New Orders to an Old Soldier: Optimizing NK Cells for Adoptive Immunotherapy in Hematology
Abstract
:1. Introduction
2. Recent Advances in NK Cell Biology
3. Impaired NK Cell Function in Hematological Malignancies
4. The Role of NK Cell Therapy in Hematological Malignancies
4.1. Administration of Autologous NK Cells
4.2. Administration of Allogeneic NK Cells
4.3. NK Cell Engineering—“CAR-NK Cell Therapy”
5. Challenges in Manufacturing of Clinical-Grade NK and CAR-NK Cell Therapies and Strategies to Overcome Them
6. Concluding Remarks
Author Contributions
Funding
Conflicts of Interest
References
- Tanaka, J.; Miller, J.S. Recent progress in and challenges in cellular therapy using NK cells for hematological malignancies. Blood Rev. 2020, 44, 100678. [Google Scholar] [CrossRef]
- Fang, F.; Xiao, W.; Tian, Z. Challenges of NK cell-based immunotherapy in the newera. Front. Med. 2018, 12, 440–450. [Google Scholar] [CrossRef] [Green Version]
- Abel, A.M.; Yang, C.; Thakar, M.S.; Malarkannan, S. Natural killer cells: Development maturation and clinical utilization. Front. Immunol. 2018, 9, 1869. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Moretta, L.; Pietra, G.; Vacca, P.; Pende, D.; Moretta, F.; Bertaina, A.; Mingari, M.C.; Locatelli, F.; Moretta, A. Human NK cells: From surface receptors to clinical applications. Immunol. Lett. 2016, 178, 15–19. [Google Scholar] [CrossRef]
- Gong, Y.; Klein Wolterink, R.G.J.; Wang, J.; Bos, G.M.J.; Germeraad, W.T.V. Chimeric antigen receptor natural killer (CAR-NK) cell design and engineering for cancer therapy. J. Hematol. Oncol. 2021, 14, 73. [Google Scholar] [CrossRef]
- Shankar, K.; Capitini, C.M.; Saha, K. Genome engineering of induced pluripotent stem cells to manufacture natural killer cell therapies. Stem. Cell Res. Ther. 2020, 11, 234. [Google Scholar] [CrossRef]
- Davis, Z.B.; Vallera, D.A.; Miller, J.S.; Felices, M. Natural killer cells unleashed: Checkpoint receptor blockade and BiKE/TriKE utilization in NK-mediated antitumor immunotherapy. Semin. Immunol. 2017, 31, 64–75. [Google Scholar] [CrossRef]
- Mehta, R.S.; Rezvani, K. Chimeric antigen receptor expressing natural killer cells forthe immunotherapy of cancer. Front. Immunol. 2018, 9, 283. [Google Scholar] [CrossRef] [Green Version]
- Eberl, G.; Colonna, M.; Di Santo, J.P.; McKenzie, A.N. Innate lymphoid cells. Innate lymphoid cells: A new paradigm in immunology. Science 2015, 348, aaa6566. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Montaldo, E.; Vacca, P.; Moretta, L.; Mingari, M.C. Development of human natural killer cells and other innate lymphoid cells. Semin. Immunol. 2014, 26, 107–113. [Google Scholar] [CrossRef]
- Sivori, S.; Vacca, P.; Del Zotto, G.; Munari, E.; Mingari, M.C.; Moretta, L. Human, NK cells: Surface receptors, inhibitory checkpoints, and translational applications. Cell Mol. Immunol. 2019, 16, 430–441. [Google Scholar] [CrossRef] [PubMed]
- Sivori, S.; Pende, D.; Quatrini, L.; Pietra, G.; Della Chiesa, M.; Vacca, P.; Tumino, N.; Moretta, F.; Mingari, M.C.; Locatelli, F.; et al. NK cells and ILCs in tumor immunotherapy. Mol. Aspects Med. 2020, 13, 100870. [Google Scholar] [CrossRef] [PubMed]
- Vivier, E.; Raulet, D.H.; Moretta, A.; Caligiuri, M.A.; Zitvogel, L.; Lanier, L.L.; Yokoyama, W.M.; Ugolini, S. Innate or adaptive immunity? The example of natural killer cells. Science 2011, 331, 44–49. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Miller, J.S.; Soignier, Y. Successful adoptive transfer and in vivo expansion of human haploidentical NK cells in patients with cancer. Blood 2005, 105, 3051–3057. [Google Scholar] [CrossRef] [Green Version]
- Cooper, M.A.; Bush, J.E.; Fehniger, T.A.; VanDeusen, J.B.; Waite, R.E.; Liu, Y.; Aguila, H.L.; Caligiuri, M.A. In vivo evidence for a dependence on interleukin 15 for survival of natural killer cells. Blood 2002, 100, 3633–3638. [Google Scholar] [CrossRef]
- Miller, J.; Rooney, C.; Curtsinger, J.; McElmurry, R.; McCullar, V.; Verneris, M.R.; Lapteva, N.; McKenna, D.; Wagner, J.E.; Blazar, B.R.; et al. Expansion and homing of adoptively transferred human natural killer cells in immunodeficient mice varies with product preparation and in vivo cytokine administration: Implications for clinical therapy. Biol. Blood Marrow. Transplant. 2014, 20, 1252–1257. [Google Scholar] [CrossRef] [Green Version]
- Fehniger, T.A.; Cooper, M.A. Harnessing NK cell memory for cancer immunotherapy. Trends Immunol. 2016, 37, 877–888. [Google Scholar] [CrossRef] [Green Version]
- Romee, R.; Schneider, S.E.; Leong, J.W.; Chase, J.M.; Keppel, C.R.; Sullivan, R.P.; Cooper, M.A.; Fehniger, T.A. Cytokine activation induces human memory-like NK cells. Blood 2012, 120, 4751–4760. [Google Scholar] [CrossRef] [Green Version]
- Ghofrani, J.; Lucar, O.; Dugan, H.; Reeves, R.K.; Jost, S. Semaphorin 7A modulates cytokine- induced memory-like responses by human natural killer cells. Eur. J. Immunol. 2019, 49, 1153–1166. [Google Scholar] [CrossRef]
- Lamb, M.G.; Rangarajan, H.G.; Tullius, B.P.; Lee, D.A. Natural killer cell therapy for hematologic malignancies: Successes, challenges, and the future. Stem. Cell Res. Ther. 2021, 12, 211. [Google Scholar] [CrossRef]
- Khaznadar, Z.; Boissel, N.; Agaugue, S.; Henry, G.; Cheok, M.; Vignon, M.; Geromin, D.; Cayuela, J.M.; Castaigne, S.; Pautas, C.; et al. Defective, NK cells in acute myeloid leukemia patients at diagnosis are associated with blast transcriptional signatures of immune evasion. J. Immunol. 2015, 195, 2580–2590. [Google Scholar] [CrossRef] [Green Version]
- Stringaris, K.; Sekine, T.; Khoder, A.; Alsuliman, A.; Razzaghi, B.; Sargeant, R.; Pavlu, J.; Brisley, G.; de Lavallade, H.; Sarvaria, A.; et al. Leukemia-induced phenotypic and functional defects in natural killer cells predict failure to achieve remission in acute myeloid leukemia. Haematologica 2014, 99, 836–847. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Kearney, C.J.; Ramsbottom, K.M.; Voskoboinik, I.; Darcy, P.K.; Oliaro, J. Loss of DNAM-1 ligand expression by acute myeloid leukemia cells renders them resistant to NK cell killing. Oncoimmunology 2016, 5, e1196308. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Scoville, S.D.; Nalin, A.P.; Chen, L.; Chen, L.; Zhang, M.H.; McConnell, K.; Beceiro Casas, S.; Ernst, G.; Traboulsi, A.A.; Hashi, N.; et al. Human AML activates the aryl hydrocarbon receptor pathway to impair NK cell development and function. Blood 2018, 132, 1792–1804. [Google Scholar] [CrossRef] [PubMed]
- Clayton, A.; Mitchell, J.P.; Court, J.; Linnane, S.; Mason, M.D.; Tabi, Z. Human tumor-derived exosomes down-modulate NKG2D expression. J. Immunol. 2008, 180, 7249–7258. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Reiners, K.S.; Topolar, D.; Henke, A.; Simhadri, V.R.; Kessler, J.; Sauer, M.; Bessler, M.; Hansen, H.P.; Tawadros, S.; Herling, M.; et al. Soluble ligands for NK cell receptors promote evasion of chronic lymphocytic leukemia cells from NK cell anti-tumor activity. Blood 2013, 121, 3658–3665. [Google Scholar] [CrossRef]
- Manso, B.A.; Zhang, H.; Mikkelson, M.G.; Gwin, K.A.; Secreto, C.R.; Ding, W.; Parikh, S.A.; Kay, N.E.; Medina, K.L. Bone marrow hematopoietic dysfunction in untreated chronic lymphocytic leukemia patients. Leukemia 2019, 33, 638–652. [Google Scholar] [CrossRef]
- Balsamo, M.; Manzini, C.; Pietra, G.; Raggi, F.; Blengio, F.; Mingari, M.C.; Varesio, L.; Moretta, L.; Bosco, M.C.; Vitale, M. Hypoxia downregulates the expression of activating receptors involved in NK-cell-mediated target cell killing without affecting ADCC. Eur. J. Immunol. 2013, 43, 2756–2764. [Google Scholar] [CrossRef]
- Vigano, S.; Alatzoglou, D.; Irving, M.; Ménétrier-Caux, C.; Caux, C.; Romero, P.; Coukos, G. Targeting, adenosine in cancer, immunotherapy to enhance, T-cell, function. Front. Immunol. 2019, 10, 925. [Google Scholar] [CrossRef] [Green Version]
- Barsoum, I.B.; Hamilton, T.K.; Li, X.; Cotechini, T.; Miles, E.A.; Siemens, D.R.; Graham, C.H. Hypoxia induces escape from innate immunity in cancer cells via increased expression of ADAM10: Role of nitric oxide. Cancer Res. 2011, 71, 7433–7441. [Google Scholar] [CrossRef] [Green Version]
- Kikushige, Y.; Miyamoto, T.; Yuda, J.; Jabbarzadeh-Tabrizi, S.; Shima, T.; Takayanagi, S.; Niiro, H.; Yurino, A.; Miyawaki, K.; Takenaka, K.; et al. A TIM-3/Gal-9 autocrine stimulatory loop drives self-renewal of human myeloid leukemia stem cells and leukemic progression. Cell Stem Cell 2015, 17, 341–352. [Google Scholar] [CrossRef] [Green Version]
- Vari, F.; Arpon, D.; Keane, C.; Hertzberg, M.S.; Talaulikar, D.; Jain, S.; Cui, Q.; Han, E.; Tobin, J.; Bird, R.; et al. Immune evasion via PD-1/PD-L1 on NK cells and monocyte/macrophages is more prominent in Hodgkin lymphoma than DLBCL. Blood 2018, 131, 1809–1819. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Burns, L.J.; Weisdorf, D.J.; DeFor, T.E.; Vesole, D.H.; Repka, T.L.; Blazar, B.R.; Burger, S.R.; Panoskaltsis-Mortari, A.; Keever-Taylor, C.A.; Zhang, M.J.; et al. IL-2-based immunotherapy after autologous transplantation for lymphoma and breast cancer induces immune activation and cytokine release: A phase I/II trial. Bone Marrow Transplant. 2003, 32, 177–186. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Tanaka, J.; Tanaka, N.; Wang, Y.H.; Mitsuhashi, K.; Ryuzaki, M.; Iizuka, Y.; Watanabe, A.; Ishiyama, M.; Shinohara, A.; Kazama, H.; et al. Phase, I study of cellular therapy using ex vivo expanded natural killer cells from autologous peripheral blood mononuclear cells combined with rituximab-containing chemotherapy for relapsed CD20-positive malignant lymphoma patients. Haematologica 2020, 105, e190–e193. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Romee, R.; Rosario, M.; Berrien-Elliott, M.M.; Wagner, J.A.; Jewell, B.A.; Schappe, T.; Leong, J.W.; Abdel-Latif, S.; Schneider, S.E.; Willey, S.; et al. Cytokine-induced memory-like natural killer cells exhibit enhanced responses against myeloid leukemia. Sci. Transl. Med. 2016, 8, 357ra123. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Passweg, J.R.; Tichelli, A.; Meyer-Monard, S.; Heim, D.; Stern, M.; Kühne, T.; Favre, G.; Gratwohl, A. Purified donor NK-lymphocyte infusion to consolidate engraftment after haploidentical stem cell transplantation. Leukemia 2004, 18, 1835–1838. [Google Scholar] [CrossRef] [PubMed]
- Rubnitz, J.E.; Inaba, H.; Ribeiro, R.C.; Pounds, S.; Rooney, B.; Bell, T.; Pui, C.H.; Leung, W. 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, 955–959. [Google Scholar] [CrossRef] [Green Version]
- Yoon, S.R.; Lee, Y.S.; Yang, S.H.; Ahn, K.H.; Lee, J.-H.; Lee, J.-H.; Kim, D.Y.; Kang, Y.A.; Jeon, M.; Seol, M.; et al. Generation of donor natural killer cells fromCD34 progenitor cells and subsequent infusion after HLA-mismatched allogeneic hematopoietic cell transplantation: A feasibility study. Bone Marrow Transplant. 2010, 45, 1038–1046. [Google Scholar] [CrossRef] [PubMed]
- Choi, I.; Yoon, S.R.; Park, S.Y.; Kim, H.; Jung, S.J.; Jang, Y.J.; Kang, M.; Yeom, Y.I.; Lee, J.L.; Kim, D.Y.; et al. Donor-derived natural killer cells infused after human leukocyte antigen-haploidentical hematopoietic cell transplantation: A dose-escalation study. Biol. Blood Marrow Transplant. 2014, 20, 696–704. [Google Scholar] [CrossRef] [Green Version]
- Bachanova, V.; Burns, L.J.; McKenna, D.H.; Curtsinger, J.; Panoskaltsis-Mortari, A.; Lindgren, B.R.; Cooley, S.; Weisdorf, D.; Miller, J.S. Allogeneic natural killer cells for refractory lymphoma. Cancer Immunol. Immunother. 2010, 59, 1739–1744. [Google Scholar] [CrossRef] [Green Version]
- Boyiadzis, M.; Agha, M.; Redner, R.L.; Sehgal, A.; Im, A.; Hou, J.Z.; Farah, R.; Dorritie, K.A.; Raptis, A.; Lim, S.H.; et al. Phase 1 clinical trial of adoptive immunotherapy using “off-the-shelf” activated natural killer cells in patients with refractory and relapsed acute myeloid leukemia. Cytotherapy 2017, 19, 1225–1232. [Google Scholar] [CrossRef] [PubMed]
- Cooley, S.; He, F.; Bachanova, V.; Vercellotti, G.M.; DeFor, T.E.; Curtsinger, J.M.; Robertson, P.; Grzywacz, B.; Conlon, K.C.; Waldmann, T.A.; et al. First-in-human trial of rhIL-15 and haploidentical natural killer cell therapy for advanced acute myeloid leukemia. Blood Adv. 2019, 3, 1970–1980. [Google Scholar] [CrossRef]
- Ciurea, S.O.; Schafer, J.R.; Bassett, R.; Denman, C.J.; Cao, K.; Willis, D.; Rondon, G.; Chen, J.; Soebbing, D.; Kaur, I.; et al. Phase 1 clinical trial using mbIL21 ex vivo-expanded donor-derived NK cells after haploidentical transplantation. Blood 2017, 130, 1857–1868. [Google Scholar] [CrossRef]
- Fate, Therapeutics Announces, Encouraging Interim, Phase 1 Data for iPSC-Derived NK Cell, Programs in Relapsed/Refractory, Acute Myeloid, Leukemia. Available online: https://ir.fatetherapeutics.com/news-releases/news-release-details/fate-therapeutics-announces-encouraging-interim-phase-1-data (accessed on 20 August 2021).
- Fate, Therapeutics Announces, Positive Interim, Clinical Data from its FT596 and FT516 Off-the-shelf, iPSC-Derived NK Cell, Programs for B-cell Lymphoma. Available online: https://ir.fatetherapeutics.com/news-releases/news-release-details/fate-therapeutics-announces-positive-interim-clinical-data-its (accessed on 20 August 2021).
- Dolstra, H.; Roeven, M.W.H.; Spanholtz, J.; Hangalapura, B.N.; Tordoir, M.; Maas, F.; Leenders, M.; Bohme, F.; Kok, N.; Trilsbeek, C.; et al. Successful, transfer of umbilical, cord blood, CD34+ hematopoietic, stem and progenitor-derived NK cells in older, acute myeloid, leukemia patients. Clin. Cancer Res. 2017, 23, 4107–4118. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Shah, N.; Li, L.; McCarty, J.; Kaur, I.; Yvon, E.; Shaim, H.; Muftuoglu, M.; Liu, E.; Orlowski, R.Z.; Cooper, L.; et al. Phase I study of cord blood-derived natural killer cells combined with autologous stem cell transplantation in multiple myeloma. Br. J. Haematol. 2017, 177, 457–466. [Google Scholar] [CrossRef] [PubMed]
- Deng, X.; Terunuma, H.; Nieda, M.; Xiao, W.; Nicol, A. Synergistic cytotoxicity of ex vivo expanded natural killer cells in combination with monoclonal antibody drugs against cancer cells. Int. Immunopharmacol. 2012, 14, 593–605. [Google Scholar] [CrossRef] [PubMed]
- Wang, W.; Erbe, A.K.; Alderson, K.A.; Phillips, E.; Gallenberger, M.; Gan, J.; Campana, D.; Hank, J.A.; Sondel, P.M. Human NK cells maintain licensing status and are subject to killer immunoglobulin-like receptor (KIR) and KIR-ligand inhibition following ex vivo expansion. Cancer Immunol. Immunother. 2016, 65, 1047–1059. [Google Scholar] [CrossRef] [Green Version]
- Kohrt, H.E.; Thielens, A.; Marabelle, A.; Sagiv-Barfi, I.; Sola, C.; Chanuc, F.; Fuseri, N.; Bonnafous, C.; Czerwinski, D.; Rajapaksa, A.; et al. Anti-KIR antibody enhancement of anti-lymphoma activity of natural killer cells as monotherapy and in combination with anti-CD20 antibodies. Blood 2014, 123, 678–686. [Google Scholar] [CrossRef] [Green Version]
- Vey, N.; Karlin, L.; Sadot-Lebouvier, S.; Broussais, F.; Berton-Rigaud, D.; Rey, J.; Charbonnier, A.; Marie, D.; Andre, P.; Paturel, C.; et al. A phase 1 study of lirilumab (antibody against killer immunoglobulin-like receptor antibody KIR2D; IPH2102) in patients with solid tumors and hematologic malignancies. Oncotarget 2018, 9, 17675–17688. [Google Scholar] [CrossRef] [Green Version]
- Carlsten, M.; Korde, N.; Kotecha, R.; Reger, R.; Bor, S.; Kazandjian, D.; Landgren, O.; Childs, R.W. Checkpoint inhibition of KIR2D with the monoclonal antibody IPH2101 induces contraction and hyporesponsiveness of NK cells in patients with myeloma. Clin. Cancer Res. 2016, 22, 5211–5222. [Google Scholar] [CrossRef] [Green Version]
- Bagot, M.; Porcu, P.; Marie-Cardine, A.; Battistella, M.; William, B.M.; Vermeer, M.; Whittaker, S.; Rotolo, F.; Ram-Wolff, C.; Khodadoust, M.S.; et al. IPH4102, a first-in-class anti-KIR3DL2 monoclonal antibody, in patients with relapsed or refractory cutaneous T-cell lymphoma: An international, first-in-human, open-label, phase 1 trial. Lancet Oncol. 2019, 20, 1160–1170. [Google Scholar] [CrossRef]
- Wang, Y.; Zhang, Y.; Hughes, T.; Zhang, J.; Caligiuri, M.A.; Benson, D.M.; Yu, J. Fratricide of NK cells in daratumumab therapy for multiple myeloma overcome by ex vivo-expanded autologous NK cells. Clin. Cancer Res. 2018, 24, 4006–4017. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Gleason, M.K.; Ross, J.A.; Warlick, E.D.; Lund, T.C.; Verneris, M.R.; Wiernik, A.; Spellman, S.; Haagenson, M.D.; Lenvik, A.J.; Litzow, M.R.; et al. CD16xCD33 bispecific killer cell engager (BiKE) activates NK cells against primary MDS and MDSC CD33+ targets. Blood 2014, 123, 3016–3026. [Google Scholar] [CrossRef] [PubMed]
- Felices, M.; Kodal, B.; Hinderlie, P.; Kaminski, M.F.; Cooley, S.; Weisdorf, D.J.; Vallera, D.A.; Miller, J.S.; Bachanova, V. Novel, CD19-targeted TriKE restores NK cell function and proliferative capacity in CLL. Blood Adv. 2019, 3, 897–907. [Google Scholar] [CrossRef] [PubMed]
- Sarhan, D.; Brandt, L.; Felices, M.; Guldevall, K.; Lenvik, T.; Hinderlie, P.; Curtsinger, J.; Warlick, E.; Spellman, S.R.; Blazar, B.R.; et al. 161533 TriKE stimulates NK-cell function to overcome myeloid-derived suppressor cells in MDS. Blood Adv. 2018, 2, 1459–1469. [Google Scholar] [CrossRef] [Green Version]
- Shah, N.N.; Baird, K.; Delbrook, C.P.; Fleisher, T.A.; Kohler, M.E.; Rampertaap, S.; Lemberg, K.; Hurley, C.K.; Kleiner, D.E.; Merchant, M.S.; et al. Acute GVHD in patients receiving IL-15/4-1BBL activated NK cells following T-cell-depleted stem cell transplantation. Blood 2015, 125, 784–792. [Google Scholar] [CrossRef]
- Bachanova, V.; Cooley, S.; Defor, T.E.; Verneris, M.R.; Zhang, B.; McKenna, D.H.; Curtsinger, J.; Panoskaltsis-Mortari, A.; Lewis, D.; Hippen, K.; et al. Clearance of acute myeloid leukemia by haploidentical natural killer cells is improved using IL-2 diphtheria toxin fusion protein. Blood 2014, 123, 3855–3863. [Google Scholar] [CrossRef]
- Shi, J.; Tricot, G.; Szmania, S.; Rosen, N.; Garg, T.K.; Malaviarachchi, P.A.; Moreno, A.; Dupont, B.; Hsu, K.C.; Baxter-Lowe, L.A.; et al. Infusion of haplo-identical killer immunoglobulin-like receptor ligand mismatched NK cells for relapsed myeloma in the setting of autologous stem cell transplantation. Br. J. Haematol. 2008, 143, 641–653. [Google Scholar] [CrossRef] [Green Version]
- Lee, D.A.; Denman, C.J.; Rondon, G.; Woodworth, G.; Chen, J.; Fisher, T.; Kaur, I.; Fernandez-Vina, M.; Cao, K.; Ciurea, S.; et al. Haploidentical, natural killer, cells infused before allogeneic, stem cell, transplantation for myeloid, malignancies: A phase I trial. Biol. Blood Marrow Transplant. 2016, 22, 1290–1298. [Google Scholar] [CrossRef] [Green Version]
- Fehniger, T.A.; Miller, J.S.; Stuart, R.K.; Cooley, S.; Salhotra, A.; Curtsinger, J.; Westervelt, P.; DiPersio, J.F.; Hillman, T.M.; Silver, N.; et al. A phase 1 trial of CNDO-109-activated, natural killer, cells in patients with high-risk, acute myeloid, leukemia. Biol. Blood Marrow Transplant. 2018, 24, 1581–1589. [Google Scholar] [CrossRef] [Green Version]
- Zhang, L.; Liu, M.; Yang, S.; Wang, J.; Feng, X.; Han, Z. Natural killer cells: Of-the-shelf cytotherapy for cancer immunosurveillance. Am. J. Cancer Res. 2021, 11, 1770–1791. [Google Scholar]
- Maude, S.L.; Laetsch, T.W.; Buechner, J.; Rives, S.; Boyer, M.; Bittencourt, H.; Bader, P.; Verneris, M.R.; Stefanski, H.E.; Myers, G.D.; et al. Tisagenlecleucel in children and young, adults with B-cell, lymphoblastic leukemia. N. Engl. J. Med. 2018, 378, 439–448. [Google Scholar] [CrossRef] [PubMed]
- Park, J.H.; Rivière, I.; Gonen, M.; Wang, X.; Sénéchal, B.; Curran, K.J.; Sauter, C.; Wang, Y.; Santomasso, B.; Mead, E.; et al. Long-term, follow-up of CD19 CAR therapy in acute, lymphoblastic leukemia. N. Engl. J. Med. 2018, 378, 449–459. [Google Scholar] [CrossRef]
- Daher, M.; Rezvani, K. Next generation natural killer cells for cancer immunotherapy: The promise of genetic engineering. Curr. Opin. Immunol. 2018, 51, 146–153. [Google Scholar] [CrossRef] [PubMed]
- Morris, M.A.; Ley, K. Trafficking of natural killer cells. Curr. Mol. Med. 2004, 4, 431–438. [Google Scholar] [CrossRef] [PubMed]
- Vitale, M.; Cantoni, C.; Della Chiesa, M.; Ferlazzo, G.; Carlomagno, S.; Pende, D.; Falco, M.; Pessino, A.; Muccio, L.; De Maria, A.; et al. An historical overview: The discovery of how, NK cells can kill enemies recruit defense troops and more. Front. Immunol. 2019, 10, 1415. [Google Scholar] [CrossRef] [Green Version]
- Nazimuddin, F.; Finklestein, J.M.; Gupta, M.; Kulikovskaya, I.; Ambrose, D.E.; Gill, S.; Lacey, S.F.; Zheng, Z.; Melenhorst, J.J.; Levine, B.L. Long-term functional persistence B cell aplasia and anti-leukemia efficacy in refractory B cell malignancies following T cell immunotherapy using CAR-redirected T cells targeting CD19. Am. Soc. Hematol. 2013, 122, 163. [Google Scholar]
- Shimasaki, N.; Fujisaki, H.; Cho, D.; Masselli, M.; Lockey, T.; Eldridge, P.; Leung, W.; Campana, D. A clinically adaptable method to enhance the cytotoxicity of natural killer cells against B-cell malignancies. Cytotherapy 2012, 14, 830–840. [Google Scholar] [CrossRef]
- Oelsner, S.; Friede, M.E.; Zhang, C.; Wagner, J.; Badura, S.; Bader, P.; Ullrich, E.; Ottmann, O.G.; Klingemann, H.; Tonn, T.; et al. Continuously expanding CAR NK-92 cells display selective cytotoxicity against B-cell leukemia and lymphoma. Cytotherapy 2017, 19, 235–249. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Liu, E.; Tong, Y.; Dotti, G.; Shaim, H.; Savoldo, B.; Mukherjee, M.; Orange, J.; Wan, X.; Lu, X.; Reynolds, A.; 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, 520–531. [Google Scholar] [CrossRef]
- Li, Y.; Hermanson, D.L.; Moriarity, B.S.; Kaufman, D.S. Human iPSC-derived natural kille cells engineered with chimeric, antigen receptors enhance anti-tumor activity. Cell Stem Cell 2018, 23, 181–192. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Romanski, A.; Uherek, C.; Bug, G.; Seifried, E.; Klingemann, H.; Wels, W.S.; Ottmann, O.G.; Tonn, T. CD19-CAR engineered NK-92 cells are sufficient to overcome NK cell resistance in B-cell malignancies. J. Cell Mol. Med. 2016, 20, 1287–1294. [Google Scholar] [CrossRef]
- Suerth, J.D.; Morgan, M.A.; Kloess, S.; Heckl, D.; Neudörfl, C.; Falk, C.S.; Koehl, U.; Schambach, A. Efficient generation of gene-modified human natural killer cells via alpharetroviral vectors. J. Mol. Med. 2016, 94, 83–93. [Google Scholar] [CrossRef]
- Chu, Y.; Hochberg, J.; Yahr, A.; Ayello, J.; van de Ven, C.; Barth, M.; Czuczman, M.; Cairo, M.S. 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, 333–344. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Chu, Y.; Yahr, A.; Huang, B.; Ayello, J.; Barth, M.; Cairo, M.S. 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, e1341031. [Google Scholar] [CrossRef] [Green Version]
- Jiang, H.; Zhang, W.; Shang, P.; Zhang, H.; Fu, W.; Ye, F.; Zeng, T.; Huang, H.; Zhang, X.; Sun, W.; et al. Transfection of chimeric anti-CD138 gene enhances natural killer cell activation and killing of multiple myeloma cells. Mol. Oncol. 2014, 8, 297–310. [Google Scholar] [CrossRef] [PubMed]
- Chu, J.; Deng, Y.; Benson, D.M.; He, S.; Hughes, T.; Zhang, J.; Peng, Y.; Mao, H.; Yi, L.; Ghoshal, K.; 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, 917–927. [Google Scholar] [CrossRef] [Green Version]
- Chen, K.H.; Wada, M.; Pinz, K.G.; Liu, H.; Lin, K.W.; Jares, A.; Firor, A.E.; Shuai, X.; Salman, H.; Golightly, M.; et al. Preclinical targeting of aggressive T-cell malignancies using anti-CD5 chimeric antigen receptor. Leukemia 2017, 31, 2151–2160. [Google Scholar] [CrossRef] [Green Version]
- Tang, X.; Yang, L.; Li, Z.; Nalin, A.P.; Dai, H.; Xu, T.; Yin, J.; You, F.; Zhu, M.; Shen, W.; 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, 1083–1089, Erratum in 2018, 8, 1899. [Google Scholar] [PubMed]
- Liu, E.; Marin, D.; Banerjee, P.; Macapinlac, H.A.; Thompson, P.; Basar, R.; Nassif Kerbauy, L.; Overman, B.; Thall, P.; Kaplan, M.; et al. Use of CAR-transduced natural killer cells in CD19-positive lymphoid tumors. N. Engl. J. Med. 2020, 382, 545–553. [Google Scholar] [CrossRef]
- Li, X.; He, C.; Liu, C.; Ma, J.; Ma, P.; Cui, H.; Tao, H.; Gao, B. Expansion of NK cells from PBMCs using immobilized 4-1BBL and interleukin-21. Int. J. Oncol. 2015, 47, 335–342. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Denman, C.J.; Senyukov, V.V.; Somanchi, S.S.; Phatarpekar, P.V.; Kopp, L.M.; Johnson, J.L.; Singh, H.; Hurton, L.; Maiti, S.N.; Huls, M.H.; et al. Membrane-bound IL-21 promotes sustained ex vivo proliferation of human natural killer cells. PLoS ONE 2012, 7, e30264. [Google Scholar] [CrossRef] [PubMed]
- Fujisaki, H.; Kakuda, H.; Imai, C.; Mullighan, C.G.; Campana, D. Replicative potential of human natural killer cells. Br. J. Haematol. 2009, 145, 606–613. [Google Scholar] [CrossRef] [Green Version]
- Jiang, B.; Wu, X.; Li, X.N.; Yang, X.; Zhou, Y.; Yan, H.; Wei, A.H.; Yan, W. Expansion of NK cells by engineered K562 cells co-expressing 4-1BBL and mMICA, combined with soluble IL-21. Cell Immunol. 2014, 290, 10–20. [Google Scholar] [CrossRef] [PubMed]
- Phan, M.T.; Lee, S.H.; Kim, S.K.; Cho, D. Expansion of NK cells using genetically engineered K562 feeder cells. Methods Mol. Biol. 2016, 1441, 167–174. [Google Scholar] [PubMed]
- Fujisaki, H.; Kakuda, H.; Shimasaki, N.; Imai, C.; Ma, J.; Lockey, T.; Eldridge, P.; Leung, W.H.; Campana, D. Expansion of highly cytotoxic human natural killer cells for cancer cell therapy. Cancer Res. 2009, 69, 4010–4017. [Google Scholar] [CrossRef] [Green Version]
- Chanswangphuwana, C.; Allan, D.S.J.; Chakraborty, M.; Reger, R.N.; Childs, R.W. Augmentation of NK cell proliferation and anti-tumor immunity by transgenic expression of receptors for EPO or TPO. Mol. Ther. 2021, 29, 47–59. [Google Scholar] [CrossRef]
- Sutlu, T.; Stellan, B.; Gilljam, M.; Quezada, H.C.; Nahi, H.; Gahrton, G.; Alici, E. Clinical-grade, large-scale, feeder-free expansion of highly active human natural killer cells for adoptive immunotherapy using an automated bioreactor. Cytotherapy 2010, 12, 1044–1055. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- McKenna, D.H., Jr.; Sumstad, D.; Bostrom, N.; Kadidlo, D.M.; Fautsch, S.; McNearney, S.; Dewaard, R.; McGlave, P.B.; Weisdorf, D.J.; Wagner, J.E.; et al. Good manufacturing practices production of natural killer cells for immunotherapy: A six-year single-institution experience. Transfusion 2007, 47, 520–528. [Google Scholar] [CrossRef]
- Fernández, A.; Navarro-Zapata, A.; Escudero, A.; Matamala, N.; Ruz-Caracuel, B.; Mirones, I.; Pernas, A.; Cobo, M.; Casado, G.; Lanzarot, D.; et al. Optimizing the procedure to manufacture clinical-grade NK cells for adoptive immunotherapy. Cancers 2021, 13, 577. [Google Scholar] [CrossRef]
- Vacca, P.; Pietra, G.; Tumino, N.; Munari, E.; Mingari, M.C.; Moretta, L. Exploiting human NK cells in tumor therapy. Front. Immunol. 2020, 10, 3013. [Google Scholar] [CrossRef] [PubMed]
- Wang, X.; Jasinski, D.L.; Medina, J.L.; Spencer, D.M.; Foster, A.E.; Bayle, J.H. Inducible MyD88/CD40 synergizes with IL-15 to enhance antitumor efficacy of CAR-NK cells. Blood Adv. 2020, 4, 1950–1964. [Google Scholar] [CrossRef]
- Daher, M.; Basar, R.; Gokdemir, E.; Baran, N.; Uprety, N.; Nunez Cortes, A.K.; Mendt, M.; Kerbauy, L.N.; Banerjee, P.P.; Shanley, M.; et al. Targeting a cytokine checkpoint enhances the fitness of armored cord blood CAR-NK cells. Blood 2021, 137, 624–636. [Google Scholar] [CrossRef]
- Islam, R.; Pupovac, A.; Evtimov, V.; Boyd, N.; Shu, R.; Boyd, R.; Trounson, A. Enhancing a natural killer: Modification of NK cells for cancer, immunotherapy. Cells 2021, 10, 1058. [Google Scholar] [CrossRef] [PubMed]
- Lapteva, N.; Durett, A.G.; Sun, J.; Rollins, L.A.; Huye, L.L.; Fang, J.; Dandekar, V.; Mei, Z.; Jackson, K.; Vera, J.; et al. Large-scale ex vivo expansion and characterization of natural killer cells for clinical applications. Cytotherapy 2012, 14, 1131–1143. [Google Scholar] [CrossRef] [Green Version]
- Luevano, M.; Daryouzeh, M.; Alnabhan, R.; Querol, S.; Khakoo, S.; Madrigal, A.; Saudemont, A. The unique profile of cord blood natural killer cells balancesincomplete maturation and effective killing function upon activation. Hum. Immunol. 2012, 73, 248–257. [Google Scholar] [CrossRef]
- Luevano, M.; Madrigal, A.; Saudemont, A. Generation of natural killer cells from hematopoietic stem cells in vitro for immunotherapy. Cell Mol. Immunol. 2012, 9, 310–320. [Google Scholar] [CrossRef]
- Maki, G.; Klingemann, H.-G.; Martinson, J.A.; Tam, Y.K. Factors regulating the cytotoxic activity of the human natural killer cell line NK-92. J. Hematother. Stem Cell Res. 2001, 10, 369–383. [Google Scholar] [CrossRef]
- Tonn, T.; Schwabe, D.; Klingemann, H.G.; Becker, S.; Esser, R.; Koehl, U.; Suttorp, M.; Seifried, E.; Ottmann, O.G.; Bug, G. Treatment of patients with advanced cancer with the natural killer cell line NK-92. Cytotherapy 2013, 15, 1563–1570. [Google Scholar] [CrossRef] [PubMed]
- Zhu, H.; Kaufman, D.S. An improved method to produce clinical-scale natural killer cells from human pluripotent stem cells. Methods Mol. Biol. 2019, 2048, 107–119. [Google Scholar] [PubMed]
- Van Ostaijen-ten Dam, M.M.; Prins, H.J.; Boerman, G.H.; Vervat, C.; Pende, D.; Putter, H.; Lankester, A.; van Tol, M.J.; Zwaginga, J.J.; Schilham, M.W. Preparation of cytokine-activated NK cells for use in adoptive cell therapy in cancer patients: Protocol optimization and therapeutic potential. J. Immunother. 2016, 39, 90–100. [Google Scholar] [CrossRef] [PubMed]
- Mehta, R.S.; Shpall, E.J.; Rezvani, K. Cord blood as a source of natural killer cells. Front. Med. 2016, 2, 93. [Google Scholar] [CrossRef] [Green Version]
- Pasley, S.; Zylberberg, C.; Matosevic, S. Natural killer-92 cells maintain cytotoxicactivity after long-term cryopreservation in novel DMSO-free media. Immunol. Lett. 2017, 192, 35–41. [Google Scholar] [CrossRef]
- Domogala, A.; Madrigal, J.A.; Saudemont, A. Cryopreservation has no effect on function of natural killer cells differentiated in vitro from umbilical cord blood CD34(+) cells. Cytotherapy 2016, 18, 754–759. [Google Scholar] [CrossRef]
- Yao, X.; Jovevski, J.J.; Todd, M.F.; Xu, R.; Li, Y.; Wang, J.; Matosevic, S. Nanoparticle-mediated intracellular protection of natural killer cells avoids cryoinjury and retains potent antitumor functions. Adv. Sci. 2020, 7, 1902938. [Google Scholar] [CrossRef] [Green Version]
- 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, 1777–1786. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Sekiba, K.; Yamagami, M.; Otsuka, M.; Suzuki, T.; Kishikawa, T.; Ishibashi, R.; Ohno, M.; Sato, M.; Koike, K. Transcriptional activation of the MICA gene with an engineered CRISPR-Cas9 system. Biochem. Biophys. Res. Commun. 2017, 486, 521–525. [Google Scholar] [CrossRef] [PubMed]
- Rautela, J.; Surgenor, E.; Huntington, D.N. Efficient genome editing of human natural killer cells by CRISPR RNP. bioRxiv 2018, 406934. [Google Scholar] [CrossRef]
- Jing, Y.; Ni, Z.; Wu, J.; Higgins, L.A.; Markowski, T.W.; Kaufman, D.S.; Walcheck, B. Identification of an ADAM17 cleavage region in human CD16 (FcγRIII) and the engineering of a non-cleavable version of the receptor in NK cells. PLoS ONE 2015, 10, e0121788. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Blum, R.; Arumugam, A.; Wu, J.; Walcheck, B.; Kaufman, D. Engineering human pluripotent stem cell-derived natural killer cells to prevent CD16a shedding for enhanced anti-tumor killing. Blood 2016, 128, 1336. [Google Scholar] [CrossRef]
- Snyder, K.M.; Hullsiek, R.; Mishra, H.K.; Mendez, D.C.; Li, Y.; Rogich, A.; Kaufman, D.S.; Wu, J.; Walcheck, B. 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, 1–11. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- 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, 376–383. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Müller, S.; Bexte, T.; Gebel, V.; Kalensee, F.; Stolzenberg, E.; Hartmann, J.; Koehl, U.; Schambach, A.; Wels, W.S.; Modlich, U.; 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. [Google Scholar] [CrossRef]
- Gong, Y.; Klein Wolterink, R.G.J.; Janssen, I.; Groot, A.J.; Bos, G.M.J.; Germeraad, W.T.V. Rosuvastatin enhances VSV-G lentiviral transduction of NK cells via upregulation of the low-density lipoprotein receptor. Mol. Ther. Methods Clin. Dev. 2020, 17, 634–646. [Google Scholar] [CrossRef] [PubMed]
- Sutlu, T.; Nyström, S.; Gilljam, M.; Stellan, B.; Applequist, S.E.; Alici, E. Inhibition of intracellular antiviral defense mechanisms augments lentiviral transduction of human natural killer cells: Implications for gene therapy. Hum. Gene Ther. 2012, 23, 1090–1100. [Google Scholar] [CrossRef] [Green Version]
- Colamartino, A.B.L.; Lemieux, W.; Bifsha, P.; Nicoletti, S.; Chakravarti, N.; Sanz, J.; Roméro, H.; Selleri, S.; Béland, K.; Guiot, M.; et al. Efficient and robust NK-cell transduction with baboon envelope pseudotyped lentivector. Front. Immunol. 2019, 10, 2873. [Google Scholar] [CrossRef]
- Streltsova, M.A.; Barsov, E.; Erokhina, S.A.; Kovalenko, E.I. 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, 90–94. [Google Scholar] [CrossRef]
Patients | Donor/NK Cell Source | NK Cell Expansion Method | Conditioning Regimen Prior to NK Infusion | Adverse Event/Toxicity | Response | Reference |
---|---|---|---|---|---|---|
4 Follicular Lymphoma, 5 Diffuse Large B Cell Lymphoma | Autologous/PBMC | IL-2 and IL-15 stimulation | None | None | CR in 7/9, median F/U: 44 months | [34] |
9 AML | Allogeneic/PBMC | IL2, IL-12, IL-15, and IL-18 stimulation, CD3 depletion, CD56-positive selection | Flu + Cy | N/A | ORR 55%, CR 45% | [35] |
4 AML, 1 CML | Haploidentical/PBMC | CD3 depletion, CD56 enrichment | None * | None | 2/5 patients donor chimerism | [36] |
19 AML | Haploidentical/PBMC | CD3 depletion, IL-2 stimulation | Flu + Cy | Pleural effusion in 1 patient | CR in 5/19 | [14] |
10 AML | Haploidentical/PBMC | CD3-depletion, CD56-enrichment, IL-2 stimulation | Flu + Cy | None | CR 100% | [37] |
41 hematological malignancies | Haploidentical/PBMC | CD3-depletion, IL-15, IL-21 stimulation | None * | None | Significant reduction of leukemia progression 46% vs. 74% (historical cohort) | [38] |
29 lymphoma | Autologous/PBMC | Ex vivo IL-2 stimulation | None | None | No change in outcome compared to historical controls | [33] |
41 AML | Haploidentical/PBMC | CD3-depletion, IL-15, IL-21 and hydrocortisone stimulation | None * | Grade 2 to 4 aGVHD 28%, cGVHD 30%,fever 73% | CR 57%, 3-year leukemia progression 75% | [39] |
6 B cell NHL | Allogeneic/PBMC | CD3-depletion, IL-2 stimulation | Flu + Cy + R | None | 4/6 clinical response | [40] |
7 AML | “Off-the-shelf”/NK-92 | IL2 stimulation | None | None | 1 blast reduction, 2 SD | [41] |
26 AML | Haploidentical/PBMC | CD19 and CD3 depletion, rhIL15 stimulation | Flu + Cy | CRS in 56% of patients, neurologic toxicity in 5/9 patients | CR: 40% | [42] |
8 AML, 5 CML | Haploidentical/PBMC | CD3-depletion K562 Clone9.mbIL21 feeder cells | None * | aGVHD grade 1–2 54% | CR: 11/13 median F/U: 14.7 months | [43] |
9 AML | “Off-the-shelf“/iPSC | IL2 stimulation | Flu + Cy | 3 patients Grade 3 febrile neutropenia | 4/9 CR | [44] |
11 B cell NHL | “Off-the-shelf“/iPSC | IL 2 stimulation | Flu + Cy | None | 8/11 had objective response, CR median F/U: 5.2 months | [45] |
3 AML | “Off-the-shelf“/iPSC | IL2 stimulation | Flu + Cy | None | 1/3 CR | [44] |
14 B cell NHL | “Off-the-shelf“/iPSC | IL2 stimulation | Flu + Cy + R | None | 10/14 patients achieved objective response, 7 CR | [45] |
10 AML | Allogeneic/UCB | CD34+ selection | Flu + Cy | None | 4/10 disease free | [46] |
12 MM | Allogeneic/UCB | CD3 depletion, K562-9.mbIL21, IL-2 stimulation | Lenalidomide/melphalan | None | 10 patients achieved at least VGPR, Median F/U 21 months | [47] |
Target | Tumor Type | NK Cell Source | Structure of CAR Constructs | References |
---|---|---|---|---|
CD19 | B-cell leukemia | NK-92 cell line | Anti CD19 scFv + CD3ζ | [74] |
CD19 | B-cell leukemia | Peripheral blood | Anti CD19 scFv + 41BB-CD3ζ | [70] |
CD19 | B-cell malignancies | NK-92 | Anti-CD19 scFV + CD3ζ, CD28 + CD3ζ or CD13 + CD3ζ | [71] |
CD19 | B-cell malignancies | Cord blood | Anti-CD19 scFv + 4-1BB + CD3ζ + iCasp9 + IL-15 | [72] |
CD19 | B-cell malignancies | Peripheral blood | Anti CD19 scFv + 41BB + CD28 + CD3ζ | [75] |
CD20 | B-cell malignancies | Peripheral blood | Anti CD19 scFv + 41BB-CD3ζ | [76] |
CD20 | Burkitt lymphoma | Peripheral blood | Anti CD19 scFv + 41BB-CD3ζ + IL15 | [77] |
CD138 | Multiple myeloma | NK-92MI | Anti CD19 scFv + CD3ζ | [78] |
CS-1 | Multiple myeloma | NK-92 | Anti CD19 scFv + CD28 + CD3ζ | [79] |
CD5 | T-cell malignancies | NK-92 | Anti CD19 scFv + 41BB + CD28 + CD3ζ | [80] |
Antigen Target | Tumor | NK Cell Source | Structure of the CAR Construct | Phase of the Study | ClinicalTrials.Gov Identifier # (Number) |
---|---|---|---|---|---|
CD22 | B lymphoma | Unknown | Anti-CD22 + CD244 | I | NCT03692767 |
CD19 | B lymphoma | NK-92 | Anti-C19 + CD244 | I | NCT03690310 |
CD19/CD22 | B lymphoma | Unknown | Anti-CD19/22 + CD244 | I | NCT03824964 |
CD19 | B lymphoma | Unknown | Unknown | I | NCT04639739 |
CD19 | B lymphoma | Unknown | Unknown | I | NCT04887012 |
BCMA | Multiple myeloma | NK-92 | Anti-BCMA + CD8αTM-4-1BB-CD3ζ | I/II | NCT03940833 |
CD7 | NK/T-cell lymphoma | Unknown | Unknown | I | NCT04264078 |
CD19 | B-lymphoid malignancies | Cord blood NK cells | Anti-CD19 + CD28-CD3ζ | I/II | NCT03056339 |
CD33 | Acute myeloid leukemia | NK-92 | Anti-CD33 + CD28-4-1BB-CD3ζ | I/II | NCT02944162 |
CD7 | T-cell leukemia/lymphoma | NK-92 | Anti-CD7 + CD28-4-1BB-CD3ζ | I/II | NCT02742727 |
CD19 | B-cell malignancies | NK-92 | Anti-CD19 + CD28-4-1BB-CD3ζ | I/II | NCT02892695 |
CD19 | B lymphoma | iPS-derived NK cells | Anti-CD19 + CD244 | I | NCT03824951 |
CD19 | B-cell leukemia | Peripheral blood | Anti-CD19 + CD8αΤΜ + 4-1ΒΒ + CD3ζ | I | NCT00995137 |
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Gunduz, M.; Ataca Atilla, P.; Atilla, E. New Orders to an Old Soldier: Optimizing NK Cells for Adoptive Immunotherapy in Hematology. Biomedicines 2021, 9, 1201. https://doi.org/10.3390/biomedicines9091201
Gunduz M, Ataca Atilla P, Atilla E. New Orders to an Old Soldier: Optimizing NK Cells for Adoptive Immunotherapy in Hematology. Biomedicines. 2021; 9(9):1201. https://doi.org/10.3390/biomedicines9091201
Chicago/Turabian StyleGunduz, Mehmet, Pinar Ataca Atilla, and Erden Atilla. 2021. "New Orders to an Old Soldier: Optimizing NK Cells for Adoptive Immunotherapy in Hematology" Biomedicines 9, no. 9: 1201. https://doi.org/10.3390/biomedicines9091201