engineered with chimeric antigen receptors enhance anti-tumor activity. Cell Stem Cell. 2018;23(2):181-192.e5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Maali A, et al. A review on leukemia and iPSC technology: application in novel treatment and future. Curr Stem Cell Res Ther. 2018;13(8):665–75.

    Article  CAS  PubMed  Google Scholar 

  59. Liu E, et al. Cord blood NK cells engineered to express IL-15 and a CD19-targeted CAR show long-term persistence and potent antitumor activity. Leukemia. 2018;32(2):520–31.

    Article  CAS  PubMed  Google Scholar 

  60. Shaim H, Yvon E. Cord blood: a promising source of allogeneic natural killer cells for immunotherapy. Cytotherapy. 2015;17(1):1–2.

    Article  PubMed  Google Scholar 

  61. Sarvaria A, et al. Umbilical cord blood natural killer cells, their characteristics, and potential clinical applications. Front Immunol. 2017;8:329.

    Article  PubMed  PubMed Central  Google Scholar 

  62. Shah N, et al. antigen presenting cell-mediated expansion of human umbilical cord blood yields log-scale expansion of natural killer cells with anti-myeloma activity. PLoS ONE. 2013;8(10):e76781.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Xie G, et al. CAR-NK cells: a promising cellular immunotherapy for cancer. EBioMedicine. 2020;59:102975.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Fang F, Xiao W, Tian Z. NK cell-based immunotherapy for cancer. In: Seminars in immunology. Amsterdam: Elsevier; 2017.

    Google Scholar 

  65. Kang L, et al. Characterization and ex vivo expansion of human placenta-derived natural killer cells for cancer immunotherapy. Front Immunol. 2013;4:101.

    Article  PubMed  PubMed Central  Google Scholar 

  66. Huntington ND, Vosshenrich CA, Di Santo JP. Developmental pathways that generate natural-killer-cell diversity in mice and humans. Nat Rev Immunol. 2007;7(9):703–14.

    Article  CAS  PubMed  Google Scholar 

  67. Gong L, et al. Nanobody-engineered natural killer cell conjugates for solid tumor adoptive immunotherapy. Small. 2021;17(45):2103463.

    Article  CAS  Google Scholar 

  68. You F, et al. A novel CD7 chimeric antigen receptor-modified NK-92MI cell line targeting T-cell acute lymphoblastic leukemia. Am J Cancer Res. 2019;9(1):64.

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Duan H, Huang H, Jing G. An antibody fab fragment-based chimeric antigen receptor could efficiently eliminate human thyroid cancer cells. J Cancer. 2019;10(8):1890.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Balakrishnan A, et al. Multispecific targeting with synthetic ankyrin repeat motif chimeric antigen receptorsmultispecific CAR design with ankyrin repeat binding domains. Clin Cancer Res. 2019;25(24):7506–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Hajari Taheri F, et al. T cell engineered with a novel nanobody-based chimeric antigen receptor against VEGFR2 as a candidate for tumor immunotherapy. IUBMB Life. 2019;71(9):1259–67.

    Article  CAS  PubMed  Google Scholar 

  72. Sharifzadeh Z, et al. Genetically engineered T cells bearing chimeric nanoconstructed receptors harboring TAG-72-specific camelid single domain antibodies as targeting agents. Cancer Lett. 2013;334(2):237–44.

    Article  CAS  PubMed  Google Scholar 

  73. Rahbarizadeh F, Ahmadvand D, Sharifzadeh Z. Nanobody; an old concept and new vehicle for immunotargeting. Immunol Investig. 2011;40(3):299–338.

    Article  CAS  Google Scholar 

  74. Soltanmohammadi B, et al. Bactericidal fully human single-chain fragment variable antibodies protect mice against methicillin-resistant Staphylococcus aureus bacteraemia. Clin Transl Immunology. 2021;10(7):e1302.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Hassani M, et al. Engineered jurkat cells for targeting prostate-specific membrane antigen on prostate cancer cells by nanobody-based chimeric antigen receptor. Iran Biomed J. 2020;24(2):81–8.

    Article  PubMed  Google Scholar 

  76. Long AH, et al. 4–1BB costimulation ameliorates T cell exhaustion induced by tonic signaling of chimeric antigen receptors. Nat Med. 2015;21(6):581–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Haso W, et al. Anti-CD22–chimeric antigen receptors targeting B-cell precursor acute lymphoblastic leukemia. Blood J Am Soc Hematol. 2013;121(7):1165–74.

    CAS  Google Scholar 

  78. Fujiwara K, et al. Impact of scFv structure in chimeric antigen receptor on receptor expression efficiency and antigen recognition properties. Biochem Biophys Res Commun. 2020;527(2):350–7.

    Article  CAS  PubMed  Google Scholar 

  79. Wilkie S, et al. Retargeting of human T cells to tumor-associated MUC1: the evolution of a chimeric antigen receptor. J Immunol. 2008;180(7):4901–9.

    Article  CAS  PubMed  Google Scholar 

  80. Morgan RA, et al. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Kang CH, et al. identification of potent CD19 scFv for CAR T cells through scFv screening with NK/T-cell line. Int J Mol Sci. 2020;21(23):9163.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Liu Q, et al. Irradiated chimeric antigen receptor engineered NK-92MI cells show effective cytotoxicity against CD19+ malignancy in a mouse model. Cytotherapy. 2020;22(10):552–62.

    Article  CAS  PubMed  Google Scholar 

  83. Xu Y, et al. 2B4 co-stimulatory domain enhancing cytotoxic ability of anti-CD5 chimeric antigen receptor engineered natural killer cells against T cell malignancies. J Hematol Oncol. 2019;12(1):1–13.

    Article  Google Scholar 

  84. Thomas S, et al. An optimized GD2-targeting retroviral cassette for more potent and safer cellular therapy of neuroblastoma and other cancers. PLoS ONE. 2016;11(3):e0152196.

    Article  PubMed  PubMed Central  Google Scholar 

  85. Hege KM, et al. Safety, tumor trafficking and immunogenicity of chimeric antigen receptor (CAR)-T cells specific for TAG-72 in colorectal cancer. J Immunother Cancer. 2017;5(1):1–14.

    Article  Google Scholar 

  86. Todorovska A, et al. Design and application of diabodies, triabodies and tetrabodies for cancer targeting. J Immunol Methods. 2001;248(1–2):47–66.

    Article  CAS  PubMed  Google Scholar 

  87. Ajina A, Maher J. Strategies to address chimeric antigen receptor tonic signaling. Mol Cancer Ther. 2018;17(9):1795–815.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Hammill JA, et al. Designed ankyrin repeat proteins are effective targeting elements for chimeric antigen receptors. J Immunother Cancer. 2015;3(1):1–11.

    Article  Google Scholar 

  89. Siegler E, et al. Designed ankyrin repeat proteins as Her2 targeting domains in chimeric antigen receptor-engineered T cells. Hum Gene Ther. 2017;28(9):726–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. De Munter S, et al. Nanobody based dual specific CARs. Int J Mol Sci. 2018;19(2):403.

    Article  PubMed  PubMed Central  Google Scholar 

  91. Xie YJ, et al. Nanobody-based CAR T cells that target the tumor microenvironment inhibit the growth of solid tumors in immunocompetent mice. Proc Natl Acad Sci. 2019;116(16):7624–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Jamnani FR, et al. Targeting high affinity and epitope-distinct oligoclonal nanobodies to HER2 over-expressing tumor cells. Exp Cell Res. 2012;318(10):1112–24.

    Article  CAS  PubMed  Google Scholar 

  93. Bagheri S, et al. Selection of single chain antibody fragments binding to the extracellular domain of 4–1BB receptor by phage display technology. Tumour Biol. 2017;39(3):1010428317695924.

    Article  PubMed  Google Scholar 

  94. Zorko N, et al. FT573: Preclinical development of multiplexed-engineered iPSC-derived NK cells expressing a novel camelid nanobody chimeric antigen receptor (CAR) targeting pan-cancer antigen B7–H3. Cancer Res. 2022;82(12_Supplement):2761–2761.

    Article  Google Scholar 

  95. Sallman DA, et al. NKG2D-based chimeric antigen receptor therapy induced remission in a relapsed/refractory acute myeloid leukemia patient. Haematologica. 2018;103(9):e424.

    Article  PubMed  PubMed Central  Google Scholar 

  96. Park S, et al. Micromolar affinity CAR T cells to ICAM-1 achieves rapid tumor elimination while avoiding systemic toxicity. Sci Rep. 2017;7(1):1–15.

    PubMed  PubMed Central  Google Scholar 

  97. Brown CE, et al. Regression of glioblastoma after chimeric antigen receptor T-cell therapy. N Engl J Med. 2016;375(26):2561–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Vitale M, et al. Effect of tumor cells and tumor microenvironment on NK-cell function. Eur J Immunol. 2014;44(6):1582–92.

    Article  CAS  PubMed  Google Scholar 

  99. Cherkassky L, et al. Human CAR T cells with cell-intrinsic PD-1 check-point blockade resist tumor-mediated inhibition. J Clin Investig. 2016;126(8):3130–44.

    Article  PubMed  PubMed Central  Google Scholar 

  100. Tang N, et al. TGF-β inhibition via CRISPR promotes the long-term efficacy of CAR T cells against solid tumors. JCI Insight. 2020;5(4):e133977.

    Article  PubMed  PubMed Central  Google Scholar 

  101. Antillon K, Ross PA, Farrell MP. Directing CAR NK cells via the metabolic incorporation of CAR ligands into malignant cell glycans. ACS Chem Biol. 2022;17:1505–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Davila ML, et al. CD19 CAR-targeted T cells induce long-term remission and B Cell Aplasia in an immunocompetent mouse model of B cell acute lymphoblastic leukemia. PLoS ONE. 2013;8(4):e61338.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Gleason MK, et al. Bispecific and trispecific killer cell engagers directly activate human NK cells through CD16 signaling and induce cytotoxicity and cytokine productionBiKEs and TriKEs enhance NK cell effector function. Mol Cancer Ther. 2012;11(12):2674–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Wiernik A, et al. Targeting natural killer cells to acute myeloid leukemia in vitro with a CD16× 33 bispecific killer cell engager and ADAM17 Inhibitiontargeting NK cells to AML with a BiKE and ADAM17 inhibitor. Clin Cancer Res. 2013;19(14):3844–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Chan W, et al. A CS1-NKG2D bispecific antibody collectivel activates cytolytic immune cells against multiple myeloma. Cancer Immunol Res. 2018;6:776–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Vallera DA, et al. IL15 trispecific killer engagers (TriKE) make natural killer cells specific to CD33+ targets while also inducing persistence, in vivo expansion, and enhanced functionimprovement of bispecific antibody by insertion of IL15. Clin Cancer Res. 2016;22(14):3440–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Schmohl JU, et al. Enhanced ADCC and NK cell activation of an anticarcinoma bispecific antibody by genetic insertion of a modified IL-15 cross-linker. Mol Ther. 2016;24(7):1312–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Hegde M, et al. Tandem CAR T cells targeting HER2 and IL13Rα2 mitigate tumor antigen escape. J Clin Investig. 2016;126(8):3036–52.

    Article  PubMed  PubMed Central  Google Scholar 

  109. Genßler S, 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.

    Article  PubMed  Google Scholar 

  110. Zah E, et al. T cells expressing CD19/CD20 bispecific chimeric antigen receptors prevent antigen escape by malignant B CELLSBISPECIfic T cells prevent B-cell antigen escape. Cancer Immunol Res. 2016;4(6):498–508.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Wu C-Y, et al. Remote control of therapeutic T cells through a small molecule–gated chimeric receptor. Science. 2015;350(6258):aab4077.

    Article  PubMed  PubMed Central  Google Scholar 

  112. Hudecek M, et al. The nonsignaling extracellular spacer domain of chimeric antigen receptors is decisive for in vivo antitumor activity. Cancer Immunol Res. 2015;3(2):125–35.

    Article  CAS  PubMed  Google Scholar 

  113. Alabanza L, et al. function of novel anti-CD19 chimeric antigen receptors with human variable regions is affected by hinge and transmembrane domains. Mol Ther. 2017;25(11):2452–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Gotthardt D, et al. JAK/STAT cytokine signaling at the crossroad of NK cell development and maturation. Front Immunol. 2019;10:2590.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Seeger MA, et al. Design, construction, and characterization of a second-generation DARPin library with reduced hydrophobicity. Protein Sci. 2013;22(9):1239–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Daher M, et al. Targeting a cytokine check-point enhances the fitness of armored cord blood CAR-NK cells. Blood. 2021;137(5):624–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Bagheri S, et al. Targeting the 4–1BB co-stimulatory molecule through single chain antibodies promotes the human T-cell response. Cell Mol Biol Lett. 2020;25:28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Kagoya Y, et al. A novel chimeric antigen receptor containing a JAK–STAT signaling domain mediates superior antitumor effects. Nat Med. 2018;24(3):352–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Matosevic S. Viral and non-viral engineering of natural killer cells as emerging adoptive cancer immunotherapies. J Immunol Res. 2018;4054815.

  120. Al-Dosari MS, Gao X. Non-viral gene delivery: principle, limitations, and recent progress. AAPS J. 2009;11(4):671–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Hu Y, Tian Z-G, Zhang C. Chimeric antigen receptor (CAR)-transduced natural killer cells in tumor immunotherapy. Acta Pharmacol Sin. 2018;39(2):167–76.

    Article  CAS  PubMed  Google Scholar 

  122. Kung SK. Introduction of shRNAs into primary NK cells with lentivirus. In: Natural killer cell protocols. Springer; 2010. p. 233–47.

    Chapter  Google Scholar 

  123. June CH, Blazar BR, Riley JL. Engineering lymphocyte subsets: tools, trials and tribulations. Nat Rev Immunol. 2009;9(10):704–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Gándara C, Affleck V, Stoll EA. Manufacture of third-generation lentivirus for preclinical use, with process development considerations for translation to good manufacturing practice. Hum Gene Ther Methods. 2018;29(1):1–15.

    Article  PubMed  PubMed Central  Google Scholar 

  125. Micucci F, et al. High-efficient lentiviral vector-mediated gene transfer into primary human NK cells. Exp Hematol. 2006;34(10):1344–52.

    Article  CAS  PubMed  Google Scholar 

  126. Colamartino AB, et al. Efficient and robust NK-cell transduction with baboon envelope pseudotyped lentivector. Front Immunol. 2019;10:2873.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Gong Y, et al. Rosuvastatin enhances VSV-G lentiviral transduction of NK cells via upregulation of the low-density lipoprotein receptor. Mol Ther-Methods Clin Dev. 2020;17:634–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Sayitoglu EC, et al. Boosting natural killer cell-mediated targeting of sarcoma through DNAM-1 and NKG2D. Front Immunol. 2020;11:40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Müller N, et al. Engineering NK cells modified with an EGFRvIII-specific chimeric antigen receptor to overexpress CXCR4 improves immunotherapy of CXCL12/SDF-1α-secreting glioblastoma. J Immunother (Hagerstown, Md: 1997). 2015;38(5):197.

    Google Scholar 

  130. Tran J, Kung SK. Lentiviral vectors mediate stable and efficient gene delivery into primary murine natural killer cells. Mol Ther. 2007;15(7):1331–9.

    Article  CAS  PubMed  Google Scholar 

  131. Poletti V, Mavilio F. Interactions between retroviruses and the host cell genome. Mol Ther-Methods Clin Dev. 2018;8:31–41.

    Article  CAS  PubMed  Google Scholar 

  132. Suerth JD, et al. Efficient generation of gene-modified human natural killer cells via alpharetroviral vectors. J Mol Med. 2016;94(1):83–93.

    Article  CAS  PubMed  Google Scholar 

  133. Müller S, et al. High cytotoxic efficiency of lentivirally and alpharetrovirally engineered CD19-specific chimeric antigen receptor natural killer cells against acute lymphoblastic leukemia. Front Immunol. 2020;10:3123.

    Article  PubMed  PubMed Central  Google Scholar 

  134. Davis HE, et al. Charged polymers modulate retrovirus transduction via membrane charge neutralization and virus aggregation. Biophys J. 2004;86(2):1234–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Davis HE, Morgan JR, Yarmush ML. Polybrene increases retrovirus gene transfer efficiency by enhancing receptor-independent virus adsorption on target cell membranes. Biophys Chem. 2002;97(2–3):159–72.

    Article  CAS  PubMed  Google Scholar 

  136. De Sanctis JB, et al. expression and function of low-density lipoprotein receptors in CD3− CD16+ CD56+ cells: effect of interleukin 2. Cell Immunol. 1996;167(1):18–29.

    Article  PubMed  Google Scholar 

  137. Streltsova MA, et al. Retroviral gene transfer into primary human NK cells activated by IL-2 and K562 feeder cells expressing membrane-bound IL-21. J Immunol Methods. 2017;450:90–4.

    Article  CAS  PubMed  Google Scholar 

  138. 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. Cancer Gene Ther. 2002;9(4):390–8.

    Article  CAS  PubMed  Google Scholar 

  139. Maasho K, et al. Efficient gene transfer into the human natural killer cell line, NKL, using the Amaxa nucleofection system™. J Immunol Methods. 2004;284(1–2):133–40.

    Article  CAS  PubMed  Google Scholar 

  140. Carlsten M, Childs RW. Genetic manipulation of NK cells for cancer immunotherapy: techniques and clinical implications. Front Immunol. 2015;6:266.

    Article  PubMed  PubMed Central  Google Scholar 

  141. Chu Y, 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.

    Article  CAS  PubMed  Google Scholar 

  142. Suen WC-W, et al. Natural killer cell-based cancer immunotherapy: a review on 10 years completed clinical trials. Cancer Investig. 2018;36(8):431–57.

    Article  CAS  Google Scholar 

  143. Tipanee J, et al. Preclinical and clinical advances in transposon-based gene therapy. Biosci Rep. 2017;37(6):BSR20160614.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Wang J, et al. Purinergic targeting enhances immunotherapy of CD73+ solid tumors with piggyBac-engineered chimeric antigen receptor natural killer cells. J Immunother Cancer. 2018;6(1):1–14.

    Article  Google Scholar 

  145. Batchu RB, et al. Engraftment of mesothelin chimeric antigen receptor using a hybrid Sleeping Beauty/minicircle vector into NK-92MI cells for treatment of pancreatic cancer. Surgery. 2019;166(4):503–8.

    Article  PubMed  Google Scholar 

  146. Xue X, et al. Stable gene transfer and expression in cord blood–derived CD34+ hematopoietic stem and progenitor cells by a hyperactive Sleeping Beauty transposon system. Blood J Am Soc Hematol. 2009;114(7):1319–30.

    CAS  Google Scholar 

  147. Chu Y, 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.

    Article  CAS  PubMed  Google Scholar 

  148. Stenger D, et al. Endogenous TCR promotes in vivo persistence of CD19-CAR-T cells compared to a CRISPR/Cas9-mediated TCR knockout CAR. Blood. 2020;136(12):1407–18.

    Article  PubMed  Google Scholar 

  149. Eyquem J, et al. Targeting a CAR to the TRAC locus with CRISPR/Cas9 enhances tumour rejection. Nature. 2017;543(7643):113–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Gurney M, et al. CD38 knockout natural killer cells expressing an affinity optimized CD38 chimeric antigen receptor successfully target acute myeloid leukemia with reduced effector cell fratricide. Haematologica. 2022;107(2):437.

    Article  CAS  PubMed  Google Scholar 

  151. Maroufi F, et al. CRISPR-mediated modification of DNA methylation pattern in the new era of cancer therapy. Epigenomics. 2020;12(20):1845–59.

    Article  CAS  PubMed  Google Scholar 

  152. Kararoudi MN, et al. Generation of knock-out primary and expanded human NK cells using Cas9 ribonucleoproteins. JoVE. 2018;136:e58237.

    Google Scholar 

  153. Haapaniemi E, et al. CRISPR–Cas9 genome editing induces a p53-mediated DNA damage response. Nat Med. 2018;24(7):927–30.

    Article  CAS  PubMed  Google Scholar 

  154. Kararoudi MN et al. Optimization and validation of CAR transduction into human primary NK cells using CRISPR and AAV. Cell Rep Methods. 2022;2(6):100236.

  155. Lapteva N et al. Clinical grade purification and expansion of natural killer cells. Crit Rev™ Oncogenesis. 2014;19(1–2):121–32.

  156. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Shimasaki N, et al. Expanded and armed natural killer cells for cancer treatment. Cytotherapy. 2016;18(11):1422–34.

    Article  CAS  PubMed  Google Scholar 

  158. Imamura M, et al. Autonomous growth and increased cytotoxicity of natural killer cells expressing membrane-bound interleukin-15. Blood J Am Soc Hematol. 2014;124(7):1081–8.

    CAS  Google Scholar 

  159. Denman CJ, et al. Membrane-bound IL-21 promotes sustained ex vivo proliferation of human natural killer cells. PLoS ONE. 2012;7(1):e30264.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Rubnitz JE, et al. NKAML: a pilot study to determine the safety and feasibility of haploidentical natural killer cell transplantation in childhood acute myeloid leukemia. J Clin Oncol. 2010;28(6):955.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. June CH, Sadelain M. Chimeric antigen receptor therapy. N Engl J Med. 2018;379(1):64–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Rohr-Udilova N, et al. Deviations of the immune cell landscape between healthy liver and hepatocellular carcinoma. Sci Rep. 2018;8(1):1–11.

    Article  CAS  Google Scholar 

  163. Monzavi N, et al. Angiopoietin-like protein 8 (betatrophin) may inhibit hepatocellular carcinoma through suppressing of the Wnt signaling pathway. Iran J Basic Med Sci. 2019;22(10):1166.

    PubMed  PubMed Central  Google Scholar 

  164. Coughlan D, et al. treatment and survival of childhood neuroblastoma: evidence from a population-based study in the United States. Pediatr Hematol Oncol. 2017;34(5):320–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Yu M, et al. Development of GPC3-specific chimeric antigen receptor-engineered natural killer cells for the treatment of hepatocellular carcinoma. Mol Ther. 2018;26(2):366–78.

    Article  CAS  PubMed  Google Scholar 

  166. Liu B, et al. development of c-MET-specific chimeric antigen receptor-engineered natural killer cells with cytotoxic effects on human liver cancer HepG2 cells. Mol Med Rep. 2019;20(3):2823–31.

    CAS  PubMed  PubMed Central  Google Scholar 

  167. Wang Z, et al. Augmented anti-tumor activity of NK-92 cells expressing chimeric receptors of TGF-βR II and NKG2D. Cancer Immunol Immunother. 2017;66(4):537–48.

    Article  CAS  PubMed  Google Scholar 

  168. Wang F, Lau JKC, Yu J. The role of natural killer cell in gastrointestinal cancer: killer or helper. Oncogene. 2021;40(4):717–30.

    Article  PubMed  Google Scholar 

  169. Wu X, Huang S. HER2-specific chimeric antigen receptor-engineered natural killer cells combined with apatinib for the treatment of gastric cancer. Bull Cancer. 2019;106(11):946–58.

    Article  PubMed  Google Scholar 

  170. Zhang Q et al. Combination therapy with EpCAM-CAR-NK-92 cells and regorafenib against human colorectal cancer models. J Immunol Res. 2018;2070562.

  171. Shiozawa M, et al. Pharmacologically upregulated carcinoembryonic antigen-expression enhances the cytolytic activity of genetically-modified chimeric antigen receptor NK-92MI against colorectal cancer cells. BMC Immunol. 2018;19(1):1–13.

    Article  Google Scholar 

  172. Murakami T, et al. Novel human NK cell line carrying CAR targeting EGFRvIII induces antitumor effects in glioblastoma cells. Anticancer Res. 2018;38(9):5049–56.

    Article  CAS  PubMed  Google Scholar 

  173. Han J, 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(1):1–13.

    CAS  Google Scholar 

  174. Zhang C, et al. ErbB2/HER2-specific NK cells for targeted therapy of glioblastoma. J Natl Cancer Inst. 2016;108(5):djv375.

    Article  Google Scholar 

  175. Liu Y, et al. Targeting epidermal growth factor-overexpressing triple-negative breast cancer by natural killer cells expressing a specific chimeric antigen receptor. Cell Prolif. 2020;53(8):e12858.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Hu Z. Tissue factor as a new target for CAR-NK cell immunotherapy of triple-negative breast cancer. Sci Rep. 2020;10(1):1–13.

    CAS  Google Scholar 

  177. Ueda T, et al. 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. 2020;111(5):1478–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Ao X, et al. Anti-αFR CAR-engineered NK-92 cells display potent cytotoxicity against αFR-positive ovarian cancer. J Immunother (Hagerstown, Md: 1997). 2019;42(8):284.

    CAS  Google Scholar 

  179. Tang X, et al. 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. 2018;8(6):1083.

    CAS  PubMed  PubMed Central  Google Scholar 

  180. Salman H, et al. Preclinical targeting of human acute myeloid leukemia using CD4-specific chimeric antigen receptor (CAR) T cells and NK cells. J Cancer. 2019;10(18):4408.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Müller T, 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.

    Article  PubMed  Google Scholar 

  182. Romanski A, et al. CD 19-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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Oelsner S, et al. Genetically engineered CAR NK cells display selective cytotoxicity against FLT3-positive B-ALL and inhibit in vivo leukemia growth. Int J Cancer. 2019;145(7):1935–45.

    Article  CAS  PubMed  Google Scholar 

  184. Chu 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.

    Article  CAS  PubMed  Google Scholar 

  185. Jiang H, 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.

    Article  CAS  PubMed  Google Scholar 

  186. Chen KH, et al. Novel anti-CD3 chimeric antigen receptor targeting of aggressive T cell malignancies. Oncotarget. 2016;7(35):56219.

    Article  PubMed  PubMed Central  Google Scholar 

  187. Chen K, et al. Preclinical targeting of aggressive T-cell malignancies using anti-CD5 chimeric antigen receptor. Leukemia. 2017;31(10):2151–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Li C, et al. Robo1-specific chimeric antigen receptor natural killer cell therapy for pancreatic ductal adenocarcinoma with liver metastasis. J Cancer Res Ther. 2020;16(2):393.

    Article  PubMed  Google Scholar 

  189. Maali A, et al. Nanobodies in cell-mediated immunotherapy: on the road to fight cancer. Front Immunol. 2023;14:1012841.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Song D-G, et al. Chimeric NKG2D CAR-expressing T cell-mediated attack of human ovarian cancer is enhanced by histone deacetylase inhibition. Hum Gene Ther. 2013;24(3):295–305.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Kruschinski A, et al. Engineering antigen-specific primary human NK cells against HER-2 positive carcinomas. Proc Natl Acad Sci. 2008;105(45):17481–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Olson JA, et al. NK cells mediate reduction of GVHD by inhibiting activated, alloreactive T cells while retaining GVT effects. Blood J Am Soc Hematol. 2010;115(21):4293–301.

    CAS  Google Scholar 

  193. Sim GC, et al. IL-2 therapy promotes suppressive ICOS+ Treg expansion in melanoma patients. J Clin Investig. 2014;124(1):99–110.

    Article  CAS  PubMed  Google Scholar 

  194. Conlon KC, 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 Clin Oncol. 2015;33(1):74.

    Article  CAS  PubMed  Google Scholar 

  195. Quintarelli C, et al. 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. 2020;34(4):1102–15.

    Article  CAS  PubMed  Google Scholar 

  196. Wang X, et al. Inducible MyD88/CD40 synergizes with IL-15 to enhance antitumor efficacy of CAR-NK cells. Blood Adv. 2020;4(9):1950–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Ingegnere T, et al. Human CAR NK cells: a new non-viral method allowing high efficient transfection and strong tumor cell killing. Front Immunol. 2019;10:957.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

All authors declare that there is no acknowledgment in this manuscript.

Author information

Authors and Affiliations

  1. Department of Hematology and Blood Transfusion, Students Research Center, School of Allied Medicine, Tehran University of Medical Sciences, Tehran, Iran

    Tahereh Hojjatipour

  2. Department of Immunology, Pasteur Institute of Iran, Tehran, Iran

    Zahra Sharifzadeh & Amirhosein Maali

  3. Department of Medical Biotechnology, Faculty of Allied Medicine, Qazvin University of Medical Sciecnes, Qazvin, Iran

    Amirhosein Maali

  4. Department of Medical Laboratory Sciences, School of Paramedicine, Faculty of Allied Medicine, Qazvin University of Medical Sciences, Qazvin, 3419759811, Iran

    Mehdi Azad

Authors
  1. Tahereh Hojjatipour
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zahra Sharifzadeh
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Amirhosein Maali
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mehdi Azad
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mehdi Azad.

Ethics declarations

Conflict of interest

All authors declare there is no conflict of interest in this manuscript.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hojjatipour, T., Sharifzadeh, Z., Maali, A. et al. Chimeric antigen receptor-natural killer cells: a promising sword against insidious tumor cells. Human Cell 36, 1843–1864 (2023). https://doi.org/10.1007/s13577-023-00948-w

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13577-023-00948-w

Keywords

Search

Navigation