CAR-NK therapy approaches for targeting the immunosuppressive tumor microenvironment in solid tumors
Main Article Content
Abstract
Background: Adoptive cellular therapies have gained considerable ground while becoming an established form of therapy for hematologic malignancies, now a fifth pillar of treatment after chemotherapy, surgery, radiation and targeted therapies. The most prominent example is chimeric antigen T cell receptor therapies. These therapies have shown superior clinical efficacy in hematologic malignancies, but are less effective against solid tumors. This paper describes the combination of CAR T cells with the innate immune cells natural killer cells in solid tumors in the immunosuppressive tumor microenvironment.
Results: CAR NK cells have been shown in a number of solid tumors in the context of the immunosuppressive tumor microenvironment to have clinical efficacy and exhibit superior safety profiles when compared with original CAR T cells. In preclinical models and ongoing clinical studies, anti-tumor activity has been shown in prostate cancer, hepatocellular carcinoma, glioblastoma and ovarian cancer that benefits from the inherent cytotoxicity of natural killer cells.
Conclusion: Future studies should focus on using the advantages of CAR NK cells in clinical and translational settings.
Keywords:
CAR T cells, Natural Killer Cells, CAR-NK cells, tumor microenvironment, solid tumors
Article Details
How to Cite
HAYS, Priya.
CAR-NK therapy approaches for targeting the immunosuppressive tumor microenvironment in solid tumors.
Medical Research Archives, [S.l.], v. 12, n. 10, oct. 2024.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/5750>. Date accessed: 15 nov. 2024.
doi: https://doi.org/10.18103/mra.v12i10.5750.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
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10. Kwon M, Iacoboni G, Reguera JL, Corral LL, Morales RH, Ortiz-Maldonado V. et al. Axicabtagene ciloleucel compared to tisagenlecleucel for the treatment of aggressive B-cell lymphoma. Haematologica. 2023;108:110–21.
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13. Ni, J. et al. Single-cell RNA sequencing of tumor-infiltrating NK cells reveals that inhibition of transcription factor HIF-1α unleashes NK cell activity. Immunity 52, 1075–1087.e8 (2020).
14. Rosario, M. et al. The IL-15-based ALT-803 complex enhances FcγRIIIa-triggered NK cell responses and in vivo clearance of B cell lymphomas. Clin. Cancer Res. 22, 596–608 (2016).
15. Jin, D. et al. CD73 on tumor cells impairs antitumor T-cell responses: a novel mechanism of tumor-induced immune suppression. Cancer Res. 70, 2245–2255(2010)
16. Stagg, J. et al. Anti-CD73 antibody therapy inhibit breast tumor growth and metastasis. Proc. Natl Acad. Sci. USA 107, 1547–1552 (2010).
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20. Young, A. et al. A2AR adenosine signaling suppresses natural killer cell maturation in the tumor microenvironment. Cancer Res. 78, 1003 (2018).
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22. Giuffrida, L. et al. CRISPR/Cas9 mediated deletion of the adenosine A2A receptor enhances CAR T cell efficacy. Nat. Commun. 12, 3236 (2021).
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29. 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 32, 520–531 (2018).
30. Xiao X, Huang S, Chen S, Wang Y, Sun Q, Xu X, et al. Mechanisms of cytokine release syndrome and neurotoxicity of CAR T-cell therapy and associated prevention and management strategies. J Exp Clin Cancer Res. 2021;40:367.
31. Lindner SE, Johnson SM, Brown CE, Wang LD. Chimeric antigen receptor signaling: functional consequences and design implications. Sci Adv. 2020;6:eaaz3223.
32. Gong Y, Klein Wolterink RGJ, Wang J, Bos GMJ, Germeraad WTV. Chimeric antige receptor natural killer (CAR-NK) cell design and engineering for cancer therapy. J Hematol Oncol. 2021;14:73.
33. Zhang L, Meng Y, Feng X, Han Z. CAR-NK cells for cancer immunotherapy: from bench to bedside. Biomark Res. 2022;10:12.
34. Oei V, Siernicka M, Graczyk-Jarzynka A, et al. Intrinsic Functional Potential of NK-Cell subsets constrains retargeting driven by chimeric antigen receptors. Cancer Immunol Res 2018;6(4):467–80.
35. 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.
36. Sun C, Sun HY, Xiao WH, Zhang C, Tian ZG. Natural killer cell dysfunction in hepatocellular carcinoma and NK cell-based immunotherapy. Acta Pharmacol Sin 2015;36(10):1191–9.
37. Wu J, Mishra HK, Walcheck B. Role of ADAM17 as a regulatory checkpoint of CD16A in NK cells and as a potential target for cancer immunotherapy. J Leukoc Biol 2019;105(6):1297–303.
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39. ChatGPT, search, August 10,2024.
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41. Van den Eynde A, Gehrcken L, Verhezen T, Lau HW, Hermans C, Lambrechts H, et al. IL-15-secreting CAR natural killer cells directed toward the pan-cancer target CD70 eliminate both cancer cells and cancer-associated fibrob lasts. J Hematol Oncol. 2024;17:8.
42. Liu E, Marin D, Banerjee P, Macapinlac HA, Thompson P, Basar R, et al. Use of CAR transduced natural killer cells in CD19-positive lymphoid Tumors. N Engl J Med. 2020;382:545–53.
43. André P, Denis C, Soulas C, Bourbon-Caillet C, Lopez J, Arnoux T, et al. Anti-NKG2A mAb is a checkpoint inhibitor that promotes anti-tumor immunity by unleashing both T and NK cells. Cell. 2018;175:1731–1743.e13.
44. Wrona E, Borowiec M, Potemski P. CAR-NK Cells in the Treatment of Solid Tumors. Int. J. Mol. Sci. 2021, 22, 5899.
45. Töpfer K, Cartellieri M, Michen S, Wiedemuth R, Müller N, et al. DAP12-Based Activating Chimeric Antigen Receptor for NK Cell Tumor Immunotherapy. J. Immunol. 2015, 194, 3201–3212.
46. Lu C, Guo C, Chen H, Zhang H, Zhi L et al novel chimeric PD1-NKG2D-41BB receptor enhances antitumor activity of NK92 cells against human lung cancer H1299 cells by triggering pyroptosis. Mol. Immunol. 2020, 122, 200–206.
47. Lee YE, Ju A, Choi HW, Kim JC, Kim EE, et al. Rationally designed redirection of natural killer cells anchoring a cytotoxic ligand for pancreatic cancer treatment. J. Control. Release 2020, 326, 310–323.
48. He H, Hao S.-J, Yao L, Yang F, Di Y, Li J, et al. MicroRNA-218 inhibits cell invasion and migration of pancreatic cancer via regulating ROBO1. Cancer Biol. Ther. 2014, 15, 1333–1339.
49. Xia N, Haopeng P, Gong JU, Lu J, Chen Z, et al. Robo1-specific CAR-NK Immunotherapy Enhances Efficacy of 125I Seed Brachytherapy in an Orthotopic Mouse Model of Human Pancreatic Carcinoma. Anticancer Res. 2019, 39, 5919–5925.
50. Cao B, Liu M, Wang L, Liang B, Feng Y et al. Use of chimeric antigen receptor NK-92 cells to target mesothelin in ovarian cancer. Biochem. Biophys. Res. Commun. 2020, 524, 96–102.
51. Klapdor R, Wang S, Morgan M, Dörk T, Hacker U, et al Characterization of a Novel Third-Generation Anti-CD24-CAR against Ovarian Cancer. Int. J. Mol. Sci. 2019, 20, 660.
52. Ao X, Yang Y, Li W, Tan Y, Guo W, et al. Anti- FR CAR-engineered NK-92 Cells Display Potent Cytotoxicity Against FR-positive Ovarian Cancer. J. Immunother. 2019, 42, 284–296.
53. Subrakova VG, Kulemzin SV, Belovezhets TN, Chikaev AN, Chikaev NA et alshp-2 gene knockout upregulates CAR-driven cytotoxicity of YT NK cells. Vavilov J. Genet. Breed. 2020, 24, 80–86.
54. Vivier E, Tomasello E, Baratin M, Walzer T, Ugolini S. Functions of natural killer cells. Nat Immunol. 2008;9(5):503–10.
55. Liu E, Tong Y, Dotti G, Shaim H, Savoldo B, Mukherjee M, 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.
56. Weinkove R, George P, Dasyam N, McLellan AD. Selecting costimulatory domains for chimeric antigen receptors: functional and clinical considerations. Clin Transl Immunology. 2019;8(5):e1049.
57. Zhang Q, Bi J, Zheng X, Chen Y, Wang H, Wu W, et al. Blockade of the checkpoint receptor TIGIT prevents NK cell exhaustion and elicits potent anti-tumor immunity. Nat Immunol. 2018;19(7):723–32.
58. Judge SJ, Murphy WJ, Canter RJ. Characterizing the dysfunctional NK cell: assessing the clinical relevance of exhaustion, anergy, and senescence. Front Cell Infect Microbiol.2020;10:49.
59. Young A, Ngiow Shin F, Barkauskas Deborah S, Sult E, Hay C, Blake Stephen J, et al. Co-inhibition of CD73 and A2AR adenosine signaling improves anti-tumor immune responses. Cancer Cell. 2016;30(3):391–403.
60. Young A, Ngiow SF, Gao Y, Patch A-M, Barkauskas DS, Messaoudene M, et al. A2AR adenosine signaling suppresses natural killer cell maturation in the tumor microenvironment. Can Res. 2018;78(4):1003.
61. Shaim H, Shanley M, Basar R, Daher M, Gumin J, Zamler DB, et al. Targeting the αv integrin/TGF-β axis improves natural killer cell function against glioblastoma stem cells. J Clin Invest. 2021.
62. Ng YY, Tay JC, Wang S. CXCR1 expression to improve anticancer efficacy of intravenously injected CAR-NK cells in mice with peritoneal xenografts. Mol Ther Oncol. 2020;16:75–85.
63. Gong Y, Klein R, Wolterink R, Wang J, Gerard MJ. Chimeric antigen receptor natural killer (CAR‑NK) cell design and engineering for cancer therapy. J Hematol Oncol. 2021;14:73.
64. Pan K, Farrukh H, Reddy VCS, Xu H, Pan C-x et al. CAR race to cancer immunotherapy: from CAR T, CAR NK to CAR macrophage therapy. J Exp Clin Cancer Res. 2022;41:119.
65. Kilgour MK, Bastin DJ, Lee S-H, Ardolino M, et al. Advancements in CAR-NK therapy: lessons to be learned from CAR-T therapy. Front Immunol. 2023;14.
2. Dotti G, Gottschalk S, Savoldo B, Brenner MK. Design and Development of Therapies Using Chimeric Antigen Receptor-Expressing T Cells. Immunol Rev (2014) 257(1):107–26.
3. Perutelli F, Jones R, Griggio V, Vitale C and Coscia M (2022). Immunotherapeutic Strategies in Chronic Lymphocytic Leukemia: Advances and Challenges. Front. Oncol. 12:837531.
4. Biederstädt A and Rezvani K. Engineering the next generation of CAR‑NK immunotherapies. International Journal of Hematology (2021) 114:554–571
5. Adada M, Siegler EL, Kenderian SS. Combination Therapeutics with CAR-T Cell therapy in Gene and Cellular Immunotherapy for Cancer. Ghobadi A and DiPersio JF, Eds. (Switzerland: Springer Nature) 2022; pp. 69-91.
6. Caligiuri MA. Human natural killer cells. Blood 2008;112(3):461–9.
7. Wang W, Erbe AK, Hank JA, Morris ZS, Sondel PM. NK cell-mediated antibody dependent cellular cytotoxicity in cancer immunotherapy. Front Immunol 2015;6:368.
8. Vivier E, Raulet DH, Moretta A, et al. Innate or adaptive immunity? the example of natural killer cells. Science 2011;331(6013):44–9.
9. Lindner SE, Johnson SM, Brown CE, Wang LD. Chimeric antigen receptor signaling: functional consequences and design implications. Sci Adv. 2020;6.
10. Kwon M, Iacoboni G, Reguera JL, Corral LL, Morales RH, Ortiz-Maldonado V. et al. Axicabtagene ciloleucel compared to tisagenlecleucel for the treatment of aggressive B-cell lymphoma. Haematologica. 2023;108:110–21.
11. Zhong Y and Liu J. Emerging roles of CAR-NK cell therapies in tumor immunotherapy: current status and future directions. Cell Death Discovery (2024) 10:318.
12. Laskowski TJ, Biederstädt A and Rezvani K. Natural killer cells in antitumour adoptive cell immunotherapy. Nature Reviews. 2022;22:557-587.
13. Ni, J. et al. Single-cell RNA sequencing of tumor-infiltrating NK cells reveals that inhibition of transcription factor HIF-1α unleashes NK cell activity. Immunity 52, 1075–1087.e8 (2020).
14. Rosario, M. et al. The IL-15-based ALT-803 complex enhances FcγRIIIa-triggered NK cell responses and in vivo clearance of B cell lymphomas. Clin. Cancer Res. 22, 596–608 (2016).
15. Jin, D. et al. CD73 on tumor cells impairs antitumor T-cell responses: a novel mechanism of tumor-induced immune suppression. Cancer Res. 70, 2245–2255(2010)
16. Stagg, J. et al. Anti-CD73 antibody therapy inhibit breast tumor growth and metastasis. Proc. Natl Acad. Sci. USA 107, 1547–1552 (2010).
17. Allard B, Longhi MS, Robson SC, Stagg J. The ectonucleotidases CD39 and CD73: novel checkpoint inhibitor targets. Immunol. Rev. 276,121–144 (2017).
18. Perrot, I. et al. Blocking antibodies targeting the CD39/CD73 immunosuppressive pathway unleash immune responses in combination cancer therapies. Cell Rep. 27, 2411–2425.e9 (2019).
19. Young, A. et al. Co-inhibition of CD73 and A2AR adenosine signaling improves anti-tumor immune responses. Cancer Cell 30, 391–403 (2016).
20. Young, A. et al. A2AR adenosine signaling suppresses natural killer cell maturation in the tumor microenvironment. Cancer Res. 78, 1003 (2018).
21. Lupo K and Matosevic, S. Natural killer cells engineered with an inducible, responsive genetic construct targeting TIGIT and CD73 to relieve immunosuppression within the GBM microenvironment. J. Immunother. Cancer 8, A74–A75 (2020).
22. Giuffrida, L. et al. CRISPR/Cas9 mediated deletion of the adenosine A2A receptor enhances CAR T cell efficacy. Nat. Commun. 12, 3236 (2021).
23. Daher, M. et al. The TGF-β/SMAD signaling pathway as a mediator of NK cell dysfunction and immune evasion in myelodysplastic syndrome. Blood 130,53–53 (2017).
24. Shaim, H. et al. Targeting the αv integrin/TGF-β axis improves natural killer cell function against glioblastoma stem cells. J. Clin. Investig. https://doi.org/10.1172/JCI142116 (2021).
25. Daher J and Rezvani K. Outlook for new CAR-based therapies with a focus on CAR NK cells: what lies beyond CAR-engineered T cells in the race against cancer. Cancer Disco 11, 45–58 (2021).
26. Lanier LL, Corliss BC, Wu J, Leong C and Phillips JH. Immunoreceptor DAP12 bearing a tyrosine-based activation motif is involved in activating NK cells. Nature 391, 703–707 (1998).
27. Zhao R et al. DNAX-activating protein 10 co-stimulation enhances the anti-tumor efficacy of chimeric antigen receptor T cells. Oncoimmunology. 8, e1509173 (2018).
28. Felices M et al. Continuous treatment with IL-15 exhausts human NK cells via a metabolic defect. JCI Insight.
29. 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 32, 520–531 (2018).
30. Xiao X, Huang S, Chen S, Wang Y, Sun Q, Xu X, et al. Mechanisms of cytokine release syndrome and neurotoxicity of CAR T-cell therapy and associated prevention and management strategies. J Exp Clin Cancer Res. 2021;40:367.
31. Lindner SE, Johnson SM, Brown CE, Wang LD. Chimeric antigen receptor signaling: functional consequences and design implications. Sci Adv. 2020;6:eaaz3223.
32. Gong Y, Klein Wolterink RGJ, Wang J, Bos GMJ, Germeraad WTV. Chimeric antige receptor natural killer (CAR-NK) cell design and engineering for cancer therapy. J Hematol Oncol. 2021;14:73.
33. Zhang L, Meng Y, Feng X, Han Z. CAR-NK cells for cancer immunotherapy: from bench to bedside. Biomark Res. 2022;10:12.
34. Oei V, Siernicka M, Graczyk-Jarzynka A, et al. Intrinsic Functional Potential of NK-Cell subsets constrains retargeting driven by chimeric antigen receptors. Cancer Immunol Res 2018;6(4):467–80.
35. 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.
36. Sun C, Sun HY, Xiao WH, Zhang C, Tian ZG. Natural killer cell dysfunction in hepatocellular carcinoma and NK cell-based immunotherapy. Acta Pharmacol Sin 2015;36(10):1191–9.
37. Wu J, Mishra HK, Walcheck B. Role of ADAM17 as a regulatory checkpoint of CD16A in NK cells and as a potential target for cancer immunotherapy. J Leukoc Biol 2019;105(6):1297–303.
38. Xiea G, Dong H, Liang Y, Dongjoo H, Rizwand R et al. CAR-NK cells: A promising cellular immunotherapy for cancer. EBioMedicine.
39. ChatGPT, search, August 10,2024.
40. Xu Y, Zeng H, Jin K, Liu Z, Zhu Y, Xu L, et al. Immunosuppressive tumor-associated macrophages expressing interlukin-10 conferred poor prognosis and therapeutic vulnerability in patients with muscle-invasive bladder cancer. J Immunother Cancer. 2022;10:e003416.
41. Van den Eynde A, Gehrcken L, Verhezen T, Lau HW, Hermans C, Lambrechts H, et al. IL-15-secreting CAR natural killer cells directed toward the pan-cancer target CD70 eliminate both cancer cells and cancer-associated fibrob lasts. J Hematol Oncol. 2024;17:8.
42. Liu E, Marin D, Banerjee P, Macapinlac HA, Thompson P, Basar R, et al. Use of CAR transduced natural killer cells in CD19-positive lymphoid Tumors. N Engl J Med. 2020;382:545–53.
43. André P, Denis C, Soulas C, Bourbon-Caillet C, Lopez J, Arnoux T, et al. Anti-NKG2A mAb is a checkpoint inhibitor that promotes anti-tumor immunity by unleashing both T and NK cells. Cell. 2018;175:1731–1743.e13.
44. Wrona E, Borowiec M, Potemski P. CAR-NK Cells in the Treatment of Solid Tumors. Int. J. Mol. Sci. 2021, 22, 5899.
45. Töpfer K, Cartellieri M, Michen S, Wiedemuth R, Müller N, et al. DAP12-Based Activating Chimeric Antigen Receptor for NK Cell Tumor Immunotherapy. J. Immunol. 2015, 194, 3201–3212.
46. Lu C, Guo C, Chen H, Zhang H, Zhi L et al novel chimeric PD1-NKG2D-41BB receptor enhances antitumor activity of NK92 cells against human lung cancer H1299 cells by triggering pyroptosis. Mol. Immunol. 2020, 122, 200–206.
47. Lee YE, Ju A, Choi HW, Kim JC, Kim EE, et al. Rationally designed redirection of natural killer cells anchoring a cytotoxic ligand for pancreatic cancer treatment. J. Control. Release 2020, 326, 310–323.
48. He H, Hao S.-J, Yao L, Yang F, Di Y, Li J, et al. MicroRNA-218 inhibits cell invasion and migration of pancreatic cancer via regulating ROBO1. Cancer Biol. Ther. 2014, 15, 1333–1339.
49. Xia N, Haopeng P, Gong JU, Lu J, Chen Z, et al. Robo1-specific CAR-NK Immunotherapy Enhances Efficacy of 125I Seed Brachytherapy in an Orthotopic Mouse Model of Human Pancreatic Carcinoma. Anticancer Res. 2019, 39, 5919–5925.
50. Cao B, Liu M, Wang L, Liang B, Feng Y et al. Use of chimeric antigen receptor NK-92 cells to target mesothelin in ovarian cancer. Biochem. Biophys. Res. Commun. 2020, 524, 96–102.
51. Klapdor R, Wang S, Morgan M, Dörk T, Hacker U, et al Characterization of a Novel Third-Generation Anti-CD24-CAR against Ovarian Cancer. Int. J. Mol. Sci. 2019, 20, 660.
52. Ao X, Yang Y, Li W, Tan Y, Guo W, et al. Anti- FR CAR-engineered NK-92 Cells Display Potent Cytotoxicity Against FR-positive Ovarian Cancer. J. Immunother. 2019, 42, 284–296.
53. Subrakova VG, Kulemzin SV, Belovezhets TN, Chikaev AN, Chikaev NA et alshp-2 gene knockout upregulates CAR-driven cytotoxicity of YT NK cells. Vavilov J. Genet. Breed. 2020, 24, 80–86.
54. Vivier E, Tomasello E, Baratin M, Walzer T, Ugolini S. Functions of natural killer cells. Nat Immunol. 2008;9(5):503–10.
55. Liu E, Tong Y, Dotti G, Shaim H, Savoldo B, Mukherjee M, 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.
56. Weinkove R, George P, Dasyam N, McLellan AD. Selecting costimulatory domains for chimeric antigen receptors: functional and clinical considerations. Clin Transl Immunology. 2019;8(5):e1049.
57. Zhang Q, Bi J, Zheng X, Chen Y, Wang H, Wu W, et al. Blockade of the checkpoint receptor TIGIT prevents NK cell exhaustion and elicits potent anti-tumor immunity. Nat Immunol. 2018;19(7):723–32.
58. Judge SJ, Murphy WJ, Canter RJ. Characterizing the dysfunctional NK cell: assessing the clinical relevance of exhaustion, anergy, and senescence. Front Cell Infect Microbiol.2020;10:49.
59. Young A, Ngiow Shin F, Barkauskas Deborah S, Sult E, Hay C, Blake Stephen J, et al. Co-inhibition of CD73 and A2AR adenosine signaling improves anti-tumor immune responses. Cancer Cell. 2016;30(3):391–403.
60. Young A, Ngiow SF, Gao Y, Patch A-M, Barkauskas DS, Messaoudene M, et al. A2AR adenosine signaling suppresses natural killer cell maturation in the tumor microenvironment. Can Res. 2018;78(4):1003.
61. Shaim H, Shanley M, Basar R, Daher M, Gumin J, Zamler DB, et al. Targeting the αv integrin/TGF-β axis improves natural killer cell function against glioblastoma stem cells. J Clin Invest. 2021.
62. Ng YY, Tay JC, Wang S. CXCR1 expression to improve anticancer efficacy of intravenously injected CAR-NK cells in mice with peritoneal xenografts. Mol Ther Oncol. 2020;16:75–85.
63. Gong Y, Klein R, Wolterink R, Wang J, Gerard MJ. Chimeric antigen receptor natural killer (CAR‑NK) cell design and engineering for cancer therapy. J Hematol Oncol. 2021;14:73.
64. Pan K, Farrukh H, Reddy VCS, Xu H, Pan C-x et al. CAR race to cancer immunotherapy: from CAR T, CAR NK to CAR macrophage therapy. J Exp Clin Cancer Res. 2022;41:119.
65. Kilgour MK, Bastin DJ, Lee S-H, Ardolino M, et al. Advancements in CAR-NK therapy: lessons to be learned from CAR-T therapy. Front Immunol. 2023;14.