Review Article

CAR-NK Cells for Cancer Therapy: Molecular Redesign of the Innate Antineoplastic Response

Author(s): Oscar Cienfuegos-Jimenez, Eduardo Vazquez-Garza and Augusto Rojas-Martinez*

Volume 22, Issue 4, 2022

Published on: 12 January, 2022

Page: [303 - 318] Pages: 16

DOI: 10.2174/1566523222666211217091724

Price: $65


The Chimeric Antigen Receptor (CAR) has arisen as a powerful synthetic biology-based technology with demonstrated versatility for implementation in T and NK cells. Despite CAR T cell successes in clinical trials, several challenges remain to be addressed regarding adverse events and long-term efficacy. NK cells present an attractive alternative with intrinsic advantages over T cells for treating solid and liquid tumors. Early preclinical and clinical trials suggest at least two major advantages: improved safety and an off-the-shelf application in patients due to its HLA independence. Due to the early stages of CAR NK translation to clinical trials, limited data is currently available. By analyzing these results, it seems that CAR NK cells could offer a reduced probability of Cytokine Release Syndrome (CRS) or Graft versus Host Disease (GvHD) in cancer patients, reducing safety concerns. Furthermore, NK cell therapy approaches may be boosted by combining it with immunological checkpoint inhibitors and by implementing genetic circuits to direct CAR-bearing cell behavior. This review provides a description of the CAR technology for modifying NK cells and the translation from preclinical studies to early clinical trials in this new field of immunotherapy.

Keywords: Chimeric antigen receptor, NK cells, adoptive cell transfer, immunotherapy, cancer, gene therapy, synthetic biology.

Graphical Abstract
Fortunato A, Boddy A, Mallo D, Aktipis A, Maley CC, Pepper JW. Natural selection in cancer biology: From molecular snowflakes to trait hallmarks. Cold Spring Harb Perspect Med 2017; 7(2): a029652.
[] [PMID: 28148564]
Pan S-T, Li Z-L, He Z-X, Qiu J-X, Zhou S-F. Molecular mechanisms for tumour resistance to chemotherapy. Clin Exp Pharmacol Physiol 2016; 43(8): 723-37.
[] [PMID: 27097837]
Triolo VA. Nineteenth century foundations of cancer research origins of experimental research. Cancer Res 1964; 24(1 Part 1): 4-27.
[PMID: 14106160]
Butlin HT. The treatment of malignant disease by the injection of the toxins of erysipelas. BMJ 1883; 1(1897): 299-300.
Strauss-Albee DM, Fukuyama J, Liang EC, et al. Human NK cell repertoire diversity reflects immune experience and correlates with viral susceptibility. Sci Transl Med 2015; 7(297): 297ra115.
[] [PMID: 26203083]
Melsen JE, Lugthart G, Lankester AC, Schilham MW. Human circulating and tissue-resident CD56(bright) natural killer cell populations. Front Immunol 2016; 7: 262.
[] [PMID: 27446091]
Yu J, Freud AG, Caligiuri MA. Location and cellular stages of natural killer cell development. Trends Immunol 2013; 34(12): 573-82.
[] [PMID: 24055329]
Pfefferle A, Jacobs B, Haroun-Izquierdo A, Kveberg L, Sohlberg E, Malmberg K-J. Deciphering natural killer cell homeostasis. Front Immunol 2020; 11: 812.
[] [PMID: 32477340]
Caligiuri MA. Human natural killer cells. Blood 2008; 112(3): 461-9.
[] [PMID: 18650461]
Billadeau DD, Leibson PJ. ITAMs versus ITIMs: Striking a balance during cell regulation. J Clin Invest 2002; 109(2): 161-8.
[] [PMID: 11805126]
Barrow AD, Martin CJ, Colonna M. The natural cytotoxicity receptors in health and disease. Front Immunol 2019; 10: 909.
[] [PMID: 31134055]
Pende D, Falco M, Vitale M, et al. Killer Ig-Like receptors (KIRs): Their role in NK cell modulation and developments leading to their clinical exploitation. Front Immunol 2019; 10: 1179.
[] [PMID: 31231370]
Wensveen FM, Jelenčić V, Polić B. NKG2D: A master regulator of immune cell responsiveness. Front Immunol 2018; 9: 441.
[] [PMID: 29568297]
Zwirner NW, Domaica CI. Cytokine regulation of natural killer cell effector functions. Biofactors 2010; 36(4): 274-88.
[] [PMID: 20623510]
Salmon H, Donnadieu E. Within tumors, interactions between T cells and tumor cells are impeded by the extracellular matrix. OncoImmunology 2012; 1(6): 992-4.
[] [PMID: 23162783]
Salmon H, Franciszkiewicz K, Damotte D, et al. Matrix architecture defines the preferential localization and migration of T cells into the stroma of human lung tumors. J Clin Invest 2012; 122(3): 899-910.
[] [PMID: 22293174]
Zhang Y, Ertl HCJ. Starved and asphyxiated: How can CD8(+) T cells within a tumor microenvironment prevent tumor progression. Front Immunol 2016; 7: 32.
[] [PMID: 26904023]
Matsushita M, Freigang S, Schneider C, Conrad M, Bornkamm GW, Kopf M. T cell lipid peroxidation induces ferroptosis and prevents immunity to infection. J Exp Med 2015; 212(4): 555-68.
[] [PMID: 25824823]
Doedens AL, Phan AT, Stradner MH, et al. Hypoxia-inducible factors enhance the effector responses of CD8(+) T cells to persistent antigen. Nat Immunol 2013; 14(11): 1173-82.
[] [PMID: 24076634]
Bosticardo M, Ariotti S, Losana G, Bernabei P, Forni G, Novelli F. Biased activation of human T lymphocytes due to low extracellular pH is antagonized by B7/CD28 costimulation. Eur J Immunol 2001; 31(9): 2829-38.
[<2829::AID-IMMU2829>3.0.CO;2-U] [PMID: 11536182]
Viel S, Marçais A, Guimaraes FS-F, et al. TGF-β inhibits the activation and functions of NK cells by repressing the mTOR pathway. Sci Signal 2016; 9(415): ra19.
[] [PMID: 26884601]
Baragaño Raneros A, Suarez-Álvarez B, López-Larrea C. Secretory pathways generating immunosuppressive NKG2D ligands: New targets for therapeutic intervention. OncoImmunology 2014; 3: e28497.
[] [PMID: 25050215]
Rotte A. Combination of CTLA-4 and PD-1 blockers for treatment of cancer. J Exp Clin Cancer Res 2019; 38(1): 255.
[] [PMID: 31196207]
Myers JA, Miller JS. Exploring the NK cell platform for cancer immunotherapy. Nat Rev Clin Oncol 2021; 18(2): 85-100.
[] [PMID: 32934330]
Veluchamy JP, Kok N, van der Vliet HJ, Verheul HMW, de Gruijl TD, Spanholtz J. The rise of allogeneic natural killer cells as a platform for cancer immunotherapy: Recent innovations and future developments. Front Immunol 2017; 8: 631.
[] [PMID: 28620386]
Sakamoto N, Ishikawa T, Kokura S, et al. Phase I clinical trial of autologous NK cell therapy using novel expansion method in patients with advanced digestive cancer. J Transl Med 2015; 13: 277.
[] [PMID: 26303618]
Krause SW, Gastpar R, Andreesen R, et al. Treatment of colon and lung cancer patients with ex vivo heat shock protein 70-peptide-activated, autologous natural killer cells: A clinical phase i trial. Clin Cancer Res 2004; 10(11): 3699-707.
[] [PMID: 15173076]
Parkhurst MR, Riley JP, Dudley ME, Rosenberg SA. 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 2011; 17(19): 6287-97.
[] [PMID: 21844012]
Daher M, Melo Garcia L, Li Y, Rezvani K. CAR-NK cells: The next wave of cellular therapy for cancer. Clin Transl Immunology 2021; 10(4): e1274.
[] [PMID: 33959279]
Miller JS, Soignier Y, Panoskaltsis-Mortari A, et al. Successful adoptive transfer and in vivo expansion of human haploidentical NK cells in patients with cancer. Blood 2005; 105(8): 3051-7.
[] [PMID: 15632206]
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.
[] [PMID: 27014270]
Woll PS, Grzywacz B, Tian X, 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.
[] [PMID: 19365083]
Hermanson DL, Bendzick L, Pribyl L, et al. Induced pluripotent stem cell-derived natural killer cells for treatment of ovarian cancer. Stem Cells 2016; 34(1): 93-101.
[] [PMID: 26503833]
Ahmad ZA, Yeap SK, Ali AM, Ho WY, Alitheen NBM, Hamid M. scFv antibody: Principles and clinical application. Clin Dev Immunol 2012; 2012: 980250.
[] [PMID: 22474489]
Leyton-Castro NF, Brigido MM, Maranhão AQ. Selection of antibody fragments for CAR-T Cell therapy from phage display libraries. Methods Mol Biol 2020; 2086: 13-26.
[] [PMID: 31707665]
Krokhotin A, Du H, Hirabayashi K, et al. Computationally guided design of single-chain variable fragment improves specificity of chimeric antigen receptors. Mol Ther Oncolytics 2019; 15: 30-7.
[] [PMID: 31650023]
De Munter S, Van Parys A, Bral L, et al. Rapid and effective generation of nanobody based CARs using PCR and gibson assembly. Int J Mol Sci 2020; 21(3): E883.
[] [PMID: 32019116]
Chandran SS, Klebanoff CA. T cell receptor-based cancer immunotherapy: Emerging efficacy and pathways of resistance. Immunol Rev 2019; 290(1): 127-47.
[] [PMID: 31355495]
Alabanza L, Pegues M, Geldres C, 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.
[] [PMID: 28807568]
Bridgeman JS, Hawkins RE, Bagley S, Blaylock M, Holland M, Gilham DE. The optimal antigen response of chimeric antigen receptors harboring the CD3zeta transmembrane domain is dependent upon incorporation of the receptor into the endogenous TCR/CD3 complex. J Immunol 2010; 184(12): 6938-49.
[] [PMID: 20483753]
Fujiwara K, Tsunei A, Kusabuka H, Ogaki E, Tachibana M, Okada N. Hinge and transmembrane domains of chimeric antigen receptor regulate receptor expression and signaling threshold. Cells 2020; 9(5): E1182.
[] [PMID: 32397414]
Morin SO, Giroux V, Favre C, et al. In the absence of its cytosolic domain, the CD28 molecule still contributes to T cell activation. Cell Mol Life Sci 2015; 72(14): 2739-48.
[] [PMID: 25725801]
Gross G, Waks T, Eshhar Z. Expression of immunoglobulin-T-cell receptor chimeric molecules as functional receptors with antibody-type specificity. Proc Natl Acad Sci USA 1989; 86(24): 10024-8.
[] [PMID: 2513569]
Al-Mansour M, Al-Foheidi M, Ibrahim E. Efficacy and safety of second-generation CAR T-cell therapy in diffuse large B-cell lymphoma: A meta-analysis. Mol Clin Oncol 2020; 13(4): 33.
[] [PMID: 32789017]
Tang X-Y, Sun Y, Zhang A, et al. Third-generation CD28/4-1BB chimeric antigen receptor T cells for chemotherapy relapsed or refractory acute lymphoblastic leukaemia: A non-randomised, open-label phase I trial protocol. BMJ Open 2016; 6(12): e013904.
[] [PMID: 28039295]
Chmielewski M, Hombach AA, Abken H. Of CARs and TRUCKs: chimeric antigen receptor (CAR) T cells engineered with an inducible cytokine to modulate the tumor stroma. Immunol Rev 2014; 257(1): 83-90.
[] [PMID: 24329791]
Hyrenius-Wittsten A, Su Y, Park M, et al. SynNotch CAR circuits enhance solid tumor recognition and promote persistent antitumor activity in mouse models. Sci Transl Med 2021; 13(591): eabd8836.
[] [PMID: 33910981]
Han X, Bryson PD, Zhao Y, et al. Masked chimeric antigen receptor for tumor-specific activation. Mol Ther 2017; 25(1): 274-84.
[] [PMID: 28129121]
Fedorov VD, Themeli M, Sadelain M. PD-1- and CTLA-4-based inhibitory chimeric antigen receptors (iCARs) divert off-target immunotherapy responses. Sci Transl Med 2013; 5(215): 215ra172.
[] [PMID: 24337479]
Li T, Wang J. Therapeutic effect of dual CAR-T targeting PDL1 and MUC16 antigens on ovarian cancer cells in mice. BMC Cancer 2020; 20(1): 678.
[] [PMID: 32689954]
Grada Z, Hegde M, Byrd T, et al. TanCAR: A novel bispecific chimeric antigen receptor for cancer immunotherapy. Mol Ther Nucleic Acids 2013; 2: e105.
[] [PMID: 23839099]
Baeuerle PA, Ding J, Patel E, et al. Synthetic TRuC receptors engaging the complete T cell receptor for potent anti-tumor response. Nat Commun 2019; 10(1): 2087.
[] [PMID: 31064990]
Cho JH, Collins JJ, Wong WW. Universal chimeric antigen receptors for multiplexed and logical control of T cell responses. Cell 2018; 173(6): 1426-1438.e11.
[] [PMID: 29706540]
Choi BD, Yu X, Castano AP, et al. CAR-T cells secreting BiTEs circumvent antigen escape without detectable toxicity. Nat Biotechnol 2019; 37(9): 1049-58.
[] [PMID: 31332324]
Helsen CW, Hammill JA, Lau VWC, et al. The chimeric TAC receptor co-opts the T cell receptor yielding robust anti-tumor activity without toxicity. Nat Commun 2018; 9(1): 3049.
[] [PMID: 30076299]
Milone MC, Fish JD, Carpenito C, et al. Chimeric receptors containing CD137 signal transduction domains mediate enhanced survival of T cells and increased antileukemic efficacy in vivo. Mol Ther 2009; 17(8): 1453-64.
[] [PMID: 19384291]
Zhao Z, Condomines M, van der Stegen SJC, et al. Structural design of engineered costimulation determines tumor rejection kinetics and persistence of CAR T cells. Cancer Cell 2015; 28(4): 415-28.
[] [PMID: 26461090]
Morgan RA, Boyerinas B. Genetic modification of T cells. Biomedicines 2016; 4(2): 9.
[] [PMID: 28536376]
Ivics Z. Potent CAR-T cells engineered with sleeping beauty transposon vectors display a central memory phenotype. Gene Ther 2021; 28(1-2): 3-5.
[] [PMID: 32139891]
Pfefferle A, Huntington ND. You have got a fast CAR: chimeric antigen receptor NK cells in cancer therapy. Cancers (Basel) 2020; 12(3): 706.
[] [PMID: 32192067]
Roth TL, Puig-Saus C, Yu R, et al. Reprogramming human T cell function and specificity with non-viral genome targeting. Nature 2018; 559(7714): 405-9.
[] [PMID: 29995861]
Zhou S, Fatima S, Ma Z, et al. Evaluating the safety of retroviral vectors based on insertional oncogene activation and blocked differentiation in cultured thymocytes. Mol Ther 2016; 24(6): 1090-9.
[] [PMID: 26957223]
Maetzig T, Galla M, Baum C, Schambach A. Gammaretroviral vectors: Biology, technology and application. Viruses 2011; 3(6): 677-713.
[] [PMID: 21994751]
Papayannakos C, Daniel R. Understanding lentiviral vector chromatin targeting: Working to reduce insertional mutagenic potential for gene therapy. Gene Ther 2013; 20(6): 581-8.
[] [PMID: 23171920]
Carlsten M, Childs RW. Genetic manipulation of NK cells for cancer immunotherapy: Techniques and clinical implications. Front Immunol 2015; 6: 266.
[] [PMID: 26113846]
Denning W, Das S, Guo S, Xu J, Kappes JC, Hel Z. Optimization of the transductional efficiency of lentiviral vectors: Effect of sera and polycations. Mol Biotechnol 2013; 53(3): 308-14.
[] [PMID: 22407723]
Radek C, Bernadin O, Drechsel K, et al. Vectofusin-1 improves transduction of primary human cells with diverse retroviral and lentiviral pseudotypes, enabling robust, automated closed-system manufacturing. Hum Gene Ther 2019; 30(12): 1477-93.
[] [PMID: 31578886]
Bari R, Granzin M, Tsang KS, et al. A distinct subset of highly proliferative and lentiviral vector (LV)-transducible nk cells define a readily engineered subset for adoptive cellular therapy. Front Immunol 2019; 10: 2001.
[] [PMID: 31507603]
Tomás HA, Mestre DA, Rodrigues AF, Guerreiro MR, Carrondo MJT, Coroadinha AS. improved galv-tr glycoproteins to pseudotype lentiviral vectors: Impact of viral protease activity in the production of lv pseudotypes. Mol Ther Methods Clin Dev 2019; 15: 1-8.
[] [PMID: 31528654]
Li Y, Kurlander RJ. Comparison of anti-CD3 and anti-CD28-coated beads with soluble anti-CD3 for expanding human T cells: Differing impact on CD8 T cell phenotype and responsiveness to restimulation. J Transl Med 2010; 8: 104.
[] [PMID: 20977748]
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 Reports 2017; 9(6): 1796-812.
[] [PMID: 29173894]
Jones BS, Lamb LS, Goldman F, Di Stasi A. Improving the safety of cell therapy products by suicide gene transfer. Front Pharmacol 2014; 5: 254.
[] [PMID: 25505885]
Chou CK, Turtle CJ. Insight into mechanisms associated with cytokine release syndrome and neurotoxicity after CD19 CAR-T cell immunotherapy. Bone Marrow Transplant 2019; 54(Suppl. 2): 780-4.
[] [PMID: 31431714]
Herberman RB, Nunn ME, Holden HT, Lavrin DH. Natural cytotoxic reactivity of mouse lymphoid cells against syngeneic and allogeneic tumors. II. Characterization of effector cells. Int J Cancer 1975; 16(2): 230-9.
[] [PMID: 1080480]
Zhang Y, Wallace DL, de Lara CM, et al. In vivo kinetics of human natural killer cells: the effects of ageing and acute and chronic viral infection. Immunology 2007; 121(2): 258-65.
[] [PMID: 17346281]
Gong JH, Maki G, Klingemann HG. Characterization of a human cell line (NK-92) with phenotypical and functional characteristics of activated natural killer cells. Leukemia 1994; 8(4): 652-8.
[PMID: 8152260]
Jiang H, Zhang W, Shang P, 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.
[] [PMID: 24388357]
Spanholtz J, Preijers F, Tordoir M, et al. Clinical-grade generation of active NK cells from cord blood hematopoietic progenitor cells for immunotherapy using a closed-system culture process. PLoS One 2011; 6(6): e20740.
[] [PMID: 21698239]
Poli A, Michel T, Thérésine M, Andrès E, Hentges F, Zimmer J. CD56bright natural killer (NK) cells: An important NK cell subset. Immunology 2009; 126(4): 458-65.
[] [PMID: 19278419]
Oberoi P, Kamenjarin K, Ossa JFV, Uherek B, Bönig H, Wels WS. Directed differentiation of mobilized hematopoietic stem and progenitor cells into functional NK cells with enhanced antitumor activity. Cells 2020; 9(4): 811.
[] [PMID: 32230942]
Wang K, Han Y, Cho WC, Zhu H. The rise of human stem cell-derived natural killer cells for cancer immunotherapy. Expert Opin Biol Ther 2019; 19(2): 141-8.
[] [PMID: 30583701]
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): 181-192.e5.
[] [PMID: 30082067]
Moon WY, Powis SJ. Does natural killer cell deficiency (NKD) increase the risk of cancer? NKD may increase the risk of some virus induced cancer. Front Immunol 2019; 10: 1703.
[] [PMID: 31379882]
Jacoby E, Bielorai B, Avigdor A, et al. Locally produced CD19 CAR T cells leading to clinical remissions in medullary and extramedullary relapsed acute lymphoblastic leukemia. Am J Hematol 2018; 93(12): 1485-92.
[] [PMID: 30187944]
Henke E, Nandigama R, Ergün S. Extracellular matrix in the tumor microenvironment and its impact on cancer therapy. Front Mol Biosci 2020; 6: 160.
[] [PMID: 32118030]
Siemann DW. The unique characteristics of tumor vasculature and preclinical evidence for its selective disruption by tumor-vascular disrupting agents. Cancer Treat Rev 2011; 37(1): 63-74.
[] [PMID: 20570444]
He X, Xu C. Immune checkpoint signaling and cancer immunotherapy. Cell Res 2020; 30(8): 660-9.
[] [PMID: 32467592]
Hanahan D, Weinberg RA. Hallmarks of cancer: The next generation. Cell 2011; 144(5): 646-74.
[] [PMID: 21376230]
Buchbinder EI, Desai A. CTLA-4 and PD-1 pathways: Similarities, differences, and implications of their inhibition. Am J Clin Oncol 2016; 39(1): 98-106.
[] [PMID: 26558876]
Haen SP, Löffler MW, Rammensee H-G, Brossart P. Towards new horizons: Characterization, classification and implications of the tumour antigenic repertoire. Nat Rev Clin Oncol 2020; 17(10): 595-610.
[] [PMID: 32572208]
Liu E, Marin D, Banerjee P, et al. Use of CAR-transduced natural killer cells in CD19-positive lymphoid tumors. N Engl J Med 2020; 382(6): 545-53.
[] [PMID: 32023374]
Tang X, Yang L, Li Z, 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): 1083-9.
[PMID: 30034945]
Xiao L, Cen D, Gan H, et al. Adoptive transfer of NKG2D CAR mRNA-engineered natural killer cells in colorectal cancer patients. Mol Ther 2019; 27(6): 1114-25.
[] [PMID: 30962163]
Cheng M, Chen Y, Xiao W, Sun R, Tian Z. NK cell-based immunotherapy for malignant diseases. Cell Mol Immunol 2013; 10(3): 230-52.
[] [PMID: 23604045]
Chavez JC, Bachmeier C, Kharfan-Dabaja MA. CAR T-cell therapy for B-cell lymphomas: clinical trial results of available products. Ther Adv Hematol 2019; 10: 2040620719841581.
[] [PMID: 31019670]
Oelsner S, Wagner J, Friede ME, et al. Chimeric antigen receptor-engineered cytokine-induced killer cells overcome treatment resistance of pre-B-cell acute lymphoblastic leukemia and enhance survival. Int J Cancer 2016; 139(8): 1799-809.
[] [PMID: 27253354]
Oelsner S, Friede ME, Zhang C, et al. Continuously expanding CAR NK-92 cells display selective cytotoxicity against B-cell leukemia and lymphoma. Cytotherapy 2017; 19(2): 235-49.
[] [PMID: 27887866]
Chu Y, Yahr A, Huang B, Ayello J, Barth M, S Cairo M. 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 2017; 6(9): e1341031.
[] [PMID: 28932644]
Chen KH, Wada M, Pinz KG, et al. Preclinical targeting of aggressive T-cell malignancies using anti-CD5 chimeric antigen receptor. Leukemia 2017; 31(10): 2151-60.
[] [PMID: 28074066]
Chen X, Han J, Chu J, et al. A combinational therapy of EGFR-CAR NK cells and oncolytic herpes simplex virus 1 for breast cancer brain metastases. Oncotarget 2016; 7(19): 27764-77.
[] [PMID: 27050072]
Liu H, Yang B, Sun T, et al. Specific growth inhibition of ErbB2‑expressing human breast cancer cells by genetically modified NK‑92 cells. Oncol Rep 2015; 33(1): 95-102.
[] [PMID: 25333815]
Hargadon KM, Johnson CE, Williams CJ. Immune checkpoint blockade therapy for cancer: An overview of FDA-approved immune checkpoint inhibitors. Int Immunopharmacol 2018; 62: 29-39.
[] [PMID: 29990692]
Kumar J, Kumar R, Kumar Singh A, et al. Deletion of Cbl-b inhibits CD8+ T-cell exhaustion and promotes CAR T-cell function. J Immunother Cancer 2021; 9(1): e001688.
[] [PMID: 33462140]
Lee J, Sheen JH, Lim O, et al. Abrogation of HLA surface expression using CRISPR/Cas9 genome editing: a step toward universal T cell therapy. Sci Rep 2020; 10(1): 17753.
[] [PMID: 33082438]
Kruschinski A, Moosmann A, Poschke I, et al. Engineering antigen-specific primary human NK cells against HER-2 positive carcinomas. Proc Natl Acad Sci USA 2008; 105(45): 17481-6.
[] [PMID: 18987320]
Altvater B, Landmeier S, Pscherer S, et al. 2B4 (CD244) signaling by recombinant antigen-specific chimeric receptors costimulates natural killer cell activation to leukemia and neuroblastoma cells. Clin Cancer Res 2009; 15(15): 4857-66.
[] [PMID: 19638467]
Shimasaki N, Fujisaki H, Cho D, et al. A clinically adaptable method to enhance the cytotoxicity of natural killer cells against B-cell malignancies. Cytotherapy 2012; 14(7): 830-40.
[] [PMID: 22458956]
Tassev DV, Cheng M, Cheung N-KV. Retargeting NK92 cells using an HLA-A2-restricted, EBNA3C-specific chimeric antigen receptor. Cancer Gene Ther 2012; 19(2): 84-100.
[] [PMID: 21979579]
Sahm C, Schönfeld K, Wels WS. Expression of IL-15 in NK cells results in rapid enrichment and selective cytotoxicity of gene-modified effectors that carry a tumor-specific antigen receptor. Cancer Immunol Immunother 2012; 61(9): 1451-61.
[] [PMID: 22310931]
Esser R, Müller T, Stefes D, et al. NK cells engineered to express a GD2 -specific antigen receptor display built-in ADCC-like activity against tumour cells of neuroectodermal origin. J Cell Mol Med 2012; 16(3): 569-81.
[] [PMID: 21595822]
Zhang G, Liu R, Zhu X, et al. Retargeting NK-92 for anti-melanoma activity by a TCR-like single-domain antibody. Immunol Cell Biol 2013; 91(10): 615-24.
[] [PMID: 24100387]
Chang Y-H, Connolly J, Shimasaki N, Mimura K, Kono K, Campana D. A chimeric receptor with NKG2D specificity enhances natural killer cell activation and killing of tumor cells. Cancer Res 2013; 73(6): 1777-86.
[] [PMID: 23302231]
Chu J, Deng Y, Benson DM, 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.
[] [PMID: 24067492]
Chu Y, Hochberg J, Yahr A, 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.
[] [PMID: 25492700]
Müller N, Michen S, Tietze S, 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 2015; 38(5): 197-210.
[] [PMID: 25962108]
Han J, Chu J, Keung Chan W, et al. CAR-Engineered NK Cells targeting wild-type EGFR and EGFRvIII enhance killing of glioblastoma and patient-derived glioblastoma stem cells. Sci Rep 2015; 5: 11483.
[] [PMID: 26155832]
Töpfer K, Cartellieri M, Michen S, et al. DAP12-based activating chimeric antigen receptor for NK cell tumor immunotherapy. J Immunol 2015; 194(7): 3201-12.
[] [PMID: 25740942]
Schönfeld K, Sahm C, Zhang C, et al. Selective inhibition of tumor growth by clonal NK cells expressing an ErbB2/HER2-specific chimeric antigen receptor. Mol Ther 2015; 23(2): 330-8.
[] [PMID: 25373520]
Suerth JD, Morgan MA, Kloess S, et al. Efficient generation of gene-modified human natural killer cells via alpharetroviral vectors. J Mol Med (Berl) 2016; 94(1): 83-93.
[] [PMID: 26300042]
Genßler S, Burger MC, Zhang C, 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 2015; 5(4): e1119354.
[] [PMID: 27141401]
Kailayangiri S, Altvater B, Spurny C, et al. Targeting Ewing sarcoma with activated and GD2-specific chimeric antigen receptor-engineered human NK cells induces upregulation of immune-inhibitory HLA-G. OncoImmunology 2016; 6(1): e1250050.
[] [PMID: 28197367]
Klöß S, Oberschmidt O, Morgan M, et al. 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 2017; 28(10): 897-913.
[] [PMID: 28810809]
Liu E, Tong Y, Dotti G, 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.
[] [PMID: 28725044]
Xu Y, Liu Q, Zhong M, et al. 2B4 costimulatory domain enhancing cytotoxic ability of anti-CD5 chimeric antigen receptor engineered natural killer cells against T cell malignancies. J Hematol Oncol 2019; 12(1): 49.
[] [PMID: 31097020]

Rights & Permissions Print Export Cite as
© 2023 Bentham Science Publishers | Privacy Policy