Please wait a minute...

中国生物工程杂志

CHINA BIOTECHNOLOGY
中国生物工程杂志
中国生物工程杂志  2023, Vol. 43 Issue (6): 31-42    DOI: 10.13523/j.cb.2302011
综述     
T细胞重定向双特异性抗体在肿瘤治疗中的挑战与应对策略*
秦晓静,刘雪,罗文新**()
厦门大学公共卫生学院 国家传染病诊断试剂与疫苗工程技术研究中心 厦门 361102
Challenges and Therapeutic Strategies for Bispecific T Cell-redirecting Antibodies in Tumor Treatment
QIN Xiao-jing,LIU Xue,LUO Wen-xin**()
National Institute of Diagnostics and Vaccine Development in Infections Diseases, School of Public Health, Xiamen University, Xiamen 361102, China
 全文: PDF(1469 KB)   HTML
摘要：

T细胞重定向双特异性抗体能同时结合肿瘤相关抗原和T细胞表面CD3分子,通过将T细胞与肿瘤细胞桥联而激活T细胞发挥抗肿瘤作用,是肿瘤免疫治疗中极具潜力的策略之一。该疗法已成功应用于多种血液肿瘤的治疗,但在实体瘤治疗领域进展缓慢。就近年T细胞重定向双特异性抗体在肿瘤治疗方面所面临的主要挑战及解决策略进行综述,以探讨未来有可能改善其疗效的潜在策略。
关键词： T细胞重定向双特异性抗体;  免疫治疗;  肿瘤    
Abstract:

Bispecific T cell-redirecting antibodies are designed to bind to selected tumor-associated antigens and to CD3 of the T cell receptor. Linking tumor cells and T cells results in activating T cells and inducing targeted T cell-mediated killing of the recognized tumor cells. They have become one of the most promising approaches in tumor immunotherapy. Although this therapy was successfully applied in hematological malignancies therapy, no significant progress in the treatment of solid tumors have been achieved. In this article, we review the major challenges of bispecific T cell-redirecting antibodies, and novel strategies to overcome these hurdles as well as to broaden the indications for this therapy, particularly to solid cancers.
Key words: Bispecific T cell-redirecting antibodies    Immunotherapy    Tumor
收稿日期: 2023-02-06 出版日期: 2023-07-04
ZTFLH:  Q819  
基金资助: * 博士后创新人才支持计划(BX20220189);国家自然科学基金(32070940)
通讯作者: **电子信箱:wxluo@xmu.edu.cn   
服务　　
把本文推荐给朋友
加入引用管理器
E-mail Alert
RSS
作者相关文章　　
秦晓静
刘雪
罗文新

引用本文:

秦晓静, 刘雪, 罗文新. T细胞重定向双特异性抗体在肿瘤治疗中的挑战与应对策略*[J]. 中国生物工程杂志, 2023, 43(6): 31-42.

QIN Xiao-jing, LIU Xue, LUO Wen-xin. Challenges and Therapeutic Strategies for Bispecific T Cell-redirecting Antibodies in Tumor Treatment. China Biotechnology, 2023, 43(6): 31-42.

链接本文:

https://manu60.magtech.com.cn/biotech/CN/10.13523/j.cb.2302011    或    https://manu60.magtech.com.cn/biotech/CN/Y2023/V43/I6/31

双抗药物 靶点 结构/格式 适应证 最早上市时间
Catumaxomab EpCAM×CD3 非对称性IgG like 传统抗体 恶性腹水 2009(EMA)
Blinatumomab CD19×CD3 串联型scFv,不含Fc结构 淋巴细胞白血病 2014(FDA)
Emetazumab factor IXa×
factor X		 非对称型IgG like 传统抗体 凝血因子Ⅷ缺乏 2017(FDA)
Amivantamab EGFR×c-Met 非对称型IgG like 传统抗体 血友病 2021(FDA)
Tebentafusp gp100×CD3 串联型scFv,不含Fc结构 不可切除或转移性葡萄膜黑色素瘤 2022(FDA)
Faricimab VEGF×Ang-2 非对称性IgG like 传统抗体 糖尿病黄斑水肿 2022(FDA)
Moseunetuzumab CD20×CD3 非对称型IgG like 传统抗体 复发性/难治性滤泡性淋巴瘤 2022(EMA)
Candonilimab PD-1×CTLA-4 对称型IgG like 传统抗体,
Fc区各串联一个抗CTLA-4的scFv		 复发性/转移性宫颈癌 2022(NMPA)
Teclistamab BCMA×CD3 非对称型IgG like 传统抗体 复发性/难治性多发骨髓瘤 2022(FDA)
表1  目前已获批上市的双特异性抗体
药物名称 靶点 适应证 临床阶段 临床编号 地区
Linvolseltamab BCMA×CD3 多发性骨髓瘤 临床Ⅰ期 NCT05137054 希腊、西班牙
Teclistamab BCMA×CD3 血液恶性肿瘤 临床Ⅰ期 NCT03145181 美国、法国、荷兰、西班牙
Elranatamab BCMA×CD3 多发性骨髓瘤 临床Ⅰ期 NCT05675449 美国
临床Ⅱ期 NCT05090566 美国、加拿大
NCT05228470 中国
NCT05014412 美国、日本、中国、英国
临床Ⅲ期 NCT05020236 阿根廷、澳大利亚、奥地利、比利时、巴西、加拿大、中国、捷克、芬兰、法国、德国、希腊、意大利、日本、韩国、墨西哥、荷兰、新西兰、挪威、波兰、西班牙、瑞典、土耳其、英国
NCT05317416 澳大利亚、奥地利、比利时、加拿大、捷克、芬兰、法国、德国、希腊、匈牙利、印度、以色列、意大利、日本、韩国、荷兰、挪威、波兰、西班牙、瑞典、中国、土耳其
EGFR BAT EGFR×CD3 局部晚期胰腺癌 临床Ⅰ期 NCT03269526 美国
转移性胰腺癌 临床Ⅱ期
ISB 1342 CD38×CD3 复发/难治性多发性骨髓瘤 临床Ⅰ期 NCT03309111 美国、法国
Talquetamab GPRC5D×CD3 复发/难治性多发性骨髓瘤 临床1期 NCT04773522 日本
血液恶性肿瘤 临床Ⅰ期 NCT04634552 美国、比利时、西班牙
临床Ⅰ期 NCT03399799 美国、比利时、荷兰、西班牙
Teclistamab BCMA×CD3 复发/难治性多发性骨髓瘤 临床Ⅰ/Ⅱ期 NCT04696809 日本
血液恶性肿瘤 临床Ⅱ期 NCT04557098 美国
Odronextamab CD20×CD3 B细胞非霍奇金淋巴瘤 临床Ⅱ期 NCT03888105 美国、中国、法国、德国、加拿大、澳大利亚、意大利、日本、韩国、波兰、新加坡、西班牙、英国
REGN5459/
REGN5458		 BCMA×CD3 慢性肾病 临床Ⅰ/Ⅱ期 NCT05092347 美国、加拿大、中国、比利时、法国、德国、意大利、荷兰、西班牙、瑞典、英国
Y150 CD38×CD3 复发/难治性多发性骨髓瘤 临床Ⅰ期 NCT05011097 中国
RGV004 CD19×CD3 难治性/复发性B细胞淋巴瘤 临床Ⅰ期 NCT04887025 中国
EMB-07 ROR1×CD3 高级/转移性实体肿瘤 临床Ⅰ期 NCT05607498 澳大利亚、中国
AMG 340 PSMA×CD3 转移性抗阉割前列腺癌 临床Ⅰ期 NCT04740034 美国
TNB-486 CD19×CD3 B细胞非霍奇金淋巴瘤 临床Ⅰ期 NCT04594642 美国、韩国
弥漫性大B细胞淋巴瘤
高级别B细胞淋巴瘤
滤泡性淋巴瘤
GEN1047 B7-H4×CD3 乳腺癌 临床Ⅰ/Ⅱ期 NCT05180474 丹麦、法国、西班牙
子宫癌
卵巢癌
鳞状非小细胞肺癌
Mosunetuzumab CD20×CD3 大B细胞淋巴瘤 临床Ⅱ期 NCT04889716 美国
ARB202 CDH17×CD3 胃肠道癌 临床Ⅰ期 NCT05411133 澳大利亚、中国、新加坡
胆管癌
肝癌
结直肠癌
胰腺癌
胃癌
JNJ-75348780 CD22×CD3 非霍奇金淋巴瘤 临床Ⅰ期 NCT04540796 美国、法国、以色列、韩国、西班牙、中国、英国
慢性淋巴细胞白血病
Odronextamab CD20×CD3 非霍奇金淋巴瘤 临床Ⅰ期 NCT02290951 美国、法国、德国、以色列、英国
慢性淋巴细胞白血病
MGD024 CD123×CD3 急性/慢性骨髓白血病 临床Ⅰ期 NCT05362773 美国
骨髓增生异常综合征
经典霍奇金淋巴瘤
CC-1 PSMA×CD3 前列腺癌复发 临床Ⅰ期 NCT05646550 德国
GB261 CD20×CD3 非霍奇金淋巴瘤 临床Ⅰ/Ⅱ期 NCT04923048 澳大利亚
慢性淋巴细胞白血病
EMB-06 BCMA×CD3 复发/难治性多发性骨髓瘤 临床Ⅰ/Ⅱ期 NCT04735575 澳大利亚、中国
Vibecotamab CD123×CD3 急性髓系白血病 临床Ⅱ期 NCT05285813 美国
骨髓增生异常综合征
Glofitamab CD20×CD3 复发/难治性淋巴瘤 临床Ⅱ期 NCT04703686 法国
表2  部分临床在研的T细胞重定向双特异性抗体
图1  双特异性抗体的结构模式
图2  T细胞重定向双特异性抗体的作用机制
图3  前体双特异性抗体的结构示意图及其作用原理
双特异性抗体面临的挑战 特征 解决策略
细胞因子释放综合征 IL-6、IL-10、TNF-ɑ、IFN-γ水平急剧升高,引发细胞因子风暴 IL-6和TNF-α抗体药物,免疫抑制剂等
反向招募T细胞亚群 无差别招募原始/衰竭T细胞、CD4+ T细胞、调节性T细胞等 提高双特异性抗体的选择性
靶向性与非靶向性的细胞毒性 正常细胞低水平抗原表达导致有害的靶向肿瘤毒性 前药、TCR融合蛋白+抗体双功能抗体、“2+1”格式CD3双抗;双抗体内分布重排等
肿瘤微环境 免疫检查位点 T细胞功能障碍和衰竭导致抗肿瘤免疫抑制 联合免疫共抑制或免疫共刺激
免疫抑制细胞与免疫
抑制细胞因子		 免疫细胞、细胞因子有助于抑制抗肿瘤免疫反应 溶瘤病毒
T细胞耗竭、活性限制 CD3+ T细胞重定向受阻 双肿瘤抗原靶向CD3+ T细胞导向剂的研制
表3  T细胞重定向双特异性抗体面临的挑战与解决策略
[1] Wu S Y, Wu F G, Chen X Y. Antibody-incorporated nanomedicines for cancer therapy. Advanced Materials, 2022, 34(24): 2109210.
doi: 10.1002/adma.v34.24
[2] Deshaies R J. Multispecific drugs herald a new era of biopharmaceutical innovation. Nature, 2020, 580(7803): 329-338.
doi: 10.1038/s41586-020-2168-1
[3] Acheampong D O. Bispecific antibody (bsAb) construct formats and their application in cancer therapy. Protein & Peptide Letters, 2019, 26(7): 479-493.
[4] Xiong W, Chen Y H, Kang X, et al. Immunological synapse predicts effectiveness of chimeric antigen receptor cells. Molecular Therapy, 2018, 26(4): 963-975.
doi: S1525-0016(18)30027-3 pmid: 29503199
[5] Morris E C, Neelapu S S, Giavridis T, et al. Cytokine release syndrome and associated neurotoxicity in cancer immunotherapy. Nature Reviews Immunology, 2022, 22(2): 85-96.
doi: 10.1038/s41577-021-00547-6
[6] Frey N. Cytokine release syndrome: who is at risk and how to treat. Best Practice & Research Clinical Haematology, 2017, 30(4): 336-340.
[7] Frampton J E. Catumaxomab. Drugs, 2012, 72(10): 1399-1410.
doi: 10.2165/11209040-000000000-00000 pmid: 22676343
[8] Wu Z, Cheung N V. T cell engaging bispecific antibody (T-BsAb): from technology to therapeutics. Pharmacology & Therapeutics, 2018, 182: 161-175.
[9] Peters I T A, Hilders C G J M, Sier C F M, et al. Identification of cell-surface markers for detecting breast cancer cells in ovarian tissue. Archives of Gynecology and Obstetrics, 2016, 294(2): 385-393.
doi: 10.1007/s00404-016-4036-7 pmid: 26946151
[10] Tian Z, Liu M, Zhang Y, et al. Bispecific T cell engagers: an emerging therapy for management of hematologic malignancies. Journal of Hematology & Oncology, 2021, 14(1): 1-18.
[11] Singh A, Dees S, Grewal I S. Overcoming the challenges associated with CD3+ T-cell redirection in cancer. British Journal of Cancer, 2021, 124(6): 1037-1048.
doi: 10.1038/s41416-020-01225-5 pmid: 33469153
[12] Kerbauy L N, Marin N D, Kaplan M, et al. Combining AFM13, a bispecific CD30/CD16 antibody, with cytokine-activated blood and cord blood-derived NK cells facilitates CAR-like responses against CD30+ malignancies. Clin Cancer Res, 2021, 27(13): 3744-3756.
doi: 10.1158/1078-0432.CCR-21-0164 pmid: 33986022
[13] Labrijn A F, Janmaat M L, Reichert J M, et al. Bispecific antibodies: a mechanistic review of the pipeline. Nature Reviews Drug Discovery, 2019, 18(8): 585-608.
doi: 10.1038/s41573-019-0028-1 pmid: 31175342
[14] Dennis M S, Zhang M, Meng Y G, et al. Albumin binding as a general strategy for improving the pharmacokinetics of proteins. Journal of Biological Chemistry, 2002, 277(38): 35035-35043.
doi: 10.1074/jbc.M205854200 pmid: 12119302
[15] Bluemel C, Hausmann S, Fluhr P, et al. Epitope distance to the target cell membrane and antigen size determine the potency of T cell-mediated lysis by BiTE antibodies specific for a large melanoma surface antigen. Cancer Immunology, Immunotherapy, 2010, 59(8): 1197-1209.
doi: 10.1007/s00262-010-0844-y
[16] Leong S R, Sukumaran S, Hristopoulos M, et al. An anti-CD3/anti-CLL-1 bispecific antibody for the treatment of acute myeloid leukemia. Blood, 2017, 129(5): 609-618.
doi: 10.1182/blood-2016-08-735365 pmid: 27908880
[17] Betts A, van der Graaf P H. Mechanistic quantitative pharmacology strategies for the early clinical development of bispecific antibodies in oncology. Clinical Pharmacology & Therapeutics, 2020, 108(3): 528-541.
[18] Bacac M, Fauti T, Sam J, et al. A novel carcinoembryonic antigen T-cell bispecific antibody (CEA TCB) for the treatment of solid tumors. Clin Cancer Res, 2016; 22(13):3286-3297.
doi: 10.1158/1078-0432.CCR-15-1696 pmid: 26861458
[19] Wu X F, Sereno A J, Huang F, et al. Fab-based bispecific antibody formats with robust biophysical properties and biological activity. mAbs, 2015, 7(3): 470-482.
doi: 10.1080/19420862.2015.1022694 pmid: 25774965
[20] Luo Y D, Ye S, Li X K, et al. Emerging structure-function paradigm of endocrine FGFs in metabolic diseases. Trends in Pharmacological Sciences, 2019, 40(2): 142-153.
doi: S0165-6147(18)30227-X pmid: 30616873
[21] Wu L J, Huang Y W, Sienkiewicz J, et al. Bispecific BCMA-CD3 antibodies block multiple myeloma tumor growth. Cancers, 2022, 14(10): 2518.
doi: 10.3390/cancers14102518
[22] Seung E, Xing Z, Wu L, et al. A trispecific antibody targeting HER2 and T cells inhibits breast cancer growth via CD4 cells. Nature, 2022, 603(7900): 328-334.
doi: 10.1038/s41586-022-04439-0
[23] Wu L, Seung E, Xu L, et al. Trispecific antibodies enhance the therapeutic efficacy of tumor-directed T cells through T cell receptor co-stimulation. Nature Cancer, 2019, 1(1): 86-98.
doi: 10.1038/s43018-019-0004-z
[24] Damato B E, Dukes J, Goodall H, et al. Tebentafusp: T cell redirection for the treatment of metastatic uveal melanoma. Cancers, 2019, 11(7): 971.
doi: 10.3390/cancers11070971
[25] Boustany L M, LaPorte S L, Wong L, et al. A Probody T cell-engaging bispecific antibody targeting EGFR and CD 3 inhibits colon cancer growth with limited toxicity. Cancer Res, 2022, 82(22):4288-4298.
doi: 10.1158/0008-5472.CAN-21-2483 pmid: 36112781
[26] Maude S L, Teachey D T, Porter D L, et al. CD19-targeted chimeric antigen receptor T-cell therapy for acute lymphoblastic leukemia. Blood, 2015, 125(26): 4017-4023.
doi: 10.1182/blood-2014-12-580068 pmid: 25999455
[27] Strohl W R, Naso M. Bispecific T-cell redirection versus chimeric antigen receptor (CAR)-T cells as approaches to kill cancer cells. Antibodies, 2019, 8(3): 41.
doi: 10.3390/antib8030041
[28] Li J, Piskol R, Ybarra R, et al. CD3 bispecific antibody-induced cytokine release is dispensable for cytotoxic T cell activity. Science Translational Medicine, 2019, 11(508): eaax8861.
doi: 10.1126/scitranslmed.aax8861
[29] Norelli M, Camisa B, Barbiera G, et al. Monocyte-derived IL-1 and IL-6 are differentially required for cytokine-release syndrome and neurotoxicity due to CAR T cells. Nature Medicine, 2018, 24(6): 739-748.
doi: 10.1038/s41591-018-0036-4 pmid: 29808007
[30] Iwata Y, Sasaki M, Harada A, et al. Daily ascending dosing in cynomolgus monkeys to mitigate cytokine release syndrome induced by ERY22, surrogate for T-cell redirecting bispecific antibody ERY974 for cancer immunotherapy. Toxicology and Applied Pharmacology, 2019, 379: 114657.
[31] Deppisch N, Ruf P, Eissler N, et al. Efficacy and tolerability of a GD2-directed trifunctional bispecific antibody in a preclinical model: subcutaneous administration is superior to intravenous delivery. Molecular Cancer Therapeutics, 2015, 14(8): 1877-1883.
doi: 10.1158/1535-7163.MCT-15-0156 pmid: 26063765
[32] Trinklein N D, Pham D, Schellenberger U, et al. Efficient tumor killing and minimal cytokine release with novel T-cell agonist bispecific antibodies. mAbs, 2019, 11(4): 639-652.
doi: 10.1080/19420862.2019.1574521 pmid: 30698484
[33] Staflin K, Zuch de Zafra C L, Schutt L K, et al. Target arm affinities determine preclinical efficacy and safety of anti-HER2/CD 3 bispecific antibody. JCI Insight, 2020, 5(7): e133757.
doi: 10.1172/jci.insight.133757
[34] Vafa O, Trinklein N D. Perspective: designing T-cell engagers with better therapeutic windows. Frontiers in Oncology, 2020, 10: 446.
doi: 10.3389/fonc.2020.00446 pmid: 32351885
[35] Chen X Y, Kamperschroer C, Wong G, et al. A modeling framework to characterize cytokine release upon T-cell-engaging bispecific antibody treatment: methodology and opportunities. Clinical and Translational Science, 2019, 12(6): 600-608.
doi: 10.1111/cts.12662 pmid: 31268236
[36] Budde L E, Sehn L H, Matasar M, et al. Safety and efficacy of mosunetuzumab, a bispecific antibody, in patients with relapsed or refractory follicular lymphoma: a single-arm, multicentre, phase 2 study. The Lancet Oncology, 2022, 23(8): 1055-1065.
doi: 10.1016/S1470-2045(22)00335-7
[37] Haber L, Olson K, Kelly M P, et al. Generation of T-cell-redirecting bispecific antibodies with differentiated profiles of cytokine release and biodistribution by CD 3 affinity tuning. Scientific Reports, 2021, 11: 14397.
doi: 10.1038/s41598-021-93842-0
[38] Santich B H, Cheal S M, Ahmed M, et al. A self-assembling and disassembling (SADA) bispecific antibody (BsAb) platform for curative two-step pretargeted radioimmunotherapy. Clin Cancer Res, 2021, 27(2):532-541.
doi: 10.1158/1078-0432.CCR-20-2150 pmid: 32958698
[39] Peng J Q, Zhu Q, Peng Z R, et al.Patients with positive HER-2 amplification advanced gastroesophageal junction cancer achieved complete response with combined chemotherapy of AK104/cadonilimab (PD-1/CTLA-4 bispecific): a case report. Front Immunol, 2022, 13:1049518.
[40] Alinari L, Mahoney E, Patton J, et al. FTY720 increases CD74 expression and sensitizes mantle cell lymphoma cells to milatuzumab-mediated cell death. Blood, 2011, 118(26): 6893-6903.
doi: 10.1182/blood-2011-06-363879 pmid: 22042694
[41] Harrington K, Freeman D J, Kelly B, et al. Optimizing oncolytic virotherapy in cancer treatment. Nature Reviews Drug Discovery, 2019, 18(9): 689-706.
doi: 10.1038/s41573-019-0029-0 pmid: 31292532
[42] Ma R, Li Z L, Chiocca E A, et al. The emerging field of oncolytic virus-based cancer immunotherapy. Trends in Cancer, 2023, 9(2): 122-139.
doi: 10.1016/j.trecan.2022.10.003
[43] Yu F, Wang X B, Guo Z S, et al. T-cell engager-armed oncolytic vaccinia virus significantly enhances antitumor therapy. Molecular Therapy: the Journal of the American Society of Gene Therapy, 2014, 22(1): 102-111.
doi: 10.1038/mt.2013.240
[44] Wang Q M, Ma X Y, Wu H, et al. Oncolytic adenovirus with MUC16-BiTE shows enhanced antitumor immune response by reversing the tumor microenvironment in PDX model of ovarian cancer. OncoImmunology, 2022, 11(1): 2096362.
doi: 10.1080/2162402X.2022.2096362
[45] Belmontes B, Sawant D V, Zhong W, et al. Immunotherapy combinations overcome resistance to bispecific T cell engager treatment in T cell-cold solid tumors. Science Translational Medicine, 2021, 13(608): eabd1524.
doi: 10.1126/scitranslmed.abd1524
[46] Wunderlich M, Manning N, Sexton C, et al. PD-1 inhibition enhances blinatumomab response in a UCB/PDX model of relapsed pediatric B-cell acute lymphoblastic leukemia. Frontiers in Oncology, 2021, 11: 642466.
doi: 10.3389/fonc.2021.642466
[1] 韩佳, 范月蕾, 毛开云. 溶瘤病毒市场及研发格局分析*[J]. 中国生物工程杂志, 2023, 43(6): 87-101.
[2] 董蒨蒨, 李玉淼. CAR-T在血液类恶性肿瘤中的研究进展*[J]. 中国生物工程杂志, 2023, 43(6): 43-53.
[3] 李雨桐, 崔天琦, 张海林, 于广乐, 栾霁, 王海龙. 肿瘤靶向细菌Escherichia coli Nissle 1917在癌症治疗中的研究进展*[J]. 中国生物工程杂志, 2023, 43(6): 54-68.
[4] 蒋金露, 潘海峰, 于思远, 李廷栋, 葛胜祥. 疟原虫重组蛋白rVAR2及其在肿瘤靶向治疗中的应用进展*[J]. 中国生物工程杂志, 2023, 43(6): 69-75.
[5] 林鹏, 钱菁, 冯强, 雷琎, 江亚, 杨举伦. 单链抗体的制备及其在肿瘤诊疗中的应用*[J]. 中国生物工程杂志, 2023, 43(6): 76-86.
[6] 金美琴, 尚诚彰, 沈月雷. 靶向TPBG和EGFR的双特异性抗体偶联药物的构建及其抗肿瘤活性研究*[J]. 中国生物工程杂志, 2023, 43(5): 11-23.
[7] 杨子荣,杨璇,倪婷婷,潘聪,谭诗生,王姿. 可利霉素通过调控巨噬细胞极化影响黑色素瘤的增殖*[J]. 中国生物工程杂志, 2022, 42(7): 12-23.
[8] 姚芷昕,李婉明. 核酸适配体在三阴性乳腺癌诊疗中的研究进展*[J]. 中国生物工程杂志, 2022, 42(7): 62-68.
[9] 王璐,陈梦丽,何芳,项建,尹斌成,叶邦策. 工程化外泌体介导巨噬细胞清除肿瘤外泌体*[J]. 中国生物工程杂志, 2022, 42(6): 1-11.
[10] 杨换连,邱飞,王国权,刁勇. 肿瘤类器官在药物筛选和个性化用药中的研究进展*[J]. 中国生物工程杂志, 2022, 42(6): 47-53.
[11] 毛露珈,史恩宇,王瀚平,单天贺,王银松,王悦. 细菌外膜囊泡在抗肿瘤治疗方面的研究进展*[J]. 中国生物工程杂志, 2022, 42(5): 100-105.
[12] 林宏伟,刘珺懿,罗文新. CAR-T联合疗法治疗实体瘤的研究进展[J]. 中国生物工程杂志, 2022, 42(12): 37-51.
[13] 王彧,白岳丘,田易晓,王新月,黄庆生. mRNA疫苗在疾病预防与治疗中的研究进展与展望[J]. 中国生物工程杂志, 2022, 42(10): 51-59.
[14] 韩春丽,王汉杰. 工程生物活药在肿瘤免疫治疗中的应用[J]. 中国生物工程杂志, 2022, 42(10): 39-50.
[15] 张慧,陈华宁,库德莱迪·库尔班,王松娜,刘嘉扬,赵缜,叶丽. Wnt/β-catenin信号通路与癌症发生发展及其免疫治疗*[J]. 中国生物工程杂志, 2022, 42(1/2): 104-111.
主管：中国科学院 　主办：中国科学院文献情报中心 　中国生物技术发展中心 　中国生物工程学会