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Article(id=1239222193066922880, tenantId=1146029695717560320, journalId=1205117082300743687, issueId=1239222192311948159, articleNumber=null, orderNo=null, doi=10.14109/j.cnki.xyylc.2024.11.01, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=null, receivedDate=1695484800000, receivedDateStr=2023-09-24, revisedDate=null, revisedDateStr=null, acceptedDate=1720972800000, acceptedDateStr=2024-07-15, onlineDate=1773383194461, onlineDateStr=2026-03-13, pubDate=1732464000000, pubDateStr=2024-11-25, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1773383194461, onlineIssueDateStr=2026-03-13, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1773383194461, creator=13701087609, updateTime=1773383194461, updator=13701087609, issue=Issue{id=1239222192311948159, tenantId=1146029695717560320, journalId=1205117082300743687, year='2024', volume='43', issue='11', pageStart='801', pageEnd='880', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=0, createTime=1773383194282, creator=13701087609, updateTime=1773384015681, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1239225637551002124, tenantId=1146029695717560320, journalId=1205117082300743687, issueId=1239222192311948159, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1239225637551002125, tenantId=1146029695717560320, journalId=1205117082300743687, issueId=1239222192311948159, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=801, endPage=808, ext={EN=ArticleExt(id=1239222193813508999, articleId=1239222193066922880, tenantId=1146029695717560320, journalId=1205117082300743687, language=EN, title=Construction strategy of CAR-NK cells and its research progress in tumor immunotherapy, columnId=1207314219599499390, journalTitle=Chinese Journal of New Drugs and Clinical Remedies, columnName=Review, runingTitle=null, highlight=null, articleAbstract=

Chimeric antigen receptor（CAR）- T cell therapy has changed the traditional treatment of hematological malignancies and has shown significant efficacy. However, the clinical application of CAR-T cells is limited by long production cycle, high price, and side effects such as cytokine storm, so it can not be widely used in clinical practice. Natural killer（NK）cells are an important part of the body’s innate immune response. Compared with CAR-T cells, CAR-NK cells can significantly reduce the probability of neurotoxicity, cytokine storm, and graft versus host diseases. CAR-NK cell therapy is gradually becoming a research hotspot, but there are still some urgent problems to be solved, and further optimization of the construction strategy is needed to achieve its clinical translation. This paper will review the construction strategy and the research progress in tumor immunotherapy based on the latest literatures at home and abroad, in order to provide valuable reference for application of NK cells in the treatment of malignant tumors.

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嵌合抗原受体（CAR）- T细胞疗法改变了传统血液系统恶性肿瘤的治疗方法，显示出显著疗效。然而，CAR-T细胞因制作周期长、价格高昂和细胞因子释放综合征等副作用的限制，无法在临床广泛应用。自然杀伤（NK）细胞是机体固有免疫反应的重要组成部分，与CAR-T细胞相比，CAR-NK细胞的神经毒性、细胞因子释放综合征及引起移植物抗宿主病的概率均显著降低。临床前研究和临床试验证明了CAR-NK细胞疗法治疗恶性肿瘤的安全性和可行性，正逐渐成为肿瘤免疫治疗的研究热点，但也存在一些亟需解决的问题，仍需进一步优化构建策略以实现临床转化。本文综合国内外最新的研究成果，对CAR-NK细胞构建策略及其在肿瘤免疫治疗领域的研究进展作一综述，以期为NK细胞在恶性肿瘤治疗中的应用提供有价值的参考。

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高洁
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胡佳琪，女，硕士在读，主要从事风湿免疫疾病的研究，E-mail:

高洁，女，副主任医师，博士，主要从事风湿免疫疾病的治疗工作，E-mail:

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胡佳琪，女，硕士在读，主要从事风湿免疫疾病的研究，E-mail:

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胡佳琪，女，硕士在读，主要从事风湿免疫疾病的研究，E-mail:

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高洁，女，副主任医师，博士，主要从事风湿免疫疾病的治疗工作，E-mail:

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高洁，女，副主任医师，博士，主要从事风湿免疫疾病的治疗工作，E-mail:

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Preparing for CAR T cell therapy: patient selection, bridging therapies and lymphodepletion[J]. Nat Rev Clin Oncol, 2022, 19（5）: 342-355., articleTitle=Preparing for CAR T cell therapy: patient selection, bridging therapies and lymphodepletion, refAbstract=null), Reference(id=1239232808808403825, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239222193066922880, doi=null, pmid=null, pmcid=null, year=2021, volume=11, issue=4, pageStart=69, pageEnd=null, url=null, language=null, rfNumber=[2], rfOrder=1, authorNames=STERNER RC, STERNER RM, journalName=Blood Cancer J, refType=null, unstructuredReference=STERNER RC, STERNER RM. CAR-T cell therapy: current limitations and potential strategies[J]. Blood Cancer J, 2021, 11（4）: 69., articleTitle=CAR-T cell therapy: current limitations and potential strategies, refAbstract=null), Reference(id=1239232808896484213, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239222193066922880, doi=null, pmid=null, pmcid=null, year=2015, volume=6, issue=null, pageStart=286, pageEnd=null, url=null, language=null, rfNumber=[3], rfOrder=2, authorNames=LIM O, JUNG MY, HWANG YK, journalName=Front Immunol, refType=null, unstructuredReference=LIM O, JUNG MY, HWANG YK, et al. Present and future of allogeneic natural killer cell therapy[J]. Front Immunol, 2015, 6 :286., articleTitle=Present and future of allogeneic natural killer cell therapy, refAbstract=null), Reference(id=1239232809009730427, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239222193066922880, doi=null, pmid=null, pmcid=null, year=2019, volume=74, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[4], rfOrder=3, authorNames=WANG L, DOU M, MA Q, journalName=Int Immunopharmacol, refType=null, unstructuredReference=WANG L, DOU M, MA Q, et al. Chimeric antigen receptor（CAR）-modified NK cells against cancer: opportunities and challenges[J]. Int Immunopharmacol, 2019, 74 : 105695., articleTitle=Chimeric antigen receptor（CAR）-modified NK cells against cancer: opportunities and challenges, refAbstract=null), Reference(id=1239232809110393731, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239222193066922880, doi=null, pmid=null, pmcid=null, year=2020, volume=13, issue=null, pageStart=1, pageEnd=22, url=null, language=null, rfNumber=[5], rfOrder=4, authorNames=YILMAZ A, CUI H, CALIGIURI MA, journalName=J Hematol Oncol, refType=null, unstructuredReference=YILMAZ A, CUI H, CALIGIURI MA, et al. Chimeric antigen receptor-engineered natural killer cells for cancer immunotherapy[J]. J Hematol Oncol, 2020, 13 : 1-22., articleTitle=Chimeric antigen receptor-engineered natural killer cells for cancer immunotherapy, refAbstract=null), Reference(id=1239232809202668424, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239222193066922880, doi=null, pmid=null, pmcid=null, year=2005, volume=106, issue=1, pageStart=376, pageEnd=383, url=null, language=null, rfNumber=[6], rfOrder=5, authorNames=IMAI C, IWAMOTO S, CAMPANA D, journalName=Blood, refType=null, unstructuredReference=IMAI C, IWAMOTO S, CAMPANA D. Genetic modification of primary natural killer cells overcomes inhibitory signals and induces specific killing of leukemic cells[J]. Blood, 2005, 106（1）: 376-383., articleTitle=Genetic modification of primary natural killer cells overcomes inhibitory signals and induces specific killing of leukemic cells, refAbstract=null), Reference(id=1239232809286554508, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239222193066922880, doi=null, pmid=null, pmcid=null, year=2012, volume=119, issue=3, pageStart=696, pageEnd=706, url=null, language=null, rfNumber=[7], rfOrder=6, authorNames=SONG DG, YE Q, POUSSIN M, journalName=Blood, refType=null, unstructuredReference=SONG DG, YE Q, POUSSIN M, et al. CD27 costimulation augments the survival and antitumor activity of redirected human T cells in vivo[J]. Blood, 2012, 119（3）: 696-706., articleTitle=CD27 costimulation augments the survival and antitumor activity of redirected human T cells in vivo, refAbstract=null), Reference(id=1239232809395606417, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239222193066922880, doi=null, pmid=null, pmcid=null, year=2020, volume=38, issue=2, pageStart=233, pageEnd=244, url=null, language=null, rfNumber=[8], rfOrder=7, authorNames=MACKAY M, AFSHINNEKOO E, RUB J, journalName=Nat Biotechnol, refType=null, unstructuredReference=MACKAY M, AFSHINNEKOO E, RUB J, et al. The therapeutic landscape for cells engineered with chimeric antigen receptors[J].Nat Biotechnol, 2020, 38（2）: 233-244., articleTitle=The therapeutic landscape for cells engineered with chimeric antigen receptors, refAbstract=null), Reference(id=1239232809479492502, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239222193066922880, doi=null, pmid=null, pmcid=null, year=2019, volume=27, issue=6, pageStart=1114, pageEnd=1125, url=null, language=null, rfNumber=[9], rfOrder=8, authorNames=XIAO L, CEN D, GAN H, journalName=Mol Ther, refType=null, unstructuredReference=XIAO L, CEN D, GAN H, et al. Adoptive transfer of NKG2D CAR mRNA-engineered natural killer cells in colorectal cancer patients[J]. Mol Ther, 2019, 27（6）: 1114-1125., articleTitle=Adoptive transfer of NKG2D CAR mRNA-engineered natural killer cells in colorectal cancer patients, refAbstract=null), Reference(id=1239232809584350108, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239222193066922880, doi=null, pmid=null, pmcid=null, year=2017, volume=8, issue=null, pageStart=458, pageEnd=null, url=null, language=null, rfNumber=[10], rfOrder=9, authorNames=GRANZIN M, WAGNER J, KOHL U, journalName=Front Immunol, refType=null, unstructuredReference=GRANZIN M, WAGNER J, KOHL U, et al. Shaping of natural killer cell antitumor activity by ex vivo cultivation[J]. Front Immunol,2017, 8: 458., articleTitle=Shaping of natural killer cell antitumor activity by ex vivo cultivation, refAbstract=null), Reference(id=1239232809697596319, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239222193066922880, doi=null, pmid=null, pmcid=null, year=2001, volume=14, issue=2, pageStart=105, pageEnd=110, url=null, language=null, rfNumber=[11], rfOrder=10, authorNames=WALDMANN TA, DUBOIS S, TAGAYA Y, journalName=Immunity, refType=null, unstructuredReference=WALDMANN TA, DUBOIS S, TAGAYA Y. Contrasting roles of IL-2 and IL-15 in the life and death of lymphocytes: implications for immunotherapy[J]. Immunity, 2001, 14（2）: 105-110., articleTitle=Contrasting roles of IL-2 and IL-15 in the life and death of lymphocytes: implications for immunotherapy, refAbstract=null), Reference(id=1239232809798259616, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239222193066922880, doi=null, pmid=null, pmcid=null, year=2016, volume=4, issue=7, pageStart=574, pageEnd=581, url=null, language=null, rfNumber=[12], rfOrder=11, authorNames=KAMIYA T, CHANG YH, CAMPANA D, journalName=Cancer Immunol Res, refType=null, unstructuredReference=KAMIYA T, CHANG YH, CAMPANA D. Expanded and activated natural killer cells for immunotherapy of hepatocellular carcinoma[J]. Cancer Immunol Res, 2016, 4（7）: 574-581., articleTitle=Expanded and activated natural killer cells for immunotherapy of hepatocellular carcinoma, refAbstract=null), Reference(id=1239232809894728615, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239222193066922880, doi=null, pmid=null, pmcid=null, year=2010, volume=115, issue=11, pageStart=2167, pageEnd=2176, url=null, language=null, rfNumber=[13], rfOrder=12, authorNames=FAURIAT C, LONG EO, LJUNGGREN HG, journalName=Blood, refType=null, unstructuredReference=FAURIAT C, LONG EO, LJUNGGREN HG, et al. Regulation of human NK-cell cytokine and chemokine production by target cell recognition[J]. Blood, 2010, 115（11）: 2167-2176., articleTitle=Regulation of human NK-cell cytokine and chemokine production by target cell recognition, refAbstract=null), Reference(id=1239232809987003306, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239222193066922880, doi=null, pmid=null, pmcid=null, year=2021, volume=12, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[14], rfOrder=13, authorNames=KUCUKSEZER UC, AKTAS CETIN E, ESEN F, journalName=Front Immunol, refType=null, unstructuredReference=KUCUKSEZER UC, AKTAS CETIN E, ESEN F, et al. The role of natural killer cells in autoimmune diseases[J].Front Immunol,2021, 12 : 622306., articleTitle=The role of natural killer cells in autoimmune diseases, refAbstract=null), Reference(id=1239232810079277999, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239222193066922880, doi=null, pmid=null, pmcid=null, year=2021, volume=70, issue=10-12, pageStart=1063, pageEnd=1073, url=null, language=null, rfNumber=[15], rfOrder=14, authorNames=FATHOLLAHI A, SAMIMI LN, AKHLAGHI M, journalName=Inflamm Res, refType=null, unstructuredReference=FATHOLLAHI A, SAMIMI LN, AKHLAGHI M, et al. The role of NK cells in rheumatoid arthritis[J]. Inflamm Res, 2021, 70（10-12）: 1063-1073., articleTitle=The role of NK cells in rheumatoid arthritis, refAbstract=null), Reference(id=1239232810188329910, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239222193066922880, doi=null, pmid=null, pmcid=null, year=2004, volume=33, issue=3, pageStart=261, pageEnd=266, url=null, language=null, rfNumber=[16], rfOrder=15, authorNames=KOEHL U, SORENSEN J, ESSER R, journalName=Blood Cell Mol Dis, refType=null, unstructuredReference=KOEHL U, SORENSEN J, ESSER R, et al. IL-2 activated NK cell immunotherapy of three children after haploidentical stem cell transplantation[J]. Blood Cell Mol Dis, 2004, 33（3）: 261-266., articleTitle=IL-2 activated NK cell immunotherapy of three children after haploidentical stem cell transplantation, refAbstract=null), Reference(id=1239232810305770424, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239222193066922880, doi=null, pmid=null, pmcid=null, year=1993, volume=165, issue=1, pageStart=21, pageEnd=30, url=null, language=null, rfNumber=[17], rfOrder=16, authorNames=VOSHOL H, DULLENS HFJ, DEN OTTER W, journalName=J Immunol Methods, refType=null, unstructuredReference=VOSHOL H, DULLENS HFJ, DEN OTTER W, et al. Human natural killer cells: a convenient purification procedure and the influence of cryopreservation on cytotoxic activity[J]. J Immunol Methods, 1993, 165（1）: 21-30., articleTitle=Human natural killer cells: a convenient purification procedure and the influence of cryopreservation on cytotoxic activity, refAbstract=null), Reference(id=1239232810381267903, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239222193066922880, doi=null, pmid=null, pmcid=null, year=1986, volume=90, issue=2, pageStart=265, pageEnd=273, url=null, language=null, rfNumber=[18], rfOrder=17, authorNames=SAEKO F, MITOSHI A, MICHIO Y, journalName=J Immunol Methods, refType=null, unstructuredReference=SAEKO F, MITOSHI A, MICHIO Y, et al. Cryopreservation of human lymphocytes for assessment of lymphocyte subsets and natural killer cytotoxicity[J]. J Immunol Methods, 1986, 90（2）:265-273., articleTitle=Cryopreservation of human lymphocytes for assessment of lymphocyte subsets and natural killer cytotoxicity, refAbstract=null), Reference(id=1239232810465153990, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239222193066922880, doi=null, pmid=null, pmcid=null, year=2019, volume=3, issue=23, pageStart=4117, pageEnd=4130, url=null, language=null, rfNumber=[19], rfOrder=18, authorNames=LI L, CHEN H, MARIN D, journalName=Blood Adv, refType=null, unstructuredReference=LI L, CHEN H, MARIN D, et al. A novel immature natural killer cell subpopulation predicts relapse after cord blood transplantation[J]. Blood Adv, 2019, 3（23）: 4117-4130., articleTitle=A novel immature natural killer cell subpopulation predicts relapse after cord blood transplantation, refAbstract=null), Reference(id=1239232810557428685, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239222193066922880, doi=null, pmid=null, pmcid=null, year=2022, volume=42, issue=6, pageStart=638, pageEnd=null, url=null, language=null, rfNumber=[20], rfOrder=19, authorNames=KOH SK, PARK J, KIM SE, journalName=Ann Lab Med, refType=null, unstructuredReference=KOH SK, PARK J, KIM SE, et al. Natural killer cell expansion and cytotoxicity differ depending on the culture medium used[J]. Ann Lab Med, 2022, 42（6）: 638., articleTitle=Natural killer cell expansion and cytotoxicity differ depending on the culture medium used, refAbstract=null), Reference(id=1239232810641314771, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239222193066922880, doi=null, pmid=null, pmcid=null, year=2020, volume=37, issue=4, pageStart=426, pageEnd=427, url=null, language=null, rfNumber=[21], rfOrder=20, authorNames=KARADIMITRIS A, journalName=Cancer Cell, refType=null, unstructuredReference=KARADIMITRIS A. Cord blood CAR-NK cells: favorable initial efficacy and toxicity but durability of clinical responses not yet clear[J]. Cancer Cell, 2020, 37（4）: 426-427., articleTitle=Cord blood CAR-NK cells: favorable initial efficacy and toxicity but durability of clinical responses not yet clear, refAbstract=null), Reference(id=1239232810771338200, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239222193066922880, doi=null, pmid=null, pmcid=null, year=2019, volume=30, issue=4, pageStart=459, pageEnd=470, url=null, language=null, rfNumber=[22], rfOrder=21, authorNames=XU C, LIU D, CHEN Z, journalName=Human Gene Ther, refType=null, unstructuredReference=XU C, LIU D, CHEN Z, et al. Umbilical cord blood-derived natural killer cells combined with bevacizumab for colorectal cancer treatment[J]. Human Gene Ther, 2019, 30（4）: 459-470., articleTitle=Umbilical cord blood-derived natural killer cells combined with bevacizumab for colorectal cancer treatment, refAbstract=null), Reference(id=1239232810859418589, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239222193066922880, doi=null, pmid=null, pmcid=null, year=2019, volume=20, issue=2, pageStart=317, pageEnd=null, url=null, language=null, rfNumber=[23], rfOrder=22, authorNames=ZHANG J, ZHENG H, DIAO Y, journalName=Int J Mol Sci, refType=null, unstructuredReference=ZHANG J, ZHENG H, DIAO Y. Natural killer cells and current applications of chimeric antigen receptor-modified NK-92 cells in tumor immunotherapy[J]. Int J Mol Sci, 2019, 20（2）: 317., articleTitle=Natural killer cells and current applications of chimeric antigen receptor-modified NK-92 cells in tumor immunotherapy, refAbstract=null), Reference(id=1239232810964276195, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239222193066922880, doi=null, pmid=null, pmcid=null, year=2016, volume=65, issue=4, pageStart=485, pageEnd=492, url=null, language=null, rfNumber=[24], rfOrder=23, authorNames=SUCK G, ODENDAHL M, NOWAKOWSKA P, journalName=Cancer Immunol Immunother, refType=null, unstructuredReference=SUCK G, ODENDAHL M, NOWAKOWSKA P, et al. NK-92: an‘off-the-shelf therapeutic’ for adoptive natural killer cell-based cancer immunotherapy[J]. Cancer Immunol Immunother, 2016,65（4）: 485-492., articleTitle=NK-92: an‘off-the-shelf therapeutic’ for adoptive natural killer cell-based cancer immunotherapy, refAbstract=null), Reference(id=1239232811069133802, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239222193066922880, doi=null, pmid=null, pmcid=null, year=2021, volume=73, issue=4, pageStart=539, pageEnd=553, url=null, language=null, rfNumber=[25], rfOrder=24, authorNames=ZHAO H, ZHOU Z, LI G, journalName=Cytotechnology, refType=null, unstructuredReference=ZHAO H, ZHOU Z, LI G, et al. An NK cell line（NK92-41BB）expressing high levels of granzyme is engineered to express the high affinity chimeric genes CD16/CAR[J]. Cytotechnology, 2021, 73（4）: 539-553., articleTitle=An NK cell line（NK92-41BB）expressing high levels of granzyme is engineered to express the high affinity chimeric genes CD16/CAR, refAbstract=null), Reference(id=1239232812545528815, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239222193066922880, doi=null, pmid=null, pmcid=null, year=2020, volume=13, issue=1, pageStart=167, pageEnd=null, url=null, language=null, rfNumber=[26], rfOrder=25, authorNames=XU J, NIU T, journalName=J Hematol Oncol, refType=null, unstructuredReference=XU J, NIU T. Natural killer cell-based immunotherapy for acute myeloid leukemia[J]. J Hematol Oncol, 2020, 13（1）: 167., articleTitle=Natural killer cell-based immunotherapy for acute myeloid leukemia, refAbstract=null), Reference(id=1239232812692329462, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239222193066922880, doi=null, pmid=null, pmcid=null, year=2023, volume=13, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[27], rfOrder=26, authorNames=YANG K, ZHAO Y, SUN G, journalName=Front Immunol, refType=null, unstructuredReference=YANG K, ZHAO Y, SUN G, et al. Clinical application and prospect of immune checkpoint inhibitors for CAR-NK cell in tumor immunotherapy[J]. Front Immunol, 2023, 13 : 1081546., articleTitle=Clinical application and prospect of immune checkpoint inhibitors for CAR-NK cell in tumor immunotherapy, refAbstract=null), Reference(id=1239232812767826936, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239222193066922880, doi=null, pmid=null, pmcid=null, year=2022, volume=13, issue=1, pageStart=482, pageEnd=null, url=null, language=null, rfNumber=[28], rfOrder=27, authorNames=KESHAVARZ A, SALEHI A, KHOSRAVI S, journalName=Stem Cell Res Ther, refType=null, unstructuredReference=KESHAVARZ A, SALEHI A, KHOSRAVI S, et al. Recent findings on chimeric antigen receptor（CAR）-engineered immune cell therapy in solid tumors and hematological malignancies[J]. Stem Cell Res Ther, 2022, 13（1）: 482., articleTitle=Recent findings on chimeric antigen receptor（CAR）-engineered immune cell therapy in solid tumors and hematological malignancies, refAbstract=null), Reference(id=1239232812864295931, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239222193066922880, doi=null, pmid=null, pmcid=null, year=2022, volume=41, issue=1, pageStart=119, pageEnd=null, url=null, language=null, rfNumber=[29], rfOrder=28, authorNames=PAN K, FARRUKH H, CHITTEPU VCSR, journalName=J Exp Clin Cancer Res, refType=null, unstructuredReference=PAN K, FARRUKH H, CHITTEPU VCSR, et al. CAR race to cancer immunotherapy: from CAR T, CAR NK to CAR macrophage therapy[J]. J Exp Clin Cancer Res, 2022, 41（1）: 119., articleTitle=CAR race to cancer immunotherapy: from CAR T, CAR NK to CAR macrophage therapy, refAbstract=null), Reference(id=1239232812935599104, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239222193066922880, doi=null, pmid=null, pmcid=null, year=2022, volume=12, issue=4, pageStart=61, pageEnd=null, url=null, language=null, rfNumber=[30], rfOrder=29, authorNames=ALBINGER N, PFEIFER R, NITSCHE M, journalName=Blood Cancer J, refType=null, unstructuredReference=ALBINGER N, PFEIFER R, NITSCHE M, et al. Primary CD33-targeting CAR-NK cells for the treatment of acute myeloid leukemia[J]. Blood Cancer J, 2022, 12（4）: 61., articleTitle=Primary CD33-targeting CAR-NK cells for the treatment of acute myeloid leukemia, refAbstract=null), Reference(id=1239232813015289860, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239222193066922880, doi=null, pmid=null, pmcid=null, year=2018, volume=11, issue=6, pageStart=549, pageEnd=559, url=null, language=null, rfNumber=[31], rfOrder=30, authorNames=BARON J, WANG ES, journalName=Expert Rev Clin Pharmacol, refType=null, unstructuredReference=BARON J, WANG ES. Gemtuzumab ozogamicin for the treatment of acute myeloid leukemia[J]. Expert Rev Clin Pharmacol, 2018,11（6）: 549-559., articleTitle=Gemtuzumab ozogamicin for the treatment of acute myeloid leukemia, refAbstract=null), Reference(id=1239232813078204424, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239222193066922880, doi=null, pmid=null, pmcid=null, year=2018, volume=8, issue=6, pageStart=1083, pageEnd=1089, url=null, language=null, rfNumber=[32], rfOrder=31, authorNames=TANG X, YANG L, LI Z, journalName=Am J Cancer Res, refType=null, unstructuredReference=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[J]. Am J Cancer Res, 2018, 8（6）: 1083-1089., articleTitle=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, refAbstract=null), Reference(id=1239232813178867722, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239222193066922880, doi=null, pmid=null, pmcid=null, year=1980, volume=77, issue=3, pageStart=1588, pageEnd=1592, url=null, language=null, rfNumber=[33], rfOrder=32, authorNames=REINHERZ EL, KUNG PC, GOLDSTEIN G, journalName=Proc Nat Acad Sci, refType=null, unstructuredReference=REINHERZ EL, KUNG PC, GOLDSTEIN G, et al. Discrete stages of human intrathymic differentiation: analysis of normal thymocytes and leukemic lymphoblasts of T-cell lineage[J]. Proc Nat Acad Sci, 1980, 77（3）: 1588-1592., articleTitle=Discrete stages of human intrathymic differentiation: analysis of normal thymocytes and leukemic lymphoblasts of T-cell lineage, refAbstract=null), Reference(id=1239232813279531024, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239222193066922880, doi=null, pmid=null, pmcid=null, year=2018, volume=19, issue=12, pageStart=3924, pageEnd=null, url=null, language=null, rfNumber=[34], rfOrder=33, authorNames=ABRAMSON HN, journalName=Int J Mol Sci, refType=null, unstructuredReference=ABRAMSON HN. Monoclonal antibodies for the treatment of multiple myeloma: an update[J]. Int J Mol Sci, 2018, 19（12）:3924., articleTitle=Monoclonal antibodies for the treatment of multiple myeloma: an update, refAbstract=null), Reference(id=1239232813376000020, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239222193066922880, doi=null, pmid=null, pmcid=null, year=2021, volume=11, issue=8, pageStart=146, pageEnd=null, url=null, language=null, rfNumber=[35], rfOrder=34, authorNames=LEIVAS A, VALERI A, CORDOBA L, journalName=Blood Cancer J, refType=null, unstructuredReference=LEIVAS A, VALERI A, CORDOBA L, et al. NKG2D-CAR-transduced natural killer cells efficiently target multiple myeloma[J]. Blood Cancer J, 2021, 11（8）: 146., articleTitle=NKG2D-CAR-transduced natural killer cells efficiently target multiple myeloma, refAbstract=null), Reference(id=1239232813468274713, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239222193066922880, doi=null, pmid=null, pmcid=null, year=2020, volume=136, issue=1, pageStart=4, pageEnd=5, url=null, language=null, rfNumber=[36], rfOrder=35, authorNames=GOODRIDGE JP, BJORDAHL R, MAHMOOD S, journalName=Blood, refType=null, unstructuredReference=GOODRIDGE JP, BJORDAHL R, MAHMOOD S, et al. FT576:multi-specific off-the-shelf CAR-NK cell therapy engineered for enhanced persistence, avoidance of self-fratricide and optimized mab combination therapy to prevent antigenic escape and elicit a deep and durable response in multiple myeloma[J]. Blood, 2020,136（1）: 4-5., articleTitle=FT576:multi-specific off-the-shelf CAR-NK cell therapy engineered for enhanced persistence, avoidance of self-fratricide and optimized mab combination therapy to prevent antigenic escape and elicit a deep and durable response in multiple myeloma, refAbstract=null), Reference(id=1239232813552160797, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239222193066922880, doi=null, pmid=null, pmcid=null, year=2019, volume=134, issue=1, pageStart=3214, pageEnd=null, url=null, language=null, rfNumber=[37], rfOrder=36, authorNames=BJORDAHL R, GAIDAROVA S, GOODRIDGE JP, journalName=Blood, refType=null, unstructuredReference=BJORDAHL R, GAIDAROVA S, GOODRIDGE JP, et al. FT576:a novel multiplexed engineered off-the-shelf natural killer cell immunotherapy for the dual-targeting of CD38 and BCMA for the treatment of multiple myeloma[J]. Blood, 2019, 134（1）: 3214., articleTitle=FT576:a novel multiplexed engineered off-the-shelf natural killer cell immunotherapy for the dual-targeting of CD38 and BCMA for the treatment of multiple myeloma, refAbstract=null), Reference(id=1239232813631852577, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239222193066922880, doi=null, pmid=null, pmcid=null, year=2021, volume=12, issue=1, pageStart=200, pageEnd=null, url=null, language=null, rfNumber=[38], rfOrder=37, authorNames=MAROFI F, RAHMAN HS, THANGAVELU L, journalName=Stem Cell Res Ther, refType=null, unstructuredReference=MAROFI F, RAHMAN HS, THANGAVELU L, et al. Renaissance of armored immune effector cells, CAR-NK cells, brings the higher hope for successful cancer therapy[J]. Stem Cell Res Ther, 2021,12（1）: 200., articleTitle=Renaissance of armored immune effector cells, CAR-NK cells, brings the higher hope for successful cancer therapy, refAbstract=null), Reference(id=1239232813770264612, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239222193066922880, doi=null, pmid=null, pmcid=null, year=2011, volume=13, issue=1, pageStart=98, pageEnd=107, url=null, language=null, rfNumber=[39], rfOrder=38, authorNames=GELLER MA, COOLEY S, JUDSON P L, journalName=Cytotherapy, refType=null, unstructuredReference=GELLER MA, COOLEY S, JUDSON P L, et al. A phase Ⅱ study of allogeneic natural killer cell therapy to treat patients with recurrent ovarian and breast cancer[J]. Cytotherapy, 2011, 13（1）: 98-107., articleTitle=A phase Ⅱ study of allogeneic natural killer cell therapy to treat patients with recurrent ovarian and breast cancer, refAbstract=null), Reference(id=1239232813841567784, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239222193066922880, doi=null, pmid=null, pmcid=null, year=2020, volume=11, issue=null, pageStart=1965, pageEnd=null, url=null, language=null, rfNumber=[40], rfOrder=39, authorNames=MORGAN MA, BUNING H, SAUER M, journalName=Front Immunol, refType=null, unstructuredReference=MORGAN MA, BUNING H, SAUER M, et al. Use of cell and genome modification technologies to generate improved “off-the-shelf” CAR T and CAR NK cells[J]. Front Immunol, 2020, 11:1965., articleTitle=Use of cell and genome modification technologies to generate improved “off-the-shelf” CAR T and CAR NK cells, refAbstract=null), Reference(id=1239232813925453868, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239222193066922880, doi=null, pmid=null, pmcid=null, year=2021, volume=118, issue=45, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[41], rfOrder=40, authorNames=WANG J, TOREGROSA-ALLEN S, ELZEY BD, journalName=Proc Nat Acad Sci, refType=null, unstructuredReference=WANG J, TOREGROSA-ALLEN S, ELZEY BD, et al. Multispecific targeting of glioblastoma with tumor microenvironment-responsive multifunctional engineered NK cells[J]. Proc Nat Acad Sci, 2021,118（45）: e2107507118., articleTitle=Multispecific targeting of glioblastoma with tumor microenvironment-responsive multifunctional engineered NK cells, refAbstract=null), Reference(id=1239232814005145650, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239222193066922880, doi=null, pmid=null, pmcid=null, year=2020, volume=10, issue=1, pageStart=2815, pageEnd=null, url=null, language=null, rfNumber=[42], rfOrder=41, authorNames=HU Z, journalName=Sci Rep, refType=null, unstructuredReference=HU Z. Tissue factor as a new target for CAR-NK cell immunotherapy of triple-negative breast cancer[J]. Sci Rep, 2020, 10（1）:2815., articleTitle=Tissue factor as a new target for CAR-NK cell immunotherapy of triple-negative breast cancer, refAbstract=null), Reference(id=1239232814089031733, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239222193066922880, doi=null, pmid=null, pmcid=null, year=2012, volume=61, issue=9, pageStart=1451, pageEnd=1461, url=null, language=null, rfNumber=[43], rfOrder=42, authorNames=SAHM C, SCHONFELD K, WELS WS, journalName=Cancer Immunol Immunother, refType=null, unstructuredReference=SAHM C, SCHONFELD 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[J].Cancer Immunol Immunother, 2012, 61（9）: 1451-1461., articleTitle=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, refAbstract=null), Reference(id=1239232814189695032, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239222193066922880, doi=null, pmid=null, pmcid=null, year=2015, volume=23, issue=2, pageStart=330, pageEnd=338, url=null, language=null, rfNumber=[44], rfOrder=43, authorNames=SCHONFELD K, SAHM C, ZHANG C, journalName=Mol Ther, refType=null, unstructuredReference=SCHONFELD K, SAHM C, ZHANG C, et al. Selective inhibition of tumor growth by clonal NK cells expressing an ErbB2/HER2-specific chimeric antigen receptor[J]. Mol Ther, 2015, 23（2）:330-338., articleTitle=Selective inhibition of tumor growth by clonal NK cells expressing an ErbB2/HER2-specific chimeric antigen receptor, refAbstract=null), Reference(id=1239232814290358331, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239222193066922880, doi=null, pmid=null, pmcid=null, year=2020, volume=524, issue=1, pageStart=96, pageEnd=102, url=null, language=null, rfNumber=[45], rfOrder=44, authorNames=CAO B, LIU M, WANG L, journalName=Biochem Biophysic Res Commun, refType=null, unstructuredReference=CAO B, LIU M, WANG L, et al. Use of chimeric antigen receptor NK-92 cells to target mesothelin in ovarian cancer[J]. Biochem Biophysic Res Commun, 2020, 524（1）: 96-102., articleTitle=Use of chimeric antigen receptor NK-92 cells to target mesothelin in ovarian cancer, refAbstract=null), Reference(id=1239232814395215934, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239222193066922880, doi=null, pmid=null, pmcid=null, year=2019, volume=20, issue=3, pageStart=660, pageEnd=null, url=null, language=null, rfNumber=[46], rfOrder=45, authorNames=KLAPDOR R, WANG S, MORGAN M, journalName=Int J Mol Sci, refType=null, unstructuredReference=KLAPDOR R, WANG S, MORGAN M, et al. Characterization of a novel third-generation anti-CD24-CAR against ovarian cancer[J].Int J Mol Sci, 2019, 20（3）: 660., articleTitle=Characterization of a novel third-generation anti-CD24-CAR against ovarian cancer, refAbstract=null), Reference(id=1239232814487490626, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239222193066922880, doi=null, pmid=null, pmcid=null, year=2021, volume=11, issue=4, pageStart=1770, pageEnd=null, url=null, language=null, rfNumber=[47], rfOrder=46, authorNames=ZHANG L, LIU M, YANG S, journalName=Am J Cancer Res, refType=null, unstructuredReference=ZHANG L, LIU M, YANG S, et al. Natural killer cells: off-the-shelf cytotherapy for cancer immunosurveillance[J]. Am J Cancer Res,2021, 11（4）: 1770., articleTitle=Natural killer cells: off-the-shelf cytotherapy for cancer immunosurveillance, refAbstract=null), Reference(id=1239232814600736837, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239222193066922880, doi=null, pmid=null, pmcid=null, year=2016, volume=39, issue=2, pageStart=90, pageEnd=100, url=null, language=null, rfNumber=[48], rfOrder=47, authorNames=van OSTAIJEN-TEN DAM MM, PRINS HJ, BOERMAN GH, journalName=J Immunother, refType=null, unstructuredReference=van OSTAIJEN-TEN DAM MM, PRINS HJ, BOERMAN GH, et al.Preparation of cytokine-activated NK cells for use in adoptive cell therapy in cancer patients: protocol optimization and therapeutic potential[J]. J Immunother, 2016, 39（2）: 90-100., articleTitle=Preparation of cytokine-activated NK cells for use in adoptive cell therapy in cancer patients: protocol optimization and therapeutic potential, refAbstract=null), Reference(id=1239232814726565961, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239222193066922880, doi=null, pmid=null, pmcid=null, year=2016, volume=18, issue=6, pageStart=754, pageEnd=759, url=null, language=null, rfNumber=[49], rfOrder=48, authorNames=DOMOGALA A, MADRIGAL JA, SAUDEMONT A, journalName=Cytotherapy, refType=null, unstructuredReference=DOMOGALA A, MADRIGAL JA, SAUDEMONT A.Cryopreservation has no effect on function of natural killer cells differentiated in vitro from umbilical cord blood CD34+ cells[J].Cytotherapy, 2016, 18（6）: 754-759., articleTitle=Cryopreservation has no effect on function of natural killer cells differentiated in vitro from umbilical cord blood CD34+ cells, refAbstract=null), Reference(id=1239232814823034957, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239222193066922880, doi=null, pmid=null, pmcid=null, year=2018, volume=39, issue=2, pageStart=167, pageEnd=176, url=null, language=null, rfNumber=[50], rfOrder=49, authorNames=HU Y, TIAN Z, ZHANG C, journalName=Acta Pharmacol Sin, refType=null, unstructuredReference=HU Y, TIAN Z, ZHANG C. Chimeric antigen receptor（CAR）-transduced natural killer cells in tumor immunotherapy[J]. Acta Pharmacol Sin, 2018, 39（2）: 167-176., articleTitle=Chimeric antigen receptor（CAR）-transduced natural killer cells in tumor immunotherapy, refAbstract=null), Reference(id=1239232814944669779, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239222193066922880, doi=null, pmid=null, pmcid=null, year=2015, volume=125, issue=5, pageStart=784, pageEnd=792, url=null, language=null, rfNumber=[51], rfOrder=50, authorNames=SHAH NN, BAIRD K, DELBROOK CP, journalName=Blood, refType=null, unstructuredReference=SHAH NN, BAIRD K, DELBROOK CP, et al. Acute GVHD in patients receiving IL-15/4-1BBL activated NK cells following T-cell-depleted stem cell transplantation[J]. Blood, 2015, 125（5）: 784-792., articleTitle=Acute GVHD in patients receiving IL-15/4-1BBL activated NK cells following T-cell-depleted stem cell transplantation, refAbstract=null), Reference(id=1239232815028555860, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239222193066922880, doi=null, pmid=null, pmcid=null, year=2015, volume=17, issue=3, pageStart=245, pageEnd=249, url=null, language=null, rfNumber=[52], rfOrder=51, authorNames=KLINGEMANN H, journalName=Cytotherapy, refType=null, unstructuredReference=KLINGEMANN H. Challenges of cancer therapy with natural killer cells[J]. Cytotherapy, 2015, 17（3）: 245-249., articleTitle=Challenges of cancer therapy with natural killer cells, refAbstract=null), Reference(id=1239232815129219157, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239222193066922880, doi=null, pmid=null, pmcid=null, year=2015, volume=6, issue=null, pageStart=266, pageEnd=null, url=null, language=null, rfNumber=[53], rfOrder=52, authorNames=CARLSTEN M, CHILDS RW, journalName=Front Immunol, refType=null, unstructuredReference=CARLSTEN M, CHILDS RW. Genetic manipulation of NK cells for cancer immunotherapy: techniques and clinical implications[J].Front Immunol, 2015, 6 : 266., articleTitle=Genetic manipulation of NK cells for cancer immunotherapy: techniques and clinical implications, refAbstract=null), Reference(id=1239232815225688151, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239222193066922880, doi=null, pmid=null, pmcid=null, year=2018, volume=18, issue=9, pageStart=559, pageEnd=574, url=null, language=null, rfNumber=[54], rfOrder=53, authorNames=CROSBY CM, KRONENBERG M, journalName=Nat Rev Immunol, refType=null, unstructuredReference=CROSBY CM, KRONENBERG M. Tissue-specific functions of invariant natural killer T cells[J]. Nat Rev Immunol, 2018, 18（9）: 559-574., articleTitle=Tissue-specific functions of invariant natural killer T cells, refAbstract=null), Reference(id=1239232815317962838, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239222193066922880, doi=null, pmid=null, pmcid=null, year=2012, volume=136, issue=3, pageStart=273, pageEnd=282, url=null, language=null, rfNumber=[55], rfOrder=54, authorNames=MALLEVAEY T, SELVANANTHAM T, journalName=Immunology, refType=null, unstructuredReference=MALLEVAEY T, SELVANANTHAM T. Strategy of lipid recognition by invariant natural killer T cells:‘one for all and all for one’[J]. Immunology, 2012, 136（3）: 273-282., articleTitle=Strategy of lipid recognition by invariant natural killer T cells:‘one for all and all for one’, refAbstract=null), Reference(id=1239232815385071704, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239222193066922880, doi=null, pmid=null, pmcid=null, year=2014, volume=124, issue=18, pageStart=2824, pageEnd=2833, url=null, language=null, rfNumber=[56], rfOrder=55, authorNames=HECZEY A, LIU D, TIAN G, journalName=Blood, refType=null, unstructuredReference=HECZEY A, LIU D, TIAN G, et al. Invariant NKT cells with chimeric antigen receptor provide a novel platform for safe and effective cancer immunotherapy[J]. Blood, 2014, 124（18）:2824-2833., articleTitle=Invariant NKT cells with chimeric antigen receptor provide a novel platform for safe and effective cancer immunotherapy, refAbstract=null), Reference(id=1239232815468957787, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239222193066922880, doi=null, pmid=null, pmcid=null, year=2017, volume=17, issue=12, pageStart=733, pageEnd=745, url=null, language=null, rfNumber=[57], rfOrder=56, authorNames=NIELSEN MM, WITHERDEN DA, HAVRAN WL, journalName=Nat Rev Immunol, refType=null, unstructuredReference=NIELSEN MM, WITHERDEN DA, HAVRAN WL. γδ T cells in homeostasis and host defence of epithelial barrier tissues[J]. Nat Rev Immunol, 2017, 17（12）: 733-745., articleTitle=γδ T cells in homeostasis and host defence of epithelial barrier tissues, refAbstract=null), Reference(id=1239232815536066654, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239222193066922880, doi=null, pmid=null, pmcid=null, year=2013, volume=191, issue=3, pageStart=1346, pageEnd=1355, url=null, language=null, rfNumber=[58], rfOrder=57, authorNames=NUSSBAUMER O, GRUENBACHER G, GANDER H, journalName=J Immunol, refType=null, unstructuredReference=NUSSBAUMER O, GRUENBACHER G, GANDER H, et al.Essential requirements of zoledronate-induced cytokine and γδ T cell proliferative responses[J]. J Immunol, 2013, 191（3）:1346-1355., articleTitle=Essential requirements of zoledronate-induced cytokine and γδ T cell proliferative responses, refAbstract=null), Reference(id=1239232815598981216, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239222193066922880, doi=null, pmid=null, pmcid=null, year=2004, volume=126, issue=4, pageStart=583, pageEnd=592, url=null, language=null, rfNumber=[59], rfOrder=58, authorNames=RISCHER M, PSCHERER S, DUWE S, journalName=Br J Haematol, refType=null, unstructuredReference=RISCHER M, PSCHERER S, DUWE S, et al. Human γδ T cells as mediators of chimaeric-receptor redirected anti-tumour immunity[J]. Br J Haematol, 2004, 126（4）: 583-592., articleTitle=Human γδ T cells as mediators of chimaeric-receptor redirected anti-tumour immunity, refAbstract=null), Reference(id=1239232817041821796, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239222193066922880, doi=null, pmid=null, pmcid=null, year=2013, volume=2, issue=12, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[60], rfOrder=59, authorNames=LONG KB, BEATTY GL, journalName=Oncoimmunology, refType=null, unstructuredReference=LONG KB, BEATTY GL. Harnessing the antitumor potential of macrophages for cancer immunotherapy[J]. Oncoimmunology,2013, 2（12）: e26860., articleTitle=Harnessing the antitumor potential of macrophages for cancer immunotherapy, refAbstract=null), Reference(id=1239232817121513574, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239222193066922880, doi=null, pmid=null, pmcid=null, year=2006, volume=66, issue=2, pageStart=605, pageEnd=612, url=null, language=null, rfNumber=[61], rfOrder=60, authorNames=LEWIS CE, POLLARD JW, journalName=Cancer Res, refType=null, unstructuredReference=LEWIS CE, POLLARD JW. Distinct role of macrophages in different tumor microenvironments[J]. Cancer Res, 2006, 66（2）:605-612., articleTitle=Distinct role of macrophages in different tumor microenvironments, refAbstract=null), Reference(id=1239232817209593958, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239222193066922880, doi=null, pmid=null, pmcid=null, year=2021, volume=11, issue=1, pageStart=45, pageEnd=58, url=null, language=null, rfNumber=[62], rfOrder=61, authorNames=DAHER M, REZVANI K, journalName=Cancer Discov, refType=null, unstructuredReference=DAHER M, 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[J]. Cancer Discov, 2021, 11（1）:45-58., articleTitle=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, refAbstract=null), Reference(id=1239232817293480041, tenantId=1146029695717560320, journalId=1205117082300743687, articleId=1239222193066922880, doi=null, pmid=null, pmcid=null, year=2017, volume=77, issue=13 Suppl, pageStart=4575, pageEnd=null, url=null, language=null, rfNumber=[63], rfOrder=62, authorNames=KLICHINSKY M, RUELLA M, SHESTOVA O, journalName=Cancer Res, refType=null, unstructuredReference=KLICHINSKY M, RUELLA M, SHESTOVA O, et al. Chimeric antigen receptor macrophages（CARMA）for adoptive cellular immunotherapy of solid tumors[J]. 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CAR-NK细胞的构建策略及其在肿瘤免疫治疗中的研究进展
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胡佳琪 , 高洁
中国新药与临床杂志 | 综述 2024,43(11): 801-808
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中国新药与临床杂志 | 综述 2024, 43(11): 801-808
CAR-NK细胞的构建策略及其在肿瘤免疫治疗中的研究进展
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胡佳琪 , 高洁
作者信息
  • 海军军医大学第一附属医院 风湿免疫科，上海　200433

    • 胡佳琪，女，硕士在读，主要从事风湿免疫疾病的研究，E-mail:

    高洁，女，副主任医师，博士，主要从事风湿免疫疾病的治疗工作，E-mail:

通讯作者:

高洁
Construction strategy of CAR-NK cells and its research progress in tumor immunotherapy
Jia-qi HU , Jie GAO
Affiliations
  • Rheumatology and Immunology Department, the First Affiliated Hospital of Naval Medical University, SHANGHAI 200433,China
出版时间: 2024-11-25 doi: 10.14109/j.cnki.xyylc.2024.11.01
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嵌合抗原受体（CAR）- T细胞疗法改变了传统血液系统恶性肿瘤的治疗方法，显示出显著疗效。然而，CAR-T细胞因制作周期长、价格高昂和细胞因子释放综合征等副作用的限制，无法在临床广泛应用。自然杀伤（NK）细胞是机体固有免疫反应的重要组成部分，与CAR-T细胞相比，CAR-NK细胞的神经毒性、细胞因子释放综合征及引起移植物抗宿主病的概率均显著降低。临床前研究和临床试验证明了CAR-NK细胞疗法治疗恶性肿瘤的安全性和可行性，正逐渐成为肿瘤免疫治疗的研究热点，但也存在一些亟需解决的问题，仍需进一步优化构建策略以实现临床转化。本文综合国内外最新的研究成果，对CAR-NK细胞构建策略及其在肿瘤免疫治疗领域的研究进展作一综述，以期为NK细胞在恶性肿瘤治疗中的应用提供有价值的参考。

嵌合抗原受体  /  自然杀伤细胞  /  血液肿瘤  /  实体瘤  /  免疫治疗

Chimeric antigen receptor（CAR）- T cell therapy has changed the traditional treatment of hematological malignancies and has shown significant efficacy. However, the clinical application of CAR-T cells is limited by long production cycle, high price, and side effects such as cytokine storm, so it can not be widely used in clinical practice. Natural killer（NK）cells are an important part of the body’s innate immune response. Compared with CAR-T cells, CAR-NK cells can significantly reduce the probability of neurotoxicity, cytokine storm, and graft versus host diseases. CAR-NK cell therapy is gradually becoming a research hotspot, but there are still some urgent problems to be solved, and further optimization of the construction strategy is needed to achieve its clinical translation. This paper will review the construction strategy and the research progress in tumor immunotherapy based on the latest literatures at home and abroad, in order to provide valuable reference for application of NK cells in the treatment of malignant tumors.

chimeric antigen receptor  /  natural killer cell  /  hematologic meoplasms  /  solid tumor  /  immunotherapy
胡佳琪, 高洁. CAR-NK细胞的构建策略及其在肿瘤免疫治疗中的研究进展. 中国新药与临床杂志, 2024 , 43 (11) : 801 -808 . DOI: 10.14109/j.cnki.xyylc.2024.11.01
Jia-qi HU, Jie GAO. Construction strategy of CAR-NK cells and its research progress in tumor immunotherapy[J]. Chinese Journal of New Drugs and Clinical Remedies, 2024 , 43 (11) : 801 -808 . DOI: 10.14109/j.cnki.xyylc.2024.11.01
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肿瘤免疫疗法是指通过调控机体自身的免疫系统，增强对肿瘤细胞的识别和杀伤能力，从而达到控制甚至特异性清除肿瘤细胞的目的，主要包括免疫检查点抑制剂治疗、过继性细胞免疫治疗、癌症疫苗等。目前，在肿瘤免疫疗法中研究最广泛的是嵌合抗原受体（chimeric antigen receptor，CAR）- T细胞疗法。美国食品和药物管理局（FDA）已经批准了多项CAR-T产品用于血液系统恶性肿瘤和实体瘤的治疗[1]，但CAR-T细胞疗法因为制备周期长、价格高昂而无法得到广泛应用，同时抗原逃逸、细胞因子释放综合征（cytokine release syndrome, CRS）、神经毒性等副作用也是不容忽视的问题[2]。与T细胞不同，自然杀伤（natural killer, NK）细胞来源广泛，寿命相对较短，且在同种异体环境下引起移植物抗宿主病（graft versus host disease, GVHD）的风险较低[3]，临床前研究和临床试验均已证明了CAR-NK细胞疗法治疗恶性肿瘤的安全性和可行性[4]。CAR-NK细胞疗法具有广阔的前景和研究价值，正逐渐成为肿瘤免疫疗法的研究新热点。
CAR-NK细胞的构建
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1　CAR的结构
CAR通常由胞外抗原结合域、铰链区、跨膜结构域和胞内信号结构域组成[5]。抗原结合域是由抗体重链可变区和轻链可变区通过连接子连接形成的单链抗体，决定CAR-NK细胞结构的特异性；铰链区通常来源于CD8、CD28和免疫球蛋白G（IgG），与靶抗原的间隔区相结合，铰链区的长度由目标抗原的位置决定，靠近细胞膜的抗原需要较长的铰链，暴露于细胞表面的抗原则需要较短的铰链；跨膜结构域介导CAR与免疫细胞膜相结合，影响CAR的表达、稳定性及信号转导；胞内信号结构域转导信号激活免疫细胞。第一代CAR-NK细胞和CAR-T细胞一样，仅含有CD3 ζ信号结构域；为了提高抗肿瘤活性，第二代CAR-T细胞增加了CD28和4-1BB（CD137）共刺激域[6]（图1）。FDA批准的axicabtagene ciloleucel（axi-cel）和brexucabtagene autoleucel（brexu-cel）两种CAR-T细胞疗法，均靶向CD19阳性的肿瘤细胞，且均包含CD28共刺激域，可增强T细胞的激活能力和持久性。临床前研究证实，其他胞内共刺激域如OX40、CD27和诱导型T细胞共刺激分子对CAR抗肿瘤作用的增效与CD28和4-1BB结构域相当。研究表明，CD27共刺激域比CD28共刺激域更能增强CAR-T细胞在体内的维持时间[7]。共刺激域通常来自CD28家族（CD28、诱导型T细胞共刺激分子）、肿瘤坏死因子受体家族（4-1BB、OX40、CD27）和淋巴细胞激活分子相关受体家族（2B4）[8]。CD3 ζ含有3个免疫受体酪氨酸激活基序，可以与NKp46、NKp30结合，参与NK细胞受体信号转导的激活过程。衔接蛋白DNAX激活蛋白12（DAP12）只含有1个免疫受体酪氨酸激活基序，能够结合脾酪氨酸激酶和Zeta链相关蛋白激酶70（ZAP70），为NK细胞抗肿瘤活性提供可替代信号通路。相较于含有CD3 ζ的NKG2DCAR-NK细胞，含DAP12的NKG2D CAR-NK细胞含有更多的干扰素-γ（IFN-γ）和更强的细胞毒性[9]。因此，含有DAP12信号域的CAR提高了NK细胞的抗肿瘤活性和特异性。此外，2B4、NKG2D也能调节NK细胞的细胞毒性，并促进细胞因子分泌过程。
2　NK细胞的来源
NK细胞主要存在于骨髓、外周血、肝脏、脾脏、肺和淋巴结中。NK细胞是先天性免疫细胞，能够迅速识别和杀死异常细胞、肿瘤细胞和病毒感染细胞。与T细胞不同，NK细胞不会诱发GVHD。随着基因改造技术的发展，NK细胞可以被进一步引入CAR和敲除抑制基因技术。目前，用于CAR基因工程的NK细胞主要来源于外周血单个核细胞（peripheral blood monocytes，PBMC）、脐带血（umbilical cord blood, UCB）单个核细胞、诱导多能干细胞（induced pluripotent stem cells，iPSC）和NK细胞系。
2.1　PBMC
PBMC是NK细胞的主要来源之一，具有易于体外扩增、无毒副作用等优点。由于NK细胞可以相对容易地从自体或同种异体PBMC中分离得到，因此大多数临床前研究使用的CAR-NK细胞都来自于外周血。PBMC来源的NK（PBMC-NK）细胞占循环淋巴细胞的10%~15%，由于NK细胞的分离、筛选过程较昂贵，因此需要通过体外扩增以增加NK细胞的表达水平。传统使用细胞因子白细胞介素（IL）-2、IL-12或IL-18与PBMC-NK细胞联合培养，可以实现PBMC-NK细胞的体外扩增并同时降低细胞毒性[10]，但扩增后表达的NK细胞与内皮细胞接触时，倾向于诱导细胞凋亡。研究发现[11]，使用IL-15扩增的NK细胞不仅避免了诱导细胞凋亡的倾向，而且可以促进NK细胞的生存及进一步扩增。KAMIYA等[12]使用人工抗原提呈细胞（artifical antigen-presenting cells, aAPCs）体外激活和扩增NK细胞，可在不到2周的时间内将PBMC-NK细胞扩增500~1 000倍。NK细胞的主要亚群根据细胞表面密度表达量被确定为CD56和CD16。在生理条件下，90%的PBMC-NK细胞表达CD56dimCD16+，CD56dim NK细胞是细胞毒性群体，除了具有溶解细胞的能力外，还可在受体介导下快速释放细胞因子。10%的PBMC-NK细胞表达CD56brightCD16-/dim，表达高亲和力的CD25、NKp44和CD117/C-kit[13]。与CD56bright相比，CD56dim NK细胞主要靶向于肿瘤细胞、病毒感染细胞和寄生虫，杀伤性更高，这些细胞启动、参与适应性免疫反应，并且对类风湿关节炎也表现出良好的治疗作用[14,15]。研究发现，将IL-2刺激的高浓缩半相合NK细胞输注入急性髓系白血病（AML）和急性淋巴细胞白血病患儿体内，结果显示无GVHD且对NK细胞治疗耐受性良好，所有患者1个月内达到完全缓解。这项试验初步表明，根据药品生产质量管理规范（good manufacturing practices, GMP）标准从外周血中分离并扩增的NK细胞在临床应用中具有可行性[16]。主要缺点是冷冻成熟的PBMC-NK细胞会显著降低其生存能力和细胞毒性，这不仅增加了运输难度，也限制了其成为“现货型”治疗的应用[17,18]。
2.2　UCB来源的NK（UCB-NK）细胞
UCB-NK细胞约占脐带血淋巴细胞的15%~30%，显著高于外周血中NK细胞占比，第一个CAR-NK细胞临床试验使用的NK细胞即来源于脐带血。与PBMC-NK细胞相比，UCB-NK细胞被认为是具有更年轻且更具增殖性的表型，但杀伤活性较低。UCB-NK细胞中的T细胞大部分是未成熟的T细胞，这就降低了GVHD的发生率。除此之外，UCB-NK细胞中调控细胞周期和增殖的基因水平更高，在维持细胞的增殖能力和持久性方面具有更高的潜能[19]。但是，UCB-NK细胞用于免疫治疗的主要局限性在于单个UCB单位的NK细胞数量相对较少，同时UCB的体积有限，因此建立高效的扩增方法以获得足够数量的NK细胞用于UCB-NK细胞免疫治疗至关重要[20]。NK细胞不受主要组织相容性复合体（major histocompatibility complex, MHC）限制，因此可以改造开发异体来源的NK细胞进行“现货型”CAR-NK细胞治疗。尽管目前只有少数CAR-NK细胞临床前研究使用UCB-NK细胞，但其抗肿瘤活性已在临床试验中得到证实[21,22]。
2.3　iPSC来源的NK（iPSC-NK）细胞
iPSC-NK细胞具有自我更新和无限增殖的潜能，同时也更易于规模生产，因此越来越引起研究者的关注，成为CAR-NK细胞产品的理想来源。利用iPSC技术“特制”的NK细胞可用于多个患者，仅单一攻击特定肿瘤细胞，对除肿瘤细胞以外的其他细胞风险较低，在体内的存活时间更短，所以副作用相对较小。考虑到iPSC-NK细胞上述属性，2018年美国FDA批准了第一个iPSC-NK细胞免疫疗法FT500用于临床研究。2022年，我国批准了首个iPSC来源细胞治疗产品的临床试验申请。在生物制药行业，iPSC-NK细胞被用于治疗肿瘤和自身免疫疾病的多项临床研究正在进行中。与PBMC-NK细胞相比，iPSC-NK细胞的生产为基因修饰提供了更有效的手段。
2.4　NK细胞系
NK细胞系主要包括NK-92、NKG、NKL、KHYG1、YT等。迄今为止，大多数CAR-NK细胞的研究都是基于NK-92细胞系开展的。NK-92是一种成熟的NK细胞系，来源于1例50岁男性非霍奇金淋巴瘤患者的外周血，可以在体外无限增殖，并且对冻融敏感性较低，因此被广泛用于CAR-NK细胞的生产[23]。由于NK-92细胞系来源于恶性淋巴瘤患者，有引起继发性肿瘤的风险，因此在植入患者体内之前必须接受辐照以防止其永久植入。NK-92细胞系还有一个主要优势是无需病毒介导即可进行基因改造[24]。此外，NK-92细胞系的细胞毒性依赖于外源性IL-2，并且不表达抗体依赖细胞介导的细胞毒性（antibody-dependent cell-mediated cytotoxicity，ADCC）所需的CD16受体，因此，NK-92细胞系无法通过ADCC实现细胞杀伤[25]。值得关注的是，IL-2依赖于NK-92细胞系和人恶性非霍奇金淋巴瘤患者NK细胞（NK-92MI）衍生物在淋巴细胞倍增的条件下表现出易于扩增、培养和激活的显著优势，同时输注后对AML细胞显示出持续、可靠的细胞毒性[26]。
CAR-NK细胞研究现状
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近年来，CAR-T细胞在血液肿瘤和实体瘤的临床治疗中取得了卓有成效的进展，但同时也出现了CRS、神经毒性和GVHD等副作用。与CAR-T细胞免疫治疗相比，CD19-CAR-NK细胞在对抗造血淋巴系统的恶性肿瘤方面有其独特的优势，主要归功于临床批准的第二代CAR-NK细胞通常包含CD3ζ结构域，与4-1BB和CD28共刺激结构域结合，从而显示出治疗非霍奇金淋巴瘤和慢性淋巴细胞白血病的突出有效性[27,28]。与活化T细胞释放的细胞因子（IL-1、IL-2、IL-6、IL-15）相比，激活的NK细胞产生IFN-γ和IFN-α，从而诱导CRS和严重神经毒性的倾向性要低得多，无需基因编辑即可实现异体回输，且不会产生GVHD。同时，NK细胞不受MHC的限制，可以将异体来源的NK细胞用于“现货型”CAR-NK细胞治疗，具有广阔的治疗前景和研究价值[29]。
1　治疗AML
AML是一种源自肿瘤髓系祖细胞的血液系统恶性疾病，主要特征是外周血或骨髓细胞中未分化的髓母细胞克隆性增殖。过去几十年，AML的治疗进展有限，标准的前期治疗仍是阿糖胞苷和蒽环类药物为基础的强化治疗。除此之外，同种异体造血干细胞移植是目前AML最有效的治疗方法，但对于器官衰竭、感染和老年患者，同种异体造血干细胞移植往往不能彻底清除肿瘤细胞，且存在诱发GVHD的风险[30]。CD33在80%以上AML患者的髓系细胞和原始粒细胞中表达。2017年，美国FDA批准吉妥珠单抗（gemtuzumab ozogamicin，GO）用于AML的治疗。GO是由靶向CD33的单克隆抗体与卡奇霉素衍生物连接而成的抗体偶联药物。研究发现，靶向CD33并载有卡奇霉素的GO进入细胞核，与DNA结合并诱导DNA双链的断裂，导致细胞周期阻滞和细胞凋亡[31]。靶向CD33的CAR-T细胞和CAR-NK细胞治疗也显示出了治疗AML的潜力。与CD33-CAR-T细胞相比，CD33-CAR-NK-92细胞具有更短的生命周期，更低的细胞毒性，同时对AML细胞也更具杀伤力。临床研究证明，CD33-CAR-NK-92细胞在治疗复发性或难治性AML中具有安全性和可行性。2018年，TANG等[32]通过在CD33单链可变片段（ScFV）和CD28之间插入Fc片段，构建包含CD28和4-1BB共刺激分子的第三代CAR结构CD33-CD28-4-1BB-CAR。与亲代NK-92细胞相比，CAR-NK-92细胞对人急性早幼粒白血病细胞（HL-60）的细胞毒性更强。在临床试验（NCT02944162）中，3例难治性/复发性AML患者被输注钴-60辐照（10Gy）CAR-NK-92细胞，这也是首次利用CAR-NK-92细胞治疗难治性/复发性AML的临床研究。值得关注的是，当每位患者输入高达5×109个细胞时，未观察到任何明显的不良反应。除此之外，KOH等[20]通过狒狒包膜伪型慢病毒载体（BaEV-LV）慢病毒感染PB-UK，构建靶向CD33的CAR-NK，在人AML细胞系OCI-AML2异种移植小鼠模型中，CD33-CAR-NK细胞清除了所有移植的骨髓和脾脏细胞，以及大部分AML细胞，却并未检测到任何副作用。除了CD33以外，CD123也可作为治疗AML的可行性靶点之一，并且CD123更易获得也更具抗肿瘤活性。
2　治疗多发性骨髓瘤
多发性骨髓瘤是以骨髓中浆细胞恶性增殖为特点的血液系统恶性肿瘤，伴有单克隆抗体免疫球蛋白和轻链蛋白的过度表达。1980年，REINHERZ等[33]首次在人类淋巴细胞表面发现了CD38，它是一种跨膜糖蛋白，广泛表达于多发性骨髓瘤细胞中以及一些调节性T细胞和NK细胞中。研究者针对多发性骨髓瘤细胞表面高表达的CD38开发了抗CD38抗体。2015年，美国FDA首次批准达雷妥尤单抗用于多发性骨髓瘤的治疗，CD38通过促进二磷酸腺苷核糖基化的产生和细胞内Ca2+的动员，在NK细胞中发挥重要作用[34]。除了CD38以外，CD138和CD319也是治疗多发性骨髓瘤的潜在靶点，CD138是诊断多发性骨髓瘤的主要标志物，CD319是治疗多发性骨髓瘤的安全性靶点。LEIVAS等[35]通过自体携带的NK细胞构建NKG2D-CAR-NKAE，证实了其治疗多发性骨髓瘤的安全性和可行性，并在150 d内未观察到任何GVHD或治疗相关毒性，同时NKG2D-CAR转导还增强了体外和体内抗肿瘤活性。FT-576细胞是一种来自iPSC的CAR-NK细胞类型，其表面均表达CD16、B细胞成熟抗原和IL-15受体α融合蛋白。临床试验表明，在治疗多发性骨髓瘤中，FT-576细胞增强了细胞毒性并且防止了B细胞成熟抗原丢失[36,37]。
3　治疗实体瘤
近年来，CAR-T细胞免疫疗法在血液系统恶性肿瘤中已经表现出令人惊喜的疗效，但在治疗转移性实体瘤中仍存在相当大的局限性，包括有限的肿瘤浸润能力、免疫抑制肿瘤微环境的存在以及明显的不良反应[38-40]。由于CAR-NK细胞治疗血液系统恶性肿瘤的可行性被广泛证实，因此越来越多的临床前研究建立了不同的CAR-NK细胞结构，并在胶质母细胞瘤、乳腺癌和卵巢癌等癌种中进行了研究，证实了其安全性和有效性。
3.1　治疗胶质母细胞瘤
CAR-NK细胞在胶质母细胞瘤治疗中获得了广泛的临床前数据。临床前研究表明，胶质母细胞瘤的肿瘤微环境异质性较大，每个已知的胶质母细胞瘤亚型均显示出与细胞可塑性相关的分子、遗传和表观遗传特征，因此胶质母细胞瘤的肿瘤微环境异质性是其治疗中亟需克服的障碍。WANG等[41]通过将靶向双唾液酸神经节苷酯（GD）2的双功能CAR与NKG2D配体和局部触发释放的CD73阻断抗体片段结合到一个单基因改造的NK细胞中，同时解决了与胶质母细胞瘤免疫耐药性相关的3个关键问题，即免疫逃逸、代谢重编程和免疫细胞浸润不良。在此基础上，研究者根据CAR-T细胞疗法治疗胶质母细胞瘤的弊端，发现可利用同时靶向突变型和野生型表皮生长因子受体（EGFR）的双特异性CAR构建转导的CAR-NK细胞疗法来避免CAR-T细胞疗法的不足。同时，临床前研究也证实改造后的CAR-NK细胞疗法可有效延长胶质母细胞瘤异体种植小鼠模型的存活时间。
3.2　治疗乳腺癌
尽管手术、化疗、放疗、内分泌治疗和分子靶向治疗在乳腺癌治疗中已经取得了重大进展，但乳腺癌仍然是女性癌症死亡的主要原因之一。在体内和体外模型中证明了针对几种不同抗原的CAR-NK细胞对乳腺癌均有效，组织因子在50%~85%的三阴性乳腺癌患者中存在，所以被选为CAR-NK的适当靶点之一，组织因子靶向的CD28-4-1BB-CD3ζ-CAR结构被转导到NK-92MI细胞内，在肿瘤衍生的异种移植模型中，改造后的CAR-NK细胞对表达组织因子的乳腺癌表现出显著的抗肿瘤活性[42]。在表达上皮细胞黏附分子（EpCAM）的乳腺癌中，靶向EpCAM的CAR和IL-15的NK-92细胞比未修饰的NK-92细胞表现了优越的选择性和细胞毒性[43]。同样，人表皮生长因子受体2（HER2）也是乳腺癌的理想靶点之一，由NK-92细胞表达的HER2导向的CD28-CD3ζ-CAR在体内、体外均表现出抗肿瘤活性[44]。
3.3　治疗卵巢癌
多项研究分析了CAR-NK细胞疗法在卵巢癌模型中的有效性。间皮素介导的CAR-NK-92细胞在构建的卵巢癌小鼠模型中能够选择性清除间皮素表达阳性的卵巢癌细胞（OVCAR-3和SKOV-3），而不是间皮素表达阴性的细胞（SK-HEP-1），并同时延长了小鼠的生存期。靶向叶酸受体α（FRα）的CAR-NK-92细胞系在卵巢癌中也显示出显著的抗肿瘤活性，在异体移植小鼠模型中，FRα-CD28-4-1BB-CD3ζ-CAR-NK细胞显著延长了存活时间[45,46]。
CAR-NK细胞免疫治疗针对不同实体瘤及不同靶抗原构建了不同的基本框架，临床前数据也表明CAR-NK细胞疗法在未来有巨大的潜力，但同时，NK细胞用于实体瘤的治疗仍然受到多方面限制，优化CAR-NK的基因编辑技术、实现NK细胞的有效扩增以及提高肿瘤微环境的持久性是亟待解决的问题。
CAR-NK细胞疗法在临床应用中的挑战
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尽管CAR-NK细胞疗法在治疗血液系统恶性肿瘤和实体瘤中具有显著优势，但目前仍处于临床研究阶段[47]，在临床应用仍存在一些局限性。首先，CAR-NK细胞在体内存活的时间相对较短。其次，NK细胞对冻融过程很敏感，其存活率和细胞毒性在冻融之后都显著降低，进一步研究发现在冻存复苏后外源性添加IL-2等细胞因子可以再次激活NK细胞功能[48,49]。再次，目前CAR-NK细胞的转染方式主要是病毒转染和非病毒转染，病毒转染效率很高，但有诱发随机插入突变的风险，慢病毒转染可以避免诱发突变的风险，但转染效率较低，因此CAR-NK细胞的转染方式仍有待改进[50]。最后，异体NK细胞可能被T细胞污染而导致GVHD和淋巴细胞增殖性疾病的发生，异体NK细胞也可能影响调节性T细胞和骨髓源性抑制细胞的正常功能，不利于CAR-NK细胞治疗发挥作用[51-53]。
NK细胞可替代类型
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NK细胞已经成为CAR疗法的研究热点，其他细胞群体同样具有其特殊优势，多项研究正在进行，以探索新免疫细胞的可行性，这将增加CAR细胞免疫疗法的细胞谱系。
1　iNKT细胞
iNKT细胞是具有先天性免疫和适应性免疫特征的特异性T细胞，可以与暴露出的抗原迅速反应，也可以适应性细胞的方式精准识别抗原。与传统T细胞不同的是，iNKT细胞的T细胞抗原受体（T cell receptor, TCR）由CD1d呈递脂质抗原识别。除此之外，iNKT细胞还可被多种与先天性免疫细胞类似的细胞因子受体激活[54]。因此，iNKT细胞在肿瘤免疫微环境中，通过识别内源性脂质感知组织完整性被破坏，通过直接分泌细胞因子，间接介导抗肿瘤活性，调节恶劣环境中其他免疫细胞，辅助机体免疫反应[55]。iNKT细胞的另一个优势是不会产生GVHD，使其成为异体细胞治疗的一个良好的选择。HECZEY等[56]研究发现，用抗GD2-CAR改造自体iNKT细胞转导含CD28-41BB ζ的第三代膜内区，在转移性神经母细胞瘤小鼠模型中表现出很强的抗肿瘤活性，且没有发生GVHD。
2　γδ T细胞
γδ T细胞占循环T细胞的1%~5%，是连接先天性免疫和适应性免疫应答的主要淋巴细胞。γδ TCR以不依赖MHC的方式识别靶抗原，唑来膦酸由于可以干扰胆固醇合成，导致异戊基焦磷酸积累，从而促进PBMC中γδ T细胞的扩增[57,58]。这一独特功能使γδ T细胞成为CAR工程的潜在治疗细胞。研究人员利用唑来膦酸从外周血扩增γ9δ2 T细胞，以抗GD2和抗CD19第一代CAR的逆转录病毒载体转导γ9δ2 T细胞，转导的γ9δ2 T细胞在体外对尤文肉瘤细胞和CD19+B细胞肿瘤细胞系表现出显著的抗肿瘤活性[59]。
3　巨噬细胞
与T细胞及其他免疫效应细胞不同的是，巨噬细胞能够迅速穿透实体肿瘤以应对肿瘤来源的趋化因子，如集落刺激因子、血管内皮生长因子、CC趋化因子配体2、巨噬细胞炎性蛋白1-α等。巨噬细胞可以用包含CD3 ζ胞内结构域的CAR来激活其特异性抗肿瘤活性[60,61]。研究者用腺病毒载体Ad5f35转导巨噬细胞的CAR，结果表明可以使巨噬细胞极化为M1型免疫促炎表型，而非极化为M2型免疫抗炎表型[62]。在卵巢癌小鼠模型中，与注射空载的巨噬细胞小鼠相比，用靶向HER2的嵌合抗原受体巨噬细胞（CAR-iMac）治疗异体移植小鼠，具有更好的抗肿瘤活性和更高的生存率[63]。
小结与展望
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CAR基因工程的出现是癌症免疫治疗的突破，尤其针对B细胞恶性肿瘤。CAR-T细胞疗法在治疗血液系统恶性肿瘤和实体瘤中取得了一定成效，但由于神经毒性、GVHD等严重不良反应，目前肿瘤细胞免疫治疗的研究重点已经从CAR-T细胞治疗转移到CAR-NK细胞治疗。临床前研究及临床试验结果表明，CAR-NK细胞疗法在安全性、可行性及疗效方面均较CAR-T细胞疗法更具优势。目前对CAR-NK细胞疗法的研究仍处于起步阶段，要将其成功运用到临床，还需要进一步优化CAR-NK细胞的构建策略，深入研究其疗效及可能的不良反应。期望在不久的将来，随着理论知识进一步完善，CAR-NK细胞疗法能成为对抗恶性肿瘤强有力的武器，使更多肿瘤患者从治疗中获益。
基金
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  • 上海市卫生健康委员会临床科研项目(202340061)
  • 海军军医大学第一附属医院基础研究面上培育项目(2023PY40)
文献
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参考文献 引证文献
排序方式：
[1]
AMINI L, SILBERT SK, MAUDE SL, et al. Preparing for CAR T cell therapy: patient selection, bridging therapies and lymphodepletion[J]. Nat Rev Clin Oncol, 2022, 19（5）: 342-355.
[2]
STERNER RC, STERNER RM. CAR-T cell therapy: current limitations and potential strategies[J]. Blood Cancer J, 2021, 11（4）: 69.
[3]
LIM O, JUNG MY, HWANG YK, et al. Present and future of allogeneic natural killer cell therapy[J]. Front Immunol, 2015, 6 :286.
[4]
WANG L, DOU M, MA Q, et al. Chimeric antigen receptor（CAR）-modified NK cells against cancer: opportunities and challenges[J]. Int Immunopharmacol, 2019, 74 : 105695.
[5]
YILMAZ A, CUI H, CALIGIURI MA, et al. Chimeric antigen receptor-engineered natural killer cells for cancer immunotherapy[J]. J Hematol Oncol, 2020, 13 : 1-22.
[6]
IMAI C, IWAMOTO S, CAMPANA D. Genetic modification of primary natural killer cells overcomes inhibitory signals and induces specific killing of leukemic cells[J]. Blood, 2005, 106（1）: 376-383.
[7]
SONG DG, YE Q, POUSSIN M, et al. CD27 costimulation augments the survival and antitumor activity of redirected human T cells in vivo[J]. Blood, 2012, 119（3）: 696-706.
[8]
MACKAY M, AFSHINNEKOO E, RUB J, et al. The therapeutic landscape for cells engineered with chimeric antigen receptors[J].Nat Biotechnol, 2020, 38（2）: 233-244.
[9]
XIAO L, CEN D, GAN H, et al. Adoptive transfer of NKG2D CAR mRNA-engineered natural killer cells in colorectal cancer patients[J]. Mol Ther, 2019, 27（6）: 1114-1125.
[10]
GRANZIN M, WAGNER J, KOHL U, et al. Shaping of natural killer cell antitumor activity by ex vivo cultivation[J]. Front Immunol,2017, 8: 458.
[11]
WALDMANN TA, DUBOIS S, TAGAYA Y. Contrasting roles of IL-2 and IL-15 in the life and death of lymphocytes: implications for immunotherapy[J]. Immunity, 2001, 14（2）: 105-110.
[12]
KAMIYA T, CHANG YH, CAMPANA D. Expanded and activated natural killer cells for immunotherapy of hepatocellular carcinoma[J]. Cancer Immunol Res, 2016, 4（7）: 574-581.
[13]
FAURIAT C, LONG EO, LJUNGGREN HG, et al. Regulation of human NK-cell cytokine and chemokine production by target cell recognition[J]. Blood, 2010, 115（11）: 2167-2176.
[14]
KUCUKSEZER UC, AKTAS CETIN E, ESEN F, et al. The role of natural killer cells in autoimmune diseases[J].Front Immunol,2021, 12 : 622306.
[15]
FATHOLLAHI A, SAMIMI LN, AKHLAGHI M, et al. The role of NK cells in rheumatoid arthritis[J]. Inflamm Res, 2021, 70（10-12）: 1063-1073.
[16]
KOEHL U, SORENSEN J, ESSER R, et al. IL-2 activated NK cell immunotherapy of three children after haploidentical stem cell transplantation[J]. Blood Cell Mol Dis, 2004, 33（3）: 261-266.
[17]
VOSHOL H, DULLENS HFJ, DEN OTTER W, et al. Human natural killer cells: a convenient purification procedure and the influence of cryopreservation on cytotoxic activity[J]. J Immunol Methods, 1993, 165（1）: 21-30.
[18]
SAEKO F, MITOSHI A, MICHIO Y, et al. Cryopreservation of human lymphocytes for assessment of lymphocyte subsets and natural killer cytotoxicity[J]. J Immunol Methods, 1986, 90（2）:265-273.
[19]
LI L, CHEN H, MARIN D, et al. A novel immature natural killer cell subpopulation predicts relapse after cord blood transplantation[J]. Blood Adv, 2019, 3（23）: 4117-4130.
[20]
KOH SK, PARK J, KIM SE, et al. Natural killer cell expansion and cytotoxicity differ depending on the culture medium used[J]. Ann Lab Med, 2022, 42（6）: 638.
[21]
KARADIMITRIS A. Cord blood CAR-NK cells: favorable initial efficacy and toxicity but durability of clinical responses not yet clear[J]. Cancer Cell, 2020, 37（4）: 426-427.
[22]
XU C, LIU D, CHEN Z, et al. Umbilical cord blood-derived natural killer cells combined with bevacizumab for colorectal cancer treatment[J]. Human Gene Ther, 2019, 30（4）: 459-470.
[23]
ZHANG J, ZHENG H, DIAO Y. Natural killer cells and current applications of chimeric antigen receptor-modified NK-92 cells in tumor immunotherapy[J]. Int J Mol Sci, 2019, 20（2）: 317.
[24]
SUCK G, ODENDAHL M, NOWAKOWSKA P, et al. NK-92: an‘off-the-shelf therapeutic’ for adoptive natural killer cell-based cancer immunotherapy[J]. Cancer Immunol Immunother, 2016,65（4）: 485-492.
[25]
ZHAO H, ZHOU Z, LI G, et al. An NK cell line（NK92-41BB）expressing high levels of granzyme is engineered to express the high affinity chimeric genes CD16/CAR[J]. Cytotechnology, 2021, 73（4）: 539-553.
[26]
XU J, NIU T. Natural killer cell-based immunotherapy for acute myeloid leukemia[J]. J Hematol Oncol, 2020, 13（1）: 167.
[27]
YANG K, ZHAO Y, SUN G, et al. Clinical application and prospect of immune checkpoint inhibitors for CAR-NK cell in tumor immunotherapy[J]. Front Immunol, 2023, 13 : 1081546.
[28]
KESHAVARZ A, SALEHI A, KHOSRAVI S, et al. Recent findings on chimeric antigen receptor（CAR）-engineered immune cell therapy in solid tumors and hematological malignancies[J]. Stem Cell Res Ther, 2022, 13（1）: 482.
[29]
PAN K, FARRUKH H, CHITTEPU VCSR, et al. CAR race to cancer immunotherapy: from CAR T, CAR NK to CAR macrophage therapy[J]. J Exp Clin Cancer Res, 2022, 41（1）: 119.
[30]
ALBINGER N, PFEIFER R, NITSCHE M, et al. Primary CD33-targeting CAR-NK cells for the treatment of acute myeloid leukemia[J]. Blood Cancer J, 2022, 12（4）: 61.
[31]
BARON J, WANG ES. Gemtuzumab ozogamicin for the treatment of acute myeloid leukemia[J]. Expert Rev Clin Pharmacol, 2018,11（6）: 549-559.
[32]
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[J]. Am J Cancer Res, 2018, 8（6）: 1083-1089.
[33]
REINHERZ EL, KUNG PC, GOLDSTEIN G, et al. Discrete stages of human intrathymic differentiation: analysis of normal thymocytes and leukemic lymphoblasts of T-cell lineage[J]. Proc Nat Acad Sci, 1980, 77（3）: 1588-1592.
[34]
ABRAMSON HN. Monoclonal antibodies for the treatment of multiple myeloma: an update[J]. Int J Mol Sci, 2018, 19（12）:3924.
[35]
LEIVAS A, VALERI A, CORDOBA L, et al. NKG2D-CAR-transduced natural killer cells efficiently target multiple myeloma[J]. Blood Cancer J, 2021, 11（8）: 146.
[36]
GOODRIDGE JP, BJORDAHL R, MAHMOOD S, et al. FT576:multi-specific off-the-shelf CAR-NK cell therapy engineered for enhanced persistence, avoidance of self-fratricide and optimized mab combination therapy to prevent antigenic escape and elicit a deep and durable response in multiple myeloma[J]. Blood, 2020,136（1）: 4-5.
[37]
BJORDAHL R, GAIDAROVA S, GOODRIDGE JP, et al. FT576:a novel multiplexed engineered off-the-shelf natural killer cell immunotherapy for the dual-targeting of CD38 and BCMA for the treatment of multiple myeloma[J]. Blood, 2019, 134（1）: 3214.
[38]
MAROFI F, RAHMAN HS, THANGAVELU L, et al. Renaissance of armored immune effector cells, CAR-NK cells, brings the higher hope for successful cancer therapy[J]. Stem Cell Res Ther, 2021,12（1）: 200.
[39]
GELLER MA, COOLEY S, JUDSON P L, et al. A phase Ⅱ study of allogeneic natural killer cell therapy to treat patients with recurrent ovarian and breast cancer[J]. Cytotherapy, 2011, 13（1）: 98-107.
[40]
MORGAN MA, BUNING H, SAUER M, et al. Use of cell and genome modification technologies to generate improved “off-the-shelf” CAR T and CAR NK cells[J]. Front Immunol, 2020, 11:1965.
[41]
WANG J, TOREGROSA-ALLEN S, ELZEY BD, et al. Multispecific targeting of glioblastoma with tumor microenvironment-responsive multifunctional engineered NK cells[J]. Proc Nat Acad Sci, 2021,118（45）: e2107507118.
[42]
HU Z. Tissue factor as a new target for CAR-NK cell immunotherapy of triple-negative breast cancer[J]. Sci Rep, 2020, 10（1）:2815.
[43]
SAHM C, SCHONFELD 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[J].Cancer Immunol Immunother, 2012, 61（9）: 1451-1461.
[44]
SCHONFELD K, SAHM C, ZHANG C, et al. Selective inhibition of tumor growth by clonal NK cells expressing an ErbB2/HER2-specific chimeric antigen receptor[J]. Mol Ther, 2015, 23（2）:330-338.
[45]
CAO B, LIU M, WANG L, et al. Use of chimeric antigen receptor NK-92 cells to target mesothelin in ovarian cancer[J]. Biochem Biophysic Res Commun, 2020, 524（1）: 96-102.
[46]
KLAPDOR R, WANG S, MORGAN M, et al. Characterization of a novel third-generation anti-CD24-CAR against ovarian cancer[J].Int J Mol Sci, 2019, 20（3）: 660.
[47]
ZHANG L, LIU M, YANG S, et al. Natural killer cells: off-the-shelf cytotherapy for cancer immunosurveillance[J]. Am J Cancer Res,2021, 11（4）: 1770.
[48]
van OSTAIJEN-TEN DAM MM, PRINS HJ, BOERMAN GH, et al.Preparation of cytokine-activated NK cells for use in adoptive cell therapy in cancer patients: protocol optimization and therapeutic potential[J]. J Immunother, 2016, 39（2）: 90-100.
[49]
DOMOGALA A, MADRIGAL JA, SAUDEMONT A.Cryopreservation has no effect on function of natural killer cells differentiated in vitro from umbilical cord blood CD34+ cells[J].Cytotherapy, 2016, 18（6）: 754-759.
[50]
HU Y, TIAN Z, ZHANG C. Chimeric antigen receptor（CAR）-transduced natural killer cells in tumor immunotherapy[J]. Acta Pharmacol Sin, 2018, 39（2）: 167-176.
[51]
SHAH NN, BAIRD K, DELBROOK CP, et al. Acute GVHD in patients receiving IL-15/4-1BBL activated NK cells following T-cell-depleted stem cell transplantation[J]. Blood, 2015, 125（5）: 784-792.
[52]
KLINGEMANN H. Challenges of cancer therapy with natural killer cells[J]. Cytotherapy, 2015, 17（3）: 245-249.
[53]
CARLSTEN M, CHILDS RW. Genetic manipulation of NK cells for cancer immunotherapy: techniques and clinical implications[J].Front Immunol, 2015, 6 : 266.
[54]
CROSBY CM, KRONENBERG M. Tissue-specific functions of invariant natural killer T cells[J]. Nat Rev Immunol, 2018, 18（9）: 559-574.
[55]
MALLEVAEY T, SELVANANTHAM T. Strategy of lipid recognition by invariant natural killer T cells:‘one for all and all for one’[J]. Immunology, 2012, 136（3）: 273-282.
[56]
HECZEY A, LIU D, TIAN G, et al. Invariant NKT cells with chimeric antigen receptor provide a novel platform for safe and effective cancer immunotherapy[J]. Blood, 2014, 124（18）:2824-2833.
[57]
NIELSEN MM, WITHERDEN DA, HAVRAN WL. γδ T cells in homeostasis and host defence of epithelial barrier tissues[J]. Nat Rev Immunol, 2017, 17（12）: 733-745.
[58]
NUSSBAUMER O, GRUENBACHER G, GANDER H, et al.Essential requirements of zoledronate-induced cytokine and γδ T cell proliferative responses[J]. J Immunol, 2013, 191（3）:1346-1355.
[59]
RISCHER M, PSCHERER S, DUWE S, et al. Human γδ T cells as mediators of chimaeric-receptor redirected anti-tumour immunity[J]. Br J Haematol, 2004, 126（4）: 583-592.
[60]
LONG KB, BEATTY GL. Harnessing the antitumor potential of macrophages for cancer immunotherapy[J]. Oncoimmunology,2013, 2（12）: e26860.
[61]
LEWIS CE, POLLARD JW. Distinct role of macrophages in different tumor microenvironments[J]. Cancer Res, 2006, 66（2）:605-612.
[62]
DAHER M, 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[J]. Cancer Discov, 2021, 11（1）:45-58.
[63]
KLICHINSKY M, RUELLA M, SHESTOVA O, et al. Chimeric antigen receptor macrophages（CARMA）for adoptive cellular immunotherapy of solid tumors[J]. Cancer Res, 2017, 77（13 Suppl）: 4575.
2024年第43卷第11期
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doi: 10.14109/j.cnki.xyylc.2024.11.01
  • 接收时间：2023-09-24
  • 首发时间：2026-03-13
  • 出版时间：2024-11-25
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  • 收稿日期：2023-09-24
  • 录用日期：2024-07-15
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上海市卫生健康委员会临床科研项目(202340061)
海军军医大学第一附属医院基础研究面上培育项目(2023PY40)
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    海军军医大学第一附属医院 风湿免疫科，上海　200433

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2种不同金属材料的力学参数
科
Family		 属数
Number of
genus		 种数
Number of
species		 占总种数比例
Percentage of
total species (%)		 属
Genus		 种数
Number of
species		 占总种数比例
Percentage of total
species (%)
鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
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