Induced pluripotent stem cell-derived natural killer cells gene-modified to express chimeric antigen receptor-targeting solid tumors

Abstract

The use of allogeneic, pluripotent stem cell-derived immune cells for cancer immunotherapy has been the subject of recent research, including clinical trials. The use of pluripotent stem cells as the source for allogeneic immune cells facilitates stringent quality control of the final product, regarding efficacy, safety, and producibility. In this review, we have described the characteristics of natural killer (NK) cells from multiple cell sources, including pluripotent stem cells, the chimeric antigen receptor (CAR)-modification method and strategy for these NK cells, and the current and planned clinical trials of CAR-modified induced pluripotent stem cell-derived NK cells.

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

Fig. 1
Fig. 2
Fig. 3

References

  1. 1.

    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. 1993;90(2):720–4.

    CAS  PubMed  Google Scholar 

  2. 2.

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

    CAS  PubMed  Google Scholar 

  3. 3.

    Klingemann H. Are natural killer cells superior CAR drivers? Oncoimmunology. 2014;3:e28147. https://doi.org/10.4161/onci.28147.

  4. 4.

    Vivier E, Nunès JA, Vély F. Natural killer cell signaling pathways. Science. 2004;306(5701):1517–9.

    CAS  PubMed  Google Scholar 

  5. 5.

    Goodridge JP, Önfelt B, Malmberg KJ. Newtonian cell interactions shape natural killer cell education. Immunol Rev. 2015;267(1):197–213.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 6.

    Kärre K. Natural killer cell recognition of missing self. Nat Immunol. 2008;9(5):477–80.

    PubMed  Google Scholar 

  7. 7.

    Sun C, Sun H, Zhang C, Tian Z. NK cell receptor imbalance and NK cell dysfunction in HBV infection and hepatocellular carcinoma. Cell Mol Immunol. 2015;12(3):292–302.

    CAS  PubMed  Google Scholar 

  8. 8.

    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.

    CAS  PubMed  Google Scholar 

  9. 9.

    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):955–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Shaffer BC, et al. 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 Transpl. 2016;22(4):705–9.

    CAS  Google Scholar 

  11. 11.

    Kalos M, Levine BL, Porter DL, et al. T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. Sci Transl Med. 2011;3(95):95ra73. https://doi.org/10.1126/scitranslmed.3002842.

  12. 12.

    Maude SL, et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med. 2014;371(16):1507–17.

    PubMed  PubMed Central  Google Scholar 

  13. 13.

    Giavridis T, Van Der Stegen SJC, Eyquem J, Hamieh M, Piersigilli A, Sadelain M. CAR T cell-induced cytokine release syndrome is mediated by macrophages and abated by IL-1 blockade letter. Nat Med. 2018;24(6):731–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Rezvani K, Rouce R, Liu E, Shpall E. Engineering natural killer cells for cancer immunotherapy. Mol Ther. 2017;25(8):1769–81.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 15.

    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.

    CAS  PubMed  Google Scholar 

  16. 16.

    Zhang C, Oberoi P, Oelsner S, et al. Chimeric antigen receptor-engineered NK-92 cells: an off-the-shelf cellular therapeutic for targeted elimination of cancer cells and induction of protective antitumor immunity. Front Immunol. 2017;8:533. https://doi.org/10.3389/fimmu.2017.00533.

  17. 17.

    Rotolo R, Leuci V, Donini C, et al. Car-based strategies beyond t lymphocytes: integrative opportunities for cancer adoptive immunotherapy. Int J Mol Sci. 2019;20(11):2839. https://doi.org/10.3390/ijms20112839.

  18. 18.

    Herrera L, et al. Adult peripheral blood and umbilical cord blood NK cells are good sources for effective CAR therapy against CD19 positive leukemic cells. Sci Rep. 2019;9(1):1–10.

    Google Scholar 

  19. 19.

    Spanholtz J, Tordoir M, Eissens D, et al. High log-scale expansion of functional human natural killer cells from umbilical cord blood CD34-positive cells for adoptive cancer immunotherapy. PLoS One. 2010;5(2):e9221. https://doi.org/10.1371/journal.pone.0009221.

  20. 20.

    Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006;126:663–76.

    CAS  PubMed  Google Scholar 

  21. 21.

    Takahashi K, et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell. 2007;131(5):861–72.

    CAS  PubMed  Google Scholar 

  22. 22.

    Yu J, Vodyanik MA, Smuga-Otto K, Antosiewicz-Bourget J, Frane JL, Tian S, Nie J, Jonsdottir GA, Ruotti V, Stewart R, Slukvin II. Induced pluripotent stem cell lines derived from human somatic cells. Science. 2007;318(21):1917–20.

    CAS  PubMed  Google Scholar 

  23. 23.

    Ghosh Z, Wilson KD, Wu Y, Hu S, Quertermous T, Wu JC. Persistent donor cell gene expression among human induced pluripotent stem cells contributes to differences with human embryonic stem cells. PLoS One. 2010;5(2):e8975. https://doi.org/10.1371/journal.pone.0008975.

  24. 24.

    Marchetto MCN, Yeo GW, Kainohana O, Marsala M, Gage FH, Muotri AR. Transcriptional signature and memory retention of human-induced pluripotent stem cells. PLoS One. 2009;4(9):e7076. https://doi.org/10.1371/journal.pone.0007076.

  25. 25.

    Valamehr B, et al. Platform for induction and maintenance of transgene-free hiPSCs resembling ground state pluripotent stem cells. Stem Cell Rep. 2014;2(3):366–81.

    CAS  Google Scholar 

  26. 26.

    Knorr DA. Clinical-scale derivation of natural killer cells from human pluripotent stem cells for cancer therapy. Stem Cells Transl Med. 2013;2(4):274–83.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Woll PS, Martin CH, Miller JS, Kaufman DS. Human embryonic stem cell-derived NK cells acquire functional receptors and cytolytic activity. J Immunol. 2005;175(8):5095–103.

    CAS  PubMed  Google Scholar 

  28. 28.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Taylor CJ, Bolton EM, Pocock S, Sharples LD, Pedersen RA, Bradley JA. Banking on human embryonic stem cells: estimating the number of donor cell lines needed for HLA matching. Lancet. 2005;366(9502):2019–25.

    PubMed  Google Scholar 

  30. 30.

    Nakatsuji N, Nakajima F, Tokunaga K. HLA-haplotype banking and iPS cells. Nat Biotechnol. 2008;26(7):739–40.

    CAS  PubMed  Google Scholar 

  31. 31.

    Hirata RK, et al. HLA-E-expressing pluripotent stem cells escape allogeneic responses and lysis by NK cells. Nat Biotechnol. 2017;35(8):765–72.

    PubMed  PubMed Central  Google Scholar 

  32. 32.

    Fauriat C, et al. Estimation of the size of the alloreactive NK cell repertoire: studies in individuals homozygous for the group A KIR haplotype. J. Immunol. 2008;181(9):6010–9.

    CAS  PubMed  Google Scholar 

  33. 33.

    Nguyen S, et al. HLA-E upregulation on IFN-γ-activated AML blasts impairs CD94/NKG2A-dependent NK cytolysis after haplo-mismatched hematopoietic SCT. Bone Marrow Transpl. 2009;43(9):693–9.

    CAS  Google Scholar 

  34. 34.

    André P, et al. Anti-NKG2A mAb is a checkpoint inhibitor that promotes anti-tumor immunity by unleashing both T and NK cells. Cell. 2018;175(7):1731.e13–1743.e13.

    Google Scholar 

  35. 35.

    Björkström NK, et al. Expression patterns of NKG2A, KIR, and CD57 define a process of CD56 dim NK-cell differentiation uncoupled from NK-cell education. Blood. 2010;116(19):3853–64.

    PubMed  Google Scholar 

  36. 36.

    Zeng J, Tang SY, Toh LL, Wang S. Generation of ‘off-the-shelf’ natural killer cells from peripheral blood cell-derived induced pluripotent stem cells. Stem Cell Rep. 2017;9(6):1796–812.

    CAS  Google Scholar 

  37. 37.

    Hermanson DL, et al. Induced pluripotent stem cell-derived natural killer cells for treatment of ovarian cancer. Stem Cells. 2016;34(1):93–101.

    CAS  PubMed  Google Scholar 

  38. 38.

    Béziat V, et al. Influence of KIR gene copy number on natural killer cell education. Blood. 2013;121(23):4703–7.

    PubMed  PubMed Central  Google Scholar 

  39. 39.

    Béziat V, et al. Tracing dynamic expansion of human NK-cell subsets by high-resolution analysis of KIR repertoires and cellular differentiation. Eur J Immunol. 2014;44(7):2192–6.

    PubMed  PubMed Central  Google Scholar 

  40. 40.

    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.

    CAS  PubMed  Google Scholar 

  41. 41.

    Li Y, Hermanson DL, Moriarity BS, Kaufman DS. Human iPSC-derived natural killer cells engineered with chimeric antigen receptors enhance anti-tumor activity. Cell Stem Cell. 2018;23(2):181.e5–192.e5.

    Google Scholar 

  42. 42.

    Ueda T, et al. Non-clinical efficacy, safety, and stable clinical cell processing of iPSC- derived anti-GPC3 CAR-expressing NK/ILC cells. Cancer Sci. 2020.

  43. 43.

    Ueda T, Kumagai A, Iriguchi S, 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):1478–1490. https://doi.org/10.1111/cas.14374.

  44. 44.

    D'Aloia MM, Zizzari IG, Sacchetti B, Pierelli L, Alimandi M. CAR-T cells: the long and winding road to solid tumors. Cell Death Dis. 2018;9(3):282.https://doi.org/10.1038/s41419-018-0278-6

  45. 45.

    Sampson JH, Archer GE, Mitchell DA, Heimberger AB, Bigner DD. Tumor-specific immunotherapy targeting the EGFRvIII mutation in patients with malignant glioma. Semin Immunol. 2008;20(5):267–75.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 46.

    Ghiringhelli F, et al. CD4 + CD25 + regulatory T cells inhibit natural killer cell functions in a transforming growth factor-β-dependent manner. J Exp Med. 2005;202(8):1075–85.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 47.

    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.

    CAS  PubMed  Google Scholar 

  48. 48.

    Fehniger TA, Caligiuri MA. Interleukin 15: biology and relevance to human disease. Blood. 2001;97(1):14–32.

    CAS  PubMed  Google Scholar 

  49. 49.

    Wrangle JM, et al. ALT-803, an IL-15 superagonist, in combination with nivolumab in patients with metastatic non-small cell lung cancer: a non-randomised, open-label, phase 1b trial. Lancet Oncol. 2018;19(5):694–704.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 50.

    Romee R, et al. First-in-human phase 1 clinical study of the IL-15 superagonist complex ALT-803 to treat relapse after transplantation. Blood. 2018;131(23):2515–27.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. 51.

    Beider K, et al. Involvement of CXCR4 and IL-2 in the homing and retention of human NK and NK T cells to the bone marrow and spleen of NOD/SCID mice. Blood. 2003;102(6):1951–8.

    CAS  PubMed  Google Scholar 

  52. 52.

    Groth A, Klöss S, Pogge Von Strandmann E, Koehl U, Koch J. Mechanisms of tumor and viral immune escape from natural killer cell-mediated surveillance. J Innate Immun. 2011;3(4):344–54.

    CAS  PubMed  Google Scholar 

  53. 53.

    Fisher B, et al. Tumor localization of adoptively transferred indium-111 labeled tumor infiltrating lymphocytes in patients with metastatic melanoma. J Clin Oncol. 1989;7(2):250–61.

    CAS  PubMed  Google Scholar 

  54. 54.

    Pockaj BA, et al. Localization of 111Indium-labeled tumor infiltrating lymphocytes to tumor in patients receiving adoptive immunotherapy. Augmentation with cyclophosphamide and correlation with response. Cancer. 1994;73(6):1731–7.

    CAS  PubMed  Google Scholar 

  55. 55.

    Paul S, Lal G. The molecular mechanism of natural killer cells function and its importance in cancer immunotherapy. Front Immunol. 2017;8.

  56. 56.

    Paul S, Lal G. The Molecular Mechanism of Natural Killer Cells Function and Its Importance in Cancer Immunotherapy. Front Immunol. 2017;8:1124. https://doi.org/10.3389/fimmu.2017.01124

  57. 57.

    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.

    CAS  PubMed  PubMed Central  Google Scholar 

  58. 58.

    Wennerberg E, Kremer V, Childs R, Lundqvist A. CXCL10-induced migration of adoptively transferred human natural killer cells toward solid tumors causes regression of tumor growth in vivo. Cancer Immunol Immunother. 2014;64(2):225–35.

    PubMed  Google Scholar 

  59. 59.

    Mikucki ME, et al. Non-redundant requirement for CXCR3 signalling during tumoricidal T-cell trafficking across tumour vascular checkpoints. Nat Commun. 2015;6.

  60. 60.

    Mikucki ME, Fisher DT, Matsuzaki J, et al. Non-redundant requirement for CXCR3 signalling during tumoricidal T-cell trafficking across tumour vascular checkpoints. Nat Commun. 2015;6:7458. https://doi.org/10.1038/ncomms8458.

  61. 61.

    Nishio N, et al. Armed oncolytic virus enhances immune functions of chimeric antigen receptor-modified T cells in solid tumors. Cancer Res. 2014;74(18):5195–205.

    CAS  PubMed  PubMed Central  Google Scholar 

  62. 62.

    Whilding LM, Vallath S, Maher J. The integrin αvβ6: a novel target for CAR T-cell immunotherapy? Biochem Soc Trans. 2016;44(2):349–55.

    CAS  PubMed  Google Scholar 

  63. 63.

    Wang W, et al. Specificity redirection by CAR with human VEGFR-1 affinity endows T lymphocytes with tumor-killing ability and anti-angiogenic potency. Gene Ther. 2013;20(10):970–8.

    CAS  PubMed  Google Scholar 

  64. 64.

    Stewart MD, Sanderson RD. Heparan sulfate in the nucleus and its control of cellular functions. Matrix Biol. 2014;35:56–9.

    CAS  PubMed  Google Scholar 

  65. 65.

    Speiser DE, Ho PC, Verdeil G. Regulatory circuits of T cell function in cancer. Nat Rev Immunol. 2016;16(10):599–611.

    CAS  PubMed  Google Scholar 

  66. 66.

    Mao Y, et al. A new effect of IL-4 on human γδ cells: promoting regulatory Vδ1 T cells via IL-10 production and inhibiting function of Vδ2 T cells. Cell Mol Immunol. 2016;13(2):217–28.

    CAS  PubMed  Google Scholar 

  67. 67.

    Krneta T, Gillgrass A, Chew M, Ashkar AA. The breast tumor microenvironment alters the phenotype and function of natural killer cells. Cell Mol Immunol. 2016;13(5):628–39.

    CAS  PubMed  Google Scholar 

  68. 68.

    Rekik R, Belhadj Hmida N, Ben Hmid A, Zamali I, Kammoun N, Ben Ahmed M. PD-1 induction through TCR activation is partially regulated by endogenous TGF-β. Cell Mol Immunol. 2015;12(5):648–9.

    CAS  PubMed  Google Scholar 

  69. 69.

    Zhang S, et al. Analysis of CD8 + Treg cells in patients with ovarian cancer: a possible mechanism for immune impairment. Cell Mol Immunol. 2015;12(5):580–91.

    CAS  PubMed  PubMed Central  Google Scholar 

  70. 70.

    Mohammed S, et al. Improving chimeric antigen receptor-modified T cell function by reversing the immunosuppressive tumor microenvironment of pancreatic cancer. Mol Ther. 2017;25(1):249–58.

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

Shin Kaneko is a founder, shareholder, and chief scientific officer of Thyas Co., Ltd., and has received research funding from Takeda Pharmaceutical Co. Ltd., Kirin Holdings Co., Ltd., Tosoh Co. Ltd., Terumo Co. Ltd., and Thyas Co., Ltd.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Shin Kaneko.

Ethics declarations

Conflict of interest

Tatsuki Ueda declares no competing financial interests.

Additional information

Publisher's Note

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

About this article

Verify currency and authenticity via CrossMark

Cite this article

Ueda, T., Kaneko, S. Induced pluripotent stem cell-derived natural killer cells gene-modified to express chimeric antigen receptor-targeting solid tumors. Int J Hematol (2020). https://doi.org/10.1007/s12185-020-02951-5

Download citation

Keywords

  • Immunotherapy
  • Chimeric antigen receptor
  • Natural killer cell
  • Induced pluripotent stem cell