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摘要: NK细胞作为固有免疫细胞在肿瘤免疫监视中发挥重要作用。相比CAR-T其神经毒性、细胞因子释放综合征等不良反应和移植物抗宿主病鲜有发生,因此有希望成为嵌合抗原受体细胞免疫治疗更好的细胞来源。目前CAR-NK细胞的研究仍多使用根据T细胞激活原理设计的CAR。该文针对NK细胞激活原理设计的CAR结构、可用于免疫治疗的NK细胞来源和CAR-NK细胞在白血病、淋巴瘤、骨髓瘤的临床前景及临床研究进展进行综述。分析得出,“现货型”CAR-NK细胞将是血液肿瘤治疗的新方向,如何增加CAR-NK细胞在体内的存活时间仍是其应用于临床亟须解决的问题。Abstract: Natural killer cell plays an important role in immune surveillance as a crucial component of the innate system. It's a promising alternative platform for CAR engineering owning to their lower risk of graft versus host disease and incidence of adverse events such as cytokine release syndrome or neurotoxicity. CAR constructs optimized for T-cell signaling and function still make up the majority of studies exploring CAR NK cells. In this review, it focuses on the details of CAR-NK technology, including the design of efficient CAR constructs and NK cell sources. It also provides an outlook on how these CAR-NK cell therapies treating various hematological malignancies, including leukemia, lymphoma and multiple myeloma. Off-the-shelf cellular therapy is likely to be the next frontier for hematological malignancies. Limitation of in vivo survival time for infused cells is the challenge urgently needs to be overcome.
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Key words:
- CAR-NK /
- adoptive cellular immunotherapy /
- hematologic tumor /
- natural killer cell
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[1] Roma S, Carpen L, Raveane A, et al. The Dual Role of Innate Lymphoid and Natural Killer Cells in Cancer. from Phenotype to Single-Cell Transcriptomics, Functions and Clinical Uses[J]. Cancers(Basel), 2021, 13(20): 5042.
[2] Shimasaki N, Jain A, Campana D. NK cells for cancer immunotherapy[J]. Nat Rev Drug Discov, 2020, 19(3): 200-218. doi: 10.1038/s41573-019-0052-1
[3] 赵恺, 徐开林. 嵌合抗原受体T细胞的结构演变及展望[J]. 中华血液学杂志, 2020, 41(11): 964-968. doi: 10.3760/cma.j.issn.0253-2727.2020.11.019
[4] Chang YH, Connolly J, Shimasaki N, et al. A chimeric receptor with NKG2D specificity enhances natural killer cell activation and killing of tumor cells[J]. Cancer Res, 2013, 73(6): 1777-1786. doi: 10.1158/0008-5472.CAN-12-3558
[5] Li Y, Hermanson DL, Moriarity BS, et al. Human iPSC-Derived Natural Killer Cells Engineered with Chimeric Antigen Receptors Enhance Anti-tumor Activity[J]. Cell Stem Cell, 2018, 23(2): 181-192.e5. doi: 10.1016/j.stem.2018.06.002
[6] Leivas A, Valeri A, Córdoba L, et al. NKG2D-CAR-transduced natural killer cells efficiently target multiple myeloma[J]. Blood Cancer J, 2021, 11(8): 146. doi: 10.1038/s41408-021-00537-w
[7] Agresta L, Hoebe K, Janssen EM. The Emerging Role of CD244 Signaling in Immune Cells of the Tumor Microenvironment[J]. Front Immunol, 2018, 9: 2809. doi: 10.3389/fimmu.2018.02809
[8] 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[J]. Clin Cancer Res, 2009, 15(15): 4857-4866. doi: 10.1158/1078-0432.CCR-08-2810
[9] 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]. J Hematol Oncol, 2019, 12(1): 49. doi: 10.1186/s13045-019-0732-7
[10] Romee R, Foley B, Lenvik T, et al. NK cell CD16 surface expression and function is regulated by a disintegrin and metalloprotease-17(ADAM17)[J]. Blood, 2013, 121(18): 3599-3608. doi: 10.1182/blood-2012-04-425397
[11] Zhu H, Blum RH, Bjordahl R, et al. Pluripotent stem cell-derived NK cells with high-affinity noncleavable CD16a mediate improved antitumor activity[J]. Blood, 2020, 135(6): 399-410. doi: 10.1182/blood.2019000621
[12] Salman H, Pinz KG, Wada M, et al. Preclinical Targeting of Human Acute Myeloid Leukemia Using CD4- specific Chimeric Antigen Receptor(CAR)T Cells and NK Cells[J]. J Cancer, 2019, 10(18): 4408-4419. doi: 10.7150/jca.28952
[13] Sivori S, Vacca P, Del Zotto G, et al. Human NK cells: surface receptors, inhibitory checkpoints, and translational applications[J]. Cell Mol Immunol, 2019, 16(5): 430-441. doi: 10.1038/s41423-019-0206-4
[14] 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[J]. Blood, 2005, 105(8): 3051-3057. doi: 10.1182/blood-2004-07-2974
[15] Scoville SD, Nalin AP, Chen L, et al. Human AML activates the aryl hydrocarbon receptor pathway to impair NK cell development and function[J]. Blood, 2018, 132(17): 1792-1804. doi: 10.1182/blood-2018-03-838474
[16] Uphoff CC, Denkmann SA, Steube KG, et al. Detection of EBV, HBV, HCV, HIV-1, HTLV-Ⅰ and-Ⅱ, and SMRV in human and other primate cell lines[J]. J Biomed Biotechnol, 2010, 2010: 904767.
[17] Luevano M, Daryouzeh M, Alnabhan R, et al. The unique profile of cord blood natural killer cells balances incomplete maturation and effective killing function upon activation[J]. Hum Immunol, 2012, 73(3): 248-257. doi: 10.1016/j.humimm.2011.12.015
[18] Nomura A, Takada H, Jin CH, et al. Functional analyses of cord blood natural killer cells and T cells: a distinctive interleukin-18 response[J]. Exp Hematol, 2001, 29(10): 1169-1176. doi: 10.1016/S0301-472X(01)00689-0
[19] 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[J]. Leukemia, 2018, 32(2): 520-531. doi: 10.1038/leu.2017.226
[20] Heipertz EL, Zynda ER, Stav-Noraas TE, et al. Current Perspectives on "Off-The-Shelf" Allogeneic NK and CAR-NK Cell Therapies[J]. Front Immunol, 2021, 12: 732135. doi: 10.3389/fimmu.2021.732135
[21] Woll PS, Grzywacz B, Tian X, et al. Human embryonic stem cells diferentiate into a homogeneous population of natural killer cells with potent in vivo antitumor activity[J]. Blood, 2009, 113(24): 6094-6101. doi: 10.1182/blood-2008-06-165225
[22] 杜为, 崔丽娟, 徐迎, 等. 脐带血单个核细胞诱导多能干细胞来源自然杀伤细胞的生物学特性[J]. 中华细胞与干细胞杂志(电子版), 2021, 11(6): 329-336. doi: 10.3877/cma.j.issn.2095-1221.2021.06.002
[23] Tang X, Yang L, Li Z, et al. Erratum: 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[J]. Am J Cancer Res, 2018, 8(9): 1899.
[24] Bachier C, Borthakur G, Hosing C, et al. A Phase 1 study of NKX101, an allogeneic CAR natural killer(NK)cell therapy, in subjects with relapsed/refractory(R/R)acute myeloid leukemia(AML)or higher-risk myelodysplastic syndrome(MDS)[J]. Blood, 2020, 136(Suppl 1): 42-43.
[25] Oelsner S, Waldmann A, Billmeier A, et al. Genetically engineered CAR NK cells display selective cytotoxicity against FLT3-positive B-ALL and inhibit in vivo leukemia growth[J]. Int J Cancer, 2019, 145(7): 1935-1945.
[26] Liu E, Marin D, Banerjee P, et al. Use of CAR-Transduced Natural Killer Cells in CD19-Positive Lymphoid Tumors[J]. N Engl J Med, 2020, 382(6): 545-553. doi: 10.1056/NEJMoa1910607
[27] Strati P, Bachanova V, Goodman A, et al. Preliminary results of a phase Ⅰ trial of FT516, an of the-shelf natural killer(NK)cell therapy derived from a clonal master induced pluripotent stem cell(iPSC)line expressing highafnity, non-cleavable CD16(hnCD16), in patients(pts)with relapsed/refractory(R/R)B-cell lymphoma(BCL)[J]. J Clin Oncol, 2021, 39(15 Suppl): 7541.
[28] 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[J]. Leukemia, 2014, 28(4): 917-927. doi: 10.1038/leu.2013.279
[29] Hambach J, Riecken K, Cichutek S, et al. Targeting CD38- expressing multiple myeloma and burkitt lymphoma cells in vitro with nanobody based chimeric antigen receptors(Nb-CARs)[J]. Cells, 2020, 9(2): 321. doi: 10.3390/cells9020321
[30] Goodridge JP, Bjordahl R, Mahmood S, et al. FT576 path to frst-of-kind clinical trial: translation of a versatile multi-antigen specifc of-the-shelf NK cell for treatment of multiple myeloma[J]. Cancer Res, 2021, 81(13 Suppl): 1550.
[31] Ryan B, Svetlana G, Karrune W, et al. FT538: Preclinical Development of an Off-the-Shelf Adoptive NK Cell Immunotherapy with Targeted Disruption of CD38 to Prevent Anti-CD38 Antibody-Mediated Fratricide and Enhance ADCC in Multiple Myeloma When Combined with Daratumumab[J]. Blood, 2019, 134(Suppl 1): 133.
[32] Soldierer M, Bister A, Haist C, et al. Genetic Engineering and Enrichment of Human NK Cells for CAR-Enhanced Immunotherapy of Hematological Malignancies[J]. Front Immunol, 2022, 13: 847008. doi: 10.3389/fimmu.2022.847008
[33] Gang M, Marin ND, Wong P, et al. CAR-modified memory-like NK cells exhibit potent responses to NK-resistant lymphomas[J]. Blood, 2020, 136(20): 2308-2318. doi: 10.1182/blood.2020006619
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