高级搜索

胰腺癌免疫治疗的前沿与未来

周文策, 张辉, 李昕, 董仕

周文策, 张辉, 李昕, 董仕. 胰腺癌免疫治疗的前沿与未来[J]. 肿瘤防治研究, 2023, 50(4): 338-344. DOI: 10.3971/j.issn.1000-8578.2023.22.1290
引用本文: 周文策, 张辉, 李昕, 董仕. 胰腺癌免疫治疗的前沿与未来[J]. 肿瘤防治研究, 2023, 50(4): 338-344. DOI: 10.3971/j.issn.1000-8578.2023.22.1290
ZHOU Wence, ZHANG Hui, LI Xin, DONG Shi. Frontier and Future of Immunotherapy for Pancreatic Cancer[J]. Cancer Research on Prevention and Treatment, 2023, 50(4): 338-344. DOI: 10.3971/j.issn.1000-8578.2023.22.1290
Citation: ZHOU Wence, ZHANG Hui, LI Xin, DONG Shi. Frontier and Future of Immunotherapy for Pancreatic Cancer[J]. Cancer Research on Prevention and Treatment, 2023, 50(4): 338-344. DOI: 10.3971/j.issn.1000-8578.2023.22.1290

胰腺癌免疫治疗的前沿与未来

基金项目: 

国家自然科学基金 82260555

甘肃省自然科学基金 21JR1RA102

甘肃省中医药科研课题 GZKP-2020-28

详细信息
    作者简介:

    周文策  博士,主任医师,教授,博士研究生导师,兰州大学第二医院院长。甘肃省领军人才,陇原创新青年人才,兰州大学临床医学人才建设计划优秀中青年骨干。甘肃省医学会肠外肠内营养学专业委员会主任委员,甘肃省医师协会普外医师分会副会长、ERAS专业委员会(主任委员),中国医师协会外科医师分会包虫病外科专委会常务委员,中国临床肿瘤学会(CSCO)胰腺癌专家委员会委员。担任World Journal of Gastrointestinal Endoscopy、《中华消化内镜杂志》《肿瘤防治研究》等多个学术期刊编委。先后荣获甘肃省优秀医师、兰州大学师德标兵、甘肃省医德医风建设先进个人、新疆转化医学青年杰出贡献奖二等奖等多个荣誉称号。长期从事肝胆胰肿瘤和消化系统疾病的临床、教学和研究工作,积极践行和传播“软镜硬镜结合” “内科外科兼修” “快速康复外科”的现代诊疗理念,形成“机器人+腹腔镜+内镜+介入”的微创技术综合治疗体系,带领团队常规开展各类复杂的消化系统微创手术。先后主持国家自然科学基金等各类科研基金12项,以第一作者或通信作者身份发表论文72篇,荣获各类省部级科技奖励14项。
    周文策(1972-),男,博士,主任医师、教授,主要从事肝胆胰肿瘤的临床和基础研究,E-mail: zhouwc129@163.com,ORCID: 0000-0002-0529-7777

  • 中图分类号: R735.9

Frontier and Future of Immunotherapy for Pancreatic Cancer

Funding: 

National Natural Science Foundation of China 82260555

Natural Science Foundation of Gansu Province 21JR1RA102

Traditional Chinese Medicine Scientific Research Project of Gansu Province, China GZKP-2020-28

  • 摘要:

    胰腺癌仍然是最致命的恶性肿瘤之一,对传统疗法的抵抗使其生存率在过去几十年内几乎未有改善,而基于肿瘤免疫的胰腺癌治疗策略,如免疫检查点抑制剂、治疗性疫苗和联合免疫疗法正显示出新的治疗希望。尽管临床试验中探索的诸多免疫疗法尚未报道出显著的治疗效果,但毋庸置疑的是免疫治疗将是胰腺癌预后改善甚至治愈的重要希望。本文介绍了目前胰腺癌免疫疗法的相关进展及遇到的瓶颈,并提出了进一步的优化方向和解决方案,希望为胰腺癌免疫治疗发展提供参考。

     

    Abstract:

    Pancreatic cancer remains as one of the most lethal malignancies. Resistance to conventional therapies has led to little improvement in the survival of pancreatic cancer patients over the past few decades. Immune-based treatment strategies for pancreatic cancer, such as immune-checkpoint inhibitors, therapeutic vaccines, and combination immunotherapies show promise. Many immunotherapies have been explored in clinical trials, but they have yet to show significant therapeutic effects. Nevertheless, immunotherapy is inevitably the future of pancreatic cancer cure. This article introduces the current research progress and bottlenecks of immunotherapy for pancreatic cancer and puts forward further optimization directions and solutions. We hope to provide a reference for the future use of immunotherapy for pancreatic cancer.

     

  • Competing interests: The authors declare that they have no competing interests.
    利益冲突声明:
    所有作者均声明不存在利益冲突。
    作者贡献:
    周文策:总体策划、提纲设计、论文撰写及审校
    张  辉:提纲修订、论文指导
    李昕、董仕:文献收集、论文修改
  • [1]

    Siegel RL, Miller KD, Fuchs HE, et al. Cancer Statistics, 2021[J]. CA Cancer J Clin, 2021, 71(1): 7-33. doi: 10.3322/caac.21654

    [2]

    Lee YE, Ju A, Choi HW, et al. Rationally designed redirection of natural killer cells anchoring a cytotoxic ligand for pancreatic cancer treatment[J]. J Control Release, 2020, 326: 310-323. doi: 10.1016/j.jconrel.2020.07.016

    [3]

    Nevala-Plagemann C, Hidalgo M, Garrido-Laguna I. From state-of-the-art treatments to novel therapies for advanced-stage pancreatic cancer[J]. Nat Rev Clin Oncol, 2020, 17(2): 108-123. doi: 10.1038/s41571-019-0281-6

    [4]

    Foley K, Kim V, Jaffee E, et al. Current progress in immunotherapy for pancreatic cancer[J]. Cancer Lett, 2016, 381(1): 244-251. doi: 10.1016/j.canlet.2015.12.020

    [5]

    Zhang A, Miao K, Sun H, et al. Tumor heterogeneity reshapes the tumor microenvironment to influence drug resistance[J]. Int J Biol Sci, 2022, 18(7): 3019-3033. doi: 10.7150/ijbs.72534

    [6]

    Guan J, Lim KS, Mekhail T, et al. Programmed Death Ligand-1 (PD-L1) Expression in the Programmed Death Receptor-1 (PD-1)/PD-L1 Blockade: A Key Player Against Various Cancers[J]. Arch Pathol Lab Med, 2017, 141(6): 851-861. doi: 10.5858/arpa.2016-0361-RA

    [7]

    Brahmer JR, Tykodi SS, Chow LQ, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer[J]. N Engl J Med, 2012, 366(26): 2455-2465. doi: 10.1056/NEJMoa1200694

    [8] 国家卫生健康委办公厅. 胰腺癌诊疗指南(2022年版)[J]. 临床肝胆病杂志, 2022, 38(5): 1006-1015. doi: 10.3969/j.issn.1001-5256.2022.05.007

    General Office of The National Health Commission. Standard for diagnosis and treatment of pancreatic cancer (2022 edition)[J]. Lin Chuang Gan Dan Bing Za Zhi, 2022, 38(5): 1006-1015. doi: 10.3969/j.issn.1001-5256.2022.05.007

    [9]

    Marabelle A, Le DT, Ascierto PA, et al. Efficacy of Pembrolizumab in Patients With Noncolorectal High Microsatellite Instability/Mismatch Repair-Deficient Cancer: Results From the PhaseⅡKEYNOTE-158 Study[J]. J Clin Oncol, 2020, 38(1): 1-10. doi: 10.1200/JCO.19.02105

    [10]

    Chia DKA, Gwee YX, Sundar R. Resistance to systemic immune checkpoint inhibition in the peritoneal niche[J]. J Immunother Cancer, 2022, 10(6): e004749. doi: 10.1136/jitc-2022-004749

    [11]

    Hu ZI, Shia J, Stadler ZK, et al. Evaluating Mismatch Repair Deficiency in Pancreatic Adenocarcinoma: Challenges and Recommendations[J]. Clin Cancer Res, 2018, 24(6): 1326-1336. doi: 10.1158/1078-0432.CCR-17-3099

    [12]

    Li TJ, Wang WQ, Yu XJ, et al. Killing the "BAD": Challenges for immunotherapy in pancreatic cancer[J]. Biochim Biophys Acta Rev Cancer, 2020, 1874(1): 188384. doi: 10.1016/j.bbcan.2020.188384

    [13]

    Chen L. Co-inhibitory molecules of the B7-CD28 family in the control of T-cell immunity[J]. Nat Rev Immunol, 2004, 4(5): 336-347. doi: 10.1038/nri1349

    [14]

    Annesley CE, Brown P. Novel agents for the treatment of childhood acute leukemia[J]. Ther Adv Hematol, 2015, 6(2): 61-79. doi: 10.1177/2040620714565963

    [15]

    Royal RE, Levy C, Turner K, et al. Phase 2 trial of single agent Ipilimumab (anti-CTLA-4) for locally advanced or metastatic pancreatic adenocarcinoma[J]. J Immunother, 2010, 33(8): 828-833. doi: 10.1097/CJI.0b013e3181eec14c

    [16]

    Bengsch F, Knoblock DM, Liu A, et al. CTLA-4/CD80 pathway regulates T cell infiltration into pancreatic cancer[J]. Cancer Immunol Immunother, 2017, 66(12): 1609-1617. doi: 10.1007/s00262-017-2053-4

    [17]

    Ren B, Cui M, Yang G, et al. Tumor microenvironment participates in metastasis of pancreatic cancer[J]. Mol Cancer, 2018, 17(1): 108. doi: 10.1186/s12943-018-0858-1

    [18]

    Le DT, Wang-Gillam A, Picozzi V, et al. Safety and survival with GVAX pancreas prime and Listeria Monocytogenes-expressing mesothelin (CRS-207) boost vaccines for metastatic pancreatic cancer[J]. J Clin Oncol, 2015, 33(12): 1325-1333. doi: 10.1200/JCO.2014.57.4244

    [19]

    Muth ST, Saung MT, Blair AB, et al. CD137 agonist-based combination immunotherapy enhances activated, effector memory T cells and prolongs survival in pancreatic adenocarcinoma[J]. Cancer Lett, 2021, 499: 99-108. doi: 10.1016/j.canlet.2020.11.041

    [20]

    Wu AA, Bever KM, Ho WJ, et al. A Phase Ⅱ Study of Allogeneic GM-CSF-Transfected Pancreatic Tumor Vaccine (GVAX) with Ipilimumab as Maintenance Treatment for Metastatic Pancreatic Cancer[J]. Clin Cancer Res, 2020, 26(19): 5129-5139. doi: 10.1158/1078-0432.CCR-20-1025

    [21]

    Nishida S, Ishikawa T, Egawa S, et al. Combination Gemcitabine and WT1 Peptide Vaccination Improves Progression-Free Survival in Advanced Pancreatic Ductal Adenocarcinoma: A Phase ⅡRandomized Study[J]. Cancer Immunol Res, 2018, 6(3): 320-331. doi: 10.1158/2326-6066.CIR-17-0386

    [22]

    Sadeghlar F, Vogt A, Mohr RU, et al. Induction of cytotoxic effector cells towards cholangiocellular, pancreatic, and colorectal tumor cells by activation of the immune checkpoint CD40/CD40L on dendritic cells[J]. Cancer Immunol Immunother, 2021, 70(5): 1451-1464. doi: 10.1007/s00262-020-02746-x

    [23]

    Wang R, Chen J, Wang W, et al. CD40L-armed oncolytic herpes simplex virus suppresses pancreatic ductal adenocarcinoma by facilitating the tumor microenvironment favorable to cytotoxic T cell response in the syngeneic mouse model[J]. J Immunother Cancer, 2022, 10(1): e003809. doi: 10.1136/jitc-2021-003809

    [24]

    Van Audenaerde JR, Marcq E, von Scheidt B, et al. Novel combination immunotherapy for pancreatic cancer: potent anti-tumor effects with CD40 agonist and interleukin-15 treatment[J]. Clin Transl Immunology, 2020, 9(8): e1165.

    [25]

    Byrne KT, Betts CB, Mick R, et al. Neoadjuvant Selicrelumab, an Agonist CD40 Antibody, Induces Changes in the Tumor Microenvironment in Patients with Resectable Pancreatic Cancer[J]. Clin Cancer Res, 2021, 27(16): 4574-4586. doi: 10.1158/1078-0432.CCR-21-1047

    [26]

    Lau SP, van Montfoort N, Kinderman P, et al. Dendritic cell vaccination and CD40-agonist combination therapy licenses T cell-dependent antitumor immunity in a pancreatic carcinoma murine model[J]. J Immunother Cancer, 2020, 8(2): e000772. doi: 10.1136/jitc-2020-000772

    [27]

    O'Hara MH, O'Reilly EM, Varadhachary G, et al. CD40 agonistic monoclonal antibody APX005M (sotigalimab) and chemotherapy, with or without nivolumab, for the treatment of metastatic pancreatic adenocarcinoma: an open-label, multicentre, phase Ⅰb study[J]. Lancet Oncol, 2021, 22(1): 118-131. doi: 10.1016/S1470-2045(20)30532-5

    [28]

    Rosenberg SA, Restifo NP, Yang JC, et al. Adoptive cell transfer: a clinical path to effective cancer immunotherapy[J]. Nat Rev Cancer, 2008, 8(4): 299-308. doi: 10.1038/nrc2355

    [29]

    Beatty GL, O'Hara MH, Lacey SF, et al. Activity of Mesothelin-Specific Chimeric Antigen Receptor T Cells Against Pancreatic Carcinoma Metastases in a Phase 1 Trial[J]. Gastroenterology, 2018, 155(1): 29-32. doi: 10.1053/j.gastro.2018.03.029

    [30]

    Liu Y, Guo Y, Wu Z, et al. Anti-EGFR chimeric antigen receptor-modified T cells in metastatic pancreatic carcinoma: A phaseⅠclinical trial[J]. Cytotherapy, 2020, 22(10): 573-580. doi: 10.1016/j.jcyt.2020.04.088

    [31]

    Raj D, Yang MH, Rodgers D, et al. Switchable CAR-T cells mediate remission in metastatic pancreatic ductal adenocarcinoma[J]. Gut, 2019, 68(6): 1052-1064. doi: 10.1136/gutjnl-2018-316595

    [32]

    Han L, Shang YM, Song YP, et al. Biological Character of RetroNectin Activated Cytokine-Induced Killer Cells[J]. J Immunol Res, 2016, 2016: 5706814.

    [33]

    Hecht JR, Bedford R, Abbruzzese JL, et al. A phase Ⅰ/Ⅱ trial of intratumoral endoscopic ultrasound injection of ONYX-015 with intravenous gemcitabine in unresectable pancreatic carcinoma[J]. Clin Cancer Res, 2003, 9(2): 555-561.

    [34]

    Barton KN, Siddiqui F, Pompa R, et al. Phase Ⅰ trial of oncolytic adenovirus-mediated cytotoxic and interleukin-12 gene therapy for the treatment of metastatic pancreatic cancer[J]. Mol Ther Oncolytics, 2020, 20: 94-104.

    [35]

    Chard LS, Maniati E, Wang P, et al. A vaccinia virus armed with interleukin-10 is a promising therapeutic agent for treatment of murine pancreatic cancer[J]. Clin Cancer Res, 2015, 21(2): 405-416. doi: 10.1158/1078-0432.CCR-14-0464

    [36]

    Marelli G, Chard Dunmall LS, Yuan M, et al. A systemically deliverable Vaccinia virus with increased capacity for intertumoral and intratumoral spread effectively treats pancreatic cancer[J]. J Immunother Cancer, 2021, 9(1): e001624. doi: 10.1136/jitc-2020-001624

    [37]

    Joyce JA, Pollard JW. Microenvironmental regulation of metastasis[J]. Nat Rev Cancer, 2009, 9(4): 239-252. doi: 10.1038/nrc2618

    [38]

    Hingorani SR, Zheng L, Bullock AJ, et al. HALO 202: Randomized Phase Ⅱ Study of PEGPH20 Plus Nab-Paclitaxel/Gemcitabine Versus Nab-Paclitaxel/Gemcitabine in Patients With Untreated, Metastatic Pancreatic Ductal Adenocarcinoma[J]. J Clin Oncol, 2018, 36(4): 359-366. doi: 10.1200/JCO.2017.74.9564

    [39]

    Kindler HL, Niedzwiecki D, Hollis D, et al. Gemcitabine plus bevacizumab compared with gemcitabine plus placebo in patients with advanced pancreatic cancer: phase Ⅲ trial of the Cancer and Leukemia Group B (CALGB 80303)[J]. J Clin Oncol, 2010, 28(22): 3617-3622. doi: 10.1200/JCO.2010.28.1386

    [40]

    Astsaturov IA, Meropol NJ, Alpaugh RK, et al. Phase Ⅱ and coagulation cascade biomarker study of bevacizumab with or without docetaxel in patients with previously treated metastatic pancreatic adenocarcinoma[J]. Am J Clin Oncol, 2011, 34(1): 70-75. doi: 10.1097/COC.0b013e3181d2734a

    [41]

    Hidalgo M, Maitra A. The hedgehog pathway and pancreatic cancer[J]. N Engl J Med, 2009, 361(21): 2094-2096. doi: 10.1056/NEJMcibr0905857

    [42]

    Pijnappel EN, Wassenaar NPM, Gurney-Champion OJ, et al. Phase Ⅰ/Ⅱ Study of LDE225 in Combination with Gemcitabine and Nab-Paclitaxel in Patients with Metastatic Pancreatic Cancer[J]. Cancers (Basel), 2021, 13(19): 4869. doi: 10.3390/cancers13194869

    [43]

    Paz-Ares L, Dvorkin M, Chen Y, et al. Durvalumab plus platinum-etoposide versus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): a randomised, controlled, open-label, phase 3 trial[J]. Lancet, 2019, 394(10212): 1929-1939. doi: 10.1016/S0140-6736(19)32222-6

    [44]

    O'Reilly EM, Oh DY, Dhani N, et al. Durvalumab With or Without Tremelimumab for Patients With Metastatic Pancreatic Ductal Adenocarcinoma: A Phase 2 Randomized Clinical Trial[J]. JAMA Oncol, 2019, 5(10): 1431-1438. doi: 10.1001/jamaoncol.2019.1588

    [45]

    Overman M, Javle M, Davis RE, et al. Randomized phase Ⅱ study of the Bruton tyrosine kinase inhibitor acalabrutinib, alone or with pembrolizumab in patients with advanced pancreatic cancer[J]. J Immunother Cancer, 2020, 8(1): e000587. doi: 10.1136/jitc-2020-000587

    [46]

    Chung V, Kos FJ, Hardwick N, et al. Evaluation of safety and efficacy of p53MVA vaccine combined with pembrolizumab in patients with advanced solid cancers[J]. Clin Transl Oncol, 2019, 21(3): 363-372. doi: 10.1007/s12094-018-1932-2

    [47]

    Ho TTB, Nasti A, Seki A, et al. Combination of gemcitabine and anti-PD-1 antibody enhances the anticancer effect of M1 macrophages and the Th1 response in a murine model of pancreatic cancer liver metastasis[J]. J Immunother Cancer, 2020, 8(2): e001367. doi: 10.1136/jitc-2020-001367

    [48]

    Weiss GJ, Blaydorn L, Beck J, et al. Phase Ⅰb/Ⅱ study of gemcitabine, nab-paclitaxel, and pembrolizumab in metastatic pancreatic adenocarcinoma[J]. Invest New Drugs, 2018, 36(1): 96-102. doi: 10.1007/s10637-017-0525-1

    [49]

    Ogasawara M, Miyashita M, Yamagishi Y, et al. Dendritic cell vaccination combined with a conventional chemotherapy for patients with relapsed or advanced pancreatic ductal adenocarcinoma: a single-center phase Ⅰ/Ⅱ trial[J]. Ther Apher Dial, 2021, 25(4): 415-424. doi: 10.1111/1744-9987.13659

    [50]

    Wu AA, Bever KM, Ho WJ, et al. A Phase Ⅱ Study of Allogeneic GM-CSF-Transfected Pancreatic Tumor Vaccine (GVAX) with Ipilimumab as Maintenance Treatment for Metastatic Pancreatic Cancer[J]. Clin Cancer Res, 2020, 26(19): 5129-5139. doi: 10.1158/1078-0432.CCR-20-1025

    [51]

    Mahalingam D, Wilkinson GA, Eng KH, et al. Pembrolizumab in Combination with the Oncolytic Virus Pelareorep and Chemotherapy in Patients with Advanced Pancreatic Adenocarcinoma: A PhaseⅠb Study[J]. Clin Cancer Res, 2020, 26(1): 71-81. doi: 10.1158/1078-0432.CCR-19-2078

    [52]

    Hirooka Y, Kasuya H, Ishikawa T, et al. A Phase Ⅰ clinical trial of EUS-guided intratumoral injection of the oncolytic virus, HF10 for unresectable locally advanced pancreatic cancer[J]. BMC Cancer, 2018, 18(1): 596. doi: 10.1186/s12885-018-4453-z

    [53]

    Alewine C, Ahmad M, Peer CJ, et al. Phase Ⅰ/Ⅱ Study of the Mesothelin-targeted Immunotoxin LMB-100 with Nab-Paclitaxel for Patients with Advanced Pancreatic Adenocarcinoma[J]. Clin Cancer Res, 2020, 26(4): 828-836. doi: 10.1158/1078-0432.CCR-19-2586

    [54] 周玲, 杨晨, 高艳, 等. 吉西他滨增强HUVEC疫苗抗胰腺癌作用实验研究[J]. 中国药理学通报, 2021, 37(7): 996-1001. doi: 10.3969/j.issn.1001-1978.2021.07.020

    Zhou L, Yang C, Gao Y, et al. Experimental study of enhanced anti-pancreatic cancer effects by combination treatment with HUVEC vaccine and gemcitabine[J]. Zhongguo Yao Li Xue Tong Bao, 2021, 37(7): 996-1001. doi: 10.3969/j.issn.1001-1978.2021.07.020

    [55]

    Suzuki N, Hazama S, Iguchi H, et al. Phase Ⅱ clinical trial of peptide cocktail therapy for patients with advanced pancreatic cancer: VENUS-PC study[J]. Cancer Sci, 2017, 108(1): 73-80. doi: 10.1111/cas.13113

    [56]

    Fujiwara K, Saung MT, Jing H, et al. Interrogating the immune-modulating roles of radiation therapy for a rational combination with immune-checkpoint inhibitors in treating pancreatic cancer[J]. J Immunother Cancer, 2020, 8(2): e000351. doi: 10.1136/jitc-2019-000351

    [57]

    Lee YH, Yu CF, Yang YC, et al. Ablative Radiotherapy Reprograms the Tumor Microenvironment of a Pancreatic Tumor in Favoring the Immune Checkpoint Blockade Therapy[J]. Int J Mol Sci, 2021, 22(4): 2091. doi: 10.3390/ijms22042091

  • 期刊类型引用(2)

    1. 王海宏,宋玉,贺凡,杨兵,唐东昕,吴文宇. 基于伏邪理论探讨循环肿瘤细胞与结直肠癌复发转移的相关性. 中医杂志. 2024(19): 1983-1987 . 百度学术
    2. 阙祖俊,田建辉. 根除休眠播散肿瘤细胞防止肿瘤转移的潜在治疗药物的研究进展. 中国肿瘤生物治疗杂志. 2024(11): 1146-1151 . 百度学术

    其他类型引用(0)

计量
  • 文章访问数:  3476
  • HTML全文浏览量:  583
  • PDF下载量:  1396
  • 被引次数: 2
出版历程
  • 收稿日期:  2022-10-31
  • 修回日期:  2023-02-09
  • 网络出版日期:  2024-01-12
  • 刊出日期:  2023-04-24

目录

    /

    返回文章
    返回
    x 关闭 永久关闭