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Chimeric Antigen Receptor T-Cell Therapy for Colorectal Cancer. ​

文献信息 ​

DOI10.3390/jcm9010182
PMID31936611
期刊Journal of clinical medicine
影响因子2.9
JCR 分区Q1
发表年份2020
被引次数41
关键词嵌合抗原受体（CAR）T细胞, 结直肠癌, 免疫治疗, 毒性, 临床试验
文献类型Journal Article, Review
ISSN2077-0383
期号9(1)
作者Daniel Sur, Andrei Havasi, Calin Cainap, Gabriel Samasca, Claudia Burz, Ovidiu Balacescu, Iulia Lupan, Diana Deleanu, AlexandruIrimie

一句话小结 ​

本综述探讨了嵌合抗原受体（CAR）T细胞疗法在结直肠癌治疗中的现状与挑战，尽管该疗法在血液恶性肿瘤中取得积极结果，但在结直肠癌中仍面临疗效有限和高昂成本等问题。通过对22篇相关文献的分析，研究强调了克服毒性、复发及肿瘤微环境不利影响的重要性，展望未来的研究方向。

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嵌合抗原受体（CAR）T细胞 · 结直肠癌 · 免疫治疗 · 毒性 · 临床试验

摘要 ​

嵌合抗原受体（CAR）T细胞疗法代表了一种新型的基因工程免疫治疗方法，用于癌症治疗。患者的T细胞经过修改后表达特定的受体，该受体能够附着于肿瘤抗原。经过修改的细胞随后重新引入患者体内，以对抗顽固的癌细胞。在血液恶性肿瘤中表现出积极结果后，这种疗法被提议用于结直肠癌等实体肿瘤。目前，关于CAR T细胞疗法在结直肠癌中的临床数据相对稀缺。在本综述中，我们总结了CAR T细胞疗法在结直肠癌中的现状、挑战及未来展望。此次综述共纳入了22篇文章。合格的研究由两位研究者从在Pubmed、Web of Science和clinicaltrials.gov上找到的49篇文章中选择并审阅。目前，这种疗法在实体肿瘤中提供的益处相对有限。除了高昂的生产和销售价格外，在结直肠癌中，CAR T细胞疗法仍面临诸如毒性增加、复发以及不利的肿瘤微环境等局限性。

英文摘要 ​

Chimeric antigen receptor (CAR) T-cell therapy represents a new genetically engineered method of immunotherapy for cancer. The patient's T-cells are modified to express a specific receptor that sticks to the tumor antigen. This modified cell is then reintroduced into the patient's body to fight the resilient cancer cells. After exhibiting positive results in hematological malignancies, this therapy is being proposed for solid tumors like colorectal cancer. The clinical data of CAR T-cell therapy in colorectal cancer is rather scarce. In this review, we summarize the current state of knowledge, challenges, and future perspectives of CAR T-cell therapy in colorectal cancer. A total of 22 articles were included in this review. Eligible studies were selected and reviewed by two researchers from 49 articles found on Pubmed, Web of Science, and clinicaltrials.gov. This therapy, at the moment, provides modest benefits in solid tumors. Not taking into consideration the high manufacturing and retail prices, there are still limitations like increased toxicities, relapses, and unfavorable tumor microenvironment for CAR T-cell therapy in colorectal cancer.

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主要研究问题 ​

  1. CAR T细胞疗法在结直肠癌的应用中面临哪些具体的挑战和限制？
  2. 与其他免疫疗法相比，CAR T细胞疗法在结直肠癌患者中的疗效如何？
  3. 当前有哪些研究正在探索CAR T细胞疗法在结直肠癌中的改进方法？
  4. 结直肠癌的肿瘤微环境对CAR T细胞疗法的效果有何影响？
  5. 如何评估CAR T细胞疗法在结直肠癌患者中的长期安全性和有效性？

核心洞察 ​

研究背景和目的 ​

结直肠癌（CRC）是全球常见的癌症之一，并且在癌症相关死亡中排名第二。尽管现有的化疗和靶向治疗手段有所改善，但对于转移性结直肠癌患者，整体生存率仍然较低。近年来，嵌合抗原受体（CAR）T细胞疗法作为一种新兴的免疫治疗方法，显示出在血液肿瘤中的有效性，本文旨在总结CAR T细胞疗法在结直肠癌中的应用现状、挑战及未来前景。

主要方法/材料/实验设计 ​

本文综述了22篇与结直肠癌相关的CAR T细胞疗法的研究，主要通过Pubmed、Web of Science和clinicaltrials.gov等数据库进行文献检索。选取的研究经过两位研究者的审核和筛选，确保其相关性和质量。

以下是CAR T细胞疗法的技术路线图：

Mermaid diagram

关键结果和发现 ​

  1. 疗效与安全性：目前的临床数据表明，CAR T细胞疗法在结直肠癌中的疗效相对有限，主要表现为毒性增加、复发率高和肿瘤微环境不利等问题。
  2. 潜在靶点：多项研究探索了不同的靶点，如CEA、GUCY2C和TAG-72等，部分靶点显示出一定的抗肿瘤活性。
  3. 临床试验：当前有多个临床试验正在进行，探讨CAR T细胞在转移性结直肠癌中的应用，包括针对EGFR、HER2等靶点的疗法。

主要结论/意义/创新性 ​

CAR T细胞疗法在结直肠癌的治疗中仍处于探索阶段，尽管其在某些靶点上显示出潜力，但整体疗效尚未达到预期。未来的研究应着重于靶点选择、联合疗法以及优化治疗方案，以提高患者的临床获益。

研究局限性和未来方向 ​

  1. 局限性：当前CAR T细胞疗法在结直肠癌的应用受限于肿瘤微环境的抑制作用、治疗后的复发以及制造和治疗成本等因素。
  2. 未来方向：未来的研究应聚焦于改善CAR T细胞的靶向性、增强其在肿瘤微环境中的生存能力，并探索与其他治疗手段（如免疫检查点抑制剂）的联合使用。

表格总结 ​

研究方面结果/发现
疗效整体疗效有限，部分靶点显示活性
安全性毒性增加、复发率高
潜在靶点CEA、GUCY2C、TAG-72等
未来方向靶点选择优化、联合疗法探索

综上所述，CAR T细胞疗法在结直肠癌的应用具有一定的前景，但仍需大量研究以克服现有的挑战并提高其临床有效性。

参考文献 ​

  1. Monoclonal antibody 3H11 chimeric antigen receptors enhance T cell effector function and exhibit efficacy against gastric cancer. - Haibo Han;Shanshan Wang;Ying Hu;Zhaowei Li;Wei Yang;Yunwei Lv;Limin Wang;Lianhai Zhang;Jiafu Ji - Oncology letters (2018)
  2. Anti-GPC3-CAR T Cells Suppress the Growth of Tumor Cells in Patient-Derived Xenografts of Hepatocellular Carcinoma. - Zhiwu Jiang;Xiaofeng Jiang;Suimin Chen;Yunxin Lai;Xinru Wei;Baiheng Li;Simiao Lin;Suna Wang;Qiting Wu;Qiubin Liang;Qifa Liu;Muyun Peng;Fenglei Yu;Jianyu Weng;Xin Du;Duanqing Pei;Pentao Liu;Yao Yao;Ping Xue;Peng Li - Frontiers in immunology (2016)
  3. Update in Systemic and Targeted Therapies in Gastrointestinal Oncology. - Nelson S Yee - Biomedicines (2018)
  4. Chimeric antigen receptor-modified T cells for the immunotherapy of patients with EGFR-expressing advanced relapsed/refractory non-small cell lung cancer. - Kaichao Feng;Yelei Guo;Hanren Dai;Yao Wang;Xiang Li;Hejin Jia;Weidong Han - Science China. Life sciences (2016)
  5. Critical factors in chimeric antigen receptor-modified T-cell (CAR-T) therapy for solid tumors. - Lingli Yan;Bainan Liu - OncoTargets and therapy (2019)
  6. MicroRNA in colorectal cancer: new perspectives for diagnosis, prognosis and treatment. - Leonilde Bonfrate;Donato F Altomare;Maria Di Lena;Elisabetta Travaglio;Maria Teresa Rotelli;Angela De Luca;Piero Portincasa - Journal of gastrointestinal and liver diseases : JGLD (2013)
  7. Inactivation of Interferon Receptor Promotes the Establishment of Immune Privileged Tumor Microenvironment. - Kanstantsin V Katlinski;Jun Gui;Yuliya V Katlinskaya;Angelíca Ortiz;Riddhita Chakraborty;Sabyasachi Bhattacharya;Christopher J Carbone;Daniel P Beiting;Melanie A Girondo;Amy R Peck;Ellen Puré;Priya Chatterji;Anil K Rustgi;J Alan Diehl;Constantinos Koumenis;Hallgeir Rui;Serge Y Fuchs - Cancer cell (2017)
  8. Triplet (FOLFOXIRI) versus doublet (FOLFOX or FOLFIRI) backbone chemotherapy as first-line treatment of metastatic colorectal cancer: A systematic review and meta-analysis. - Rui Pedro Marques;Gonçalo S Duarte;Carmelo Sterrantino;Helena Luna Pais;António Quintela;Ana Paula Martins;João Costa - Critical reviews in oncology/hematology (2017)
  9. HER2 expression status in diverse cancers: review of results from 37,992 patients. - Min Yan;Maria Schwaederle;David Arguello;Sherri Z Millis;Zoran Gatalica;Razelle Kurzrock - Cancer metastasis reviews (2015)
  10. Multi Targeted CAR-T Cell Therapies for B-Cell Malignancies. - Nirav N Shah;Theresa Maatman;Parameswaran Hari;Bryon Johnson - Frontiers in oncology (2019)

引用本文的文献 ​

  1. Emerging Role of Immunotherapy for Colorectal Cancer with Liver Metastasis. - Xianzhe Yu;Lingling Zhu;Jiewei Liu;Ming Xie;Jiang Chen;Jianguo Li - OncoTargets and therapy (2020)
  2. Immune cell labelling and tracking: implications for adoptive cell transfer therapies. - Filippo Galli;Michela Varani;Chiara Lauri;Guido Gentiloni Silveri;Livia Onofrio;Alberto Signore - EJNMMI radiopharmacy and chemistry (2021)
  3. Stem cells as therapeutic targets in colorectal cancer. - Alicja Zalewski;Adam E Snook;Scott A Waldman - Personalized medicine (2021)
  4. Tumor regression and immunity in combination therapy with anti-CEA chimeric antigen receptor T cells and anti-CEA-IL2 immunocytokine. - Seung E Cha;Maciej Kujawski;Paul J Yazaki;Christine Brown;John E Shively - Oncoimmunology (2021)
  5. GUCY2C as a biomarker to target precision therapies for patients with colorectal cancer. - Amanda N Lisby;John C Flickinger;Babar Bashir;Megan Weindorfer;Sanjna Shelukar;Madison Crutcher;Adam E Snook;Scott A Waldman - Expert review of precision medicine and drug development (2021)
  6. The Role of p53 Dysfunction in Colorectal Cancer and Its Implication for Therapy. - Maurice Michel;Leonard Kaps;Annett Maderer;Peter R Galle;Markus Moehler - Cancers (2021)
  7. Liver Immune Microenvironment and Metastasis from Colorectal Cancer-Pathogenesis and Therapeutic Perspectives. - Xuezhen Zeng;Simon E Ward;Jingying Zhou;Alfred S L Cheng - Cancers (2021)
  8. CAR-T cells: Early successes in blood cancer and challenges in solid tumors. - Hassan Dana;Ghanbar Mahmoodi Chalbatani;Seyed Amir Jalali;Hamid Reza Mirzaei;Stephan A Grupp;Eloah Rabello Suarez;Catarina Rapôso;Thomas J Webster - Acta pharmaceutica Sinica. B (2021)
  9. Cannabinoids, Medical Cannabis, and Colorectal Cancer Immunotherapy. - Mariia Zaiachuk;Nazar Pryimak;Olga Kovalchuk;Igor Kovalchuk - Frontiers in medicine (2021)
  10. A Mathematical Modeling Approach for Targeted Radionuclide and Chimeric Antigen Receptor T Cell Combination Therapy. - Vikram Adhikarla;Dennis Awuah;Alexander B Brummer;Enrico Caserta;Amrita Krishnan;Flavia Pichiorri;Megan Minnix;John E Shively;Jeffrey Y C Wong;Xiuli Wang;Russell C Rockne - Cancers (2021)

... (31 更多 篇文献)

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