MaltSci 麦伴科研

Appearance

文献精选 > 高引权威"CAR-T疗法"文献

MUC1 as a target for CAR-T therapy in head and neck squamous cell carinoma. ​

文献信息 ​

DOI10.1002/cam4.2733
PMID31800160
期刊Cancer medicine
影响因子3.1
JCR 分区Q2
发表年份2020
被引次数61
关键词CAR-T, IL22, MUC1, 头颈部鳞状细胞 carcinoma
文献类型Journal Article, Research Support, Non-U.S. Gov't
ISSN2045-7634
页码640-652
期号9(2)
作者Zi Mei, Kai Zhang, Alfred King-Yin Lam, Junwen Huang, Feng Qiu, Bin Qiao, Yi Zhang

一句话小结 ​

本研究探讨了CAR-T疗法在头颈部鳞状细胞癌（HNSCC）中的应用潜力，重点验证了MUC1作为靶标的有效性。结果显示，构建的CAR-MUC1-IL22 T细胞对MUC1+ HNSCC细胞表现出显著的细胞毒性，表明该疗法在治疗HNSCC患者中具有良好的前景。

在麦伴科研 (maltsci.com) 搜索更多文献 ​

CAR-T · IL22 · MUC1 · 头颈部鳞状细胞 carcinoma

摘要 ​

嵌合抗原受体（CAR）修饰赋予T细胞肿瘤特异性细胞毒性，从而诱导抗肿瘤免疫。然而，实体肿瘤的结构特征、特定抗原的丧失以及强大的免疫抑制环境都是使用CAR-T治疗实体肿瘤的挑战。我们研究的目的在于寻找并验证CAR-T疗法在头颈部鳞状细胞癌（HNSCC）患者中的潜力。首先，我们选择MUC1作为研究目标，并验证其在癌症组织与邻近非肿瘤组织（ANNT）中的差异表达。接下来，我们构建了第二代CAR并在体外验证了其细胞毒功能。在我们的研究中，我们发现外源性添加的人IL22重组蛋白可以增加MUC1的表达并增强T细胞的功能。此外，我们构建了一种分泌IL22的第四代CAR。最后，我们分别在体外和体内验证了两种不同CAR-T细胞的抗肿瘤功能。结果表明，CAR-MUC1-IL22 T细胞对MUC1+ HNSCC细胞具有更强和更有效的细胞毒功能。综合来看，这些结果展示了CAR-T在治疗HNSCC患者中的潜在有效性，并为MUC1+ CAR-T疗法提供了证据支持。

英文摘要 ​

The modification of chimeric antigen receptor (CAR) endowing T cells with tumor-specific cytotoxicity induces antitumor immunity. However, the structural characteristics of solid tumors, the loss of specific antigens, and the strong immunosuppressive environment are challenges to treat solid tumors with CAR-T therapy. The purpose of our study was to find and verify the potentials of CAR-T therapies for patients with head and neck squamous cell carcinoma (HNSCC). First, we selected MUC1 as our research target and verified its differential expression in cancer tissues and adjacent non-neoplastic tissues (ANNT). Next, we constructed a second-generation CAR and validated the cytotoxic function in vitro. In our study, we found that exogenous addition human IL22 recombinant protein could increase the MUC1 expression and enhance the function of T cells. In addition, we constructed a fourth-generation CAR that secretes IL22. Finally, we verified the antitumor function of two different CAR-T cells in vitro and in vivo, respectively. CAR-MUC1-IL22 T cells were found to have a stronger and more effective cytotoxic function against MUC1 + HNSCC cells. Taken together, these results demonstrate the potential effectiveness of CAR-T in the treatment of patients with HNSCC and provide evidence-based of MUC1 + CAR-T therapy.

麦伴智能科研服务 ​

智能阅读回答你对文献的任何问题，帮助理解文献中的复杂图表和公式
定位观点定位某个观点在文献中的蛛丝马迹
加入知识库完成数据提取，报告撰写等更多高级知识挖掘功能

主要研究问题 ​

  1. 除了MUC1，还有哪些其他抗原适合用于头颈部鳞状细胞癌的CAR-T治疗？
  2. 在使用MUC1作为靶点的CAR-T疗法中，IL22的作用机制是什么？
  3. 目前针对头颈部鳞状细胞癌的CAR-T疗法有哪些临床试验在进行中？
  4. MUC1的表达差异在不同患者中的变异性如何影响CAR-T治疗的效果？
  5. 如何评估MUC1+ CAR-T细胞在临床应用中的安全性和有效性？

核心洞察 ​

研究背景和目的 ​

头颈部鳞状细胞癌（HNSCC）是全球第六大常见癌症，现有治疗手段（如手术、放疗和化疗）效果有限，患者预后不佳。因此，寻找新的治疗策略至关重要。该研究旨在探讨MUC1作为靶点的CAR-T细胞疗法在HNSCC中的潜力，尤其是构建一种能分泌IL22的第四代CAR-T细胞，以提高治疗效果。

主要方法/材料/实验设计 ​

本研究采用了以下方法进行CAR-T细胞的构建和验证：

  1. MUC1表达验证：通过TCGA数据库和qRT-PCR分析MUC1在HNSCC组织中的表达情况。
  2. CAR构建：
    • 第二代CAR：构建包含MUC1单链抗体片段的CAR，结合CD8α和4-1BB、CD3ζ信号传导区域。
    • 第四代CAR：在第二代CAR基础上，添加IL22编码序列以提高CAR-T细胞的功能。
  3. 细胞培养：使用DMEM-F12培养HNSCC细胞系，并通过流式细胞术检测细胞表面MUC1的表达。
  4. T细胞制备：从人外周血单核细胞中分离CD3+ T细胞，使用CD3/CD28抗体激活。
  5. 细胞功能检测：通过共培养实验评估CAR-T细胞对HNSCC细胞的细胞毒性，使用ELISA检测细胞因子的分泌。
  6. 动物实验：在NOD/SCID小鼠模型中评估CAR-T细胞的抗肿瘤效果，定期监测肿瘤生长情况。
Mermaid diagram

关键结果和发现 ​

  1. MUC1高表达：在HNSCC组织中，MUC1的表达显著高于相邻非肿瘤组织，支持其作为治疗靶点的潜力。
  2. CAR-T细胞功能：
    • 第二代CAR-MUC1 T细胞在体外实验中显示出良好的细胞毒性。
    • 第四代CAR-MUC1-IL22 T细胞的细胞毒性更强，能够在较低的E/T比率下有效杀伤肿瘤细胞。
  3. IL22的作用：IL22的添加不仅提高了MUC1的表达，还增强了T细胞的增殖和存活能力。
  4. 体内实验结果：接受CAR-MUC1和CAR-MUC1-IL22 T细胞治疗的小鼠肿瘤生长显著抑制，且CAR-MUC1-IL22组效果更佳。

主要结论/意义/创新性 ​

本研究表明，MUC1作为CAR-T细胞治疗HNSCC的靶点具有良好的前景，尤其是结合IL22的第四代CAR-T细胞展示了更强的抗肿瘤能力。这为HNSCC的治疗提供了新的思路，并可能推动CAR-T细胞疗法在实体瘤中的应用。

研究局限性和未来方向 ​

  1. 局限性：目前研究主要基于体外和小鼠模型，临床应用尚需进一步验证。
  2. 未来方向：需要开展更多临床试验，探索MUC1靶向CAR-T细胞在HNSCC患者中的疗效和安全性。同时，研究如何提高CAR-T细胞的转染效率和存活时间，以增强其抗肿瘤效果。

参考文献 ​

  1. Mucins: the Old, the New and the Promising Factors in Hepatobiliary Carcinogenesis. - Aldona Kasprzak;Agnieszka Adamek - International journal of molecular sciences (2019)
  2. Chimeric antigen receptor T cells for sustained remissions in leukemia. - Shannon L Maude;Noelle Frey;Pamela A Shaw;Richard Aplenc;David M Barrett;Nancy J Bunin;Anne Chew;Vanessa E Gonzalez;Zhaohui Zheng;Simon F Lacey;Yolanda D Mahnke;Jan J Melenhorst;Susan R Rheingold;Angela Shen;David T Teachey;Bruce L Levine;Carl H June;David L Porter;Stephan A Grupp - The New England journal of medicine (2014)
  3. IL-22 ameliorates intestinal inflammation in a mouse model of ulcerative colitis. - Ken Sugimoto;Atsuhiro Ogawa;Emiko Mizoguchi;Yasuyo Shimomura;Akira Andoh;Atul K Bhan;Richard S Blumberg;Ramnik J Xavier;Atsushi Mizoguchi - The Journal of clinical investigation (2008)
  4. Platinum-based chemotherapy plus cetuximab in head and neck cancer. - Jan B Vermorken;Ricard Mesia;Fernando Rivera;Eva Remenar;Andrzej Kawecki;Sylvie Rottey;Jozsef Erfan;Dmytro Zabolotnyy;Heinz-Roland Kienzer;Didier Cupissol;Frederic Peyrade;Marco Benasso;Ihor Vynnychenko;Dominique De Raucourt;Carsten Bokemeyer;Armin Schueler;Nadia Amellal;Ricardo Hitt - The New England journal of medicine (2008)
  5. Closely related T-memory stem cells correlate with in vivo expansion of CAR.CD19-T cells and are preserved by IL-7 and IL-15. - Yang Xu;Ming Zhang;Carlos A Ramos;April Durett;Enli Liu;Olga Dakhova;Hao Liu;Chad J Creighton;Adrian P Gee;Helen E Heslop;Cliona M Rooney;Barbara Savoldo;Gianpietro Dotti - Blood (2014)
  6. Interleukin-22, a T(H)17 cytokine, mediates IL-23-induced dermal inflammation and acanthosis. - Yan Zheng;Dimitry M Danilenko;Patricia Valdez;Ian Kasman;Jeffrey Eastham-Anderson;Jianfeng Wu;Wenjun Ouyang - Nature (2007)
  7. Cutting edge: immune cells as sources and targets of the IL-10 family members? - Kerstin Wolk;Stefanie Kunz;Khusru Asadullah;Robert Sabat - Journal of immunology (Baltimore, Md. : 1950) (2002)
  8. IL-22/IL-22R1 signaling regulates the pathophysiology of chronic rhinosinusitis with nasal polyps via alteration of MUC1 expression. - Yasuyuki Noyama;Mitsuhiro Okano;Tazuko Fujiwara;Shin Kariya;Takaya Higaki;Takenori Haruna;Sei-Ichiro Makihara;Kengo Kanai;Takahisa Koyama;Masami Taniguchi;Jun-Ichi Ishitoya;Akira Kanda;Yoshiki Kobayashi;Mikiya Asako;Koichi Tomoda;Kazunori Nishizaki - Allergology international : official journal of the Japanese Society of Allergology (2017)
  9. PSCA and MUC1 in non-small-cell lung cancer as targets of chimeric antigen receptor T cells. - Xinru Wei;Yunxin Lai;Jin Li;Le Qin;Youdi Xu;Ruocong Zhao;Baiheng Li;Simiao Lin;Suna Wang;Qiting Wu;Qiubin Liang;Muyun Peng;Fenglei Yu;Yangqiu Li;Xuchao Zhang;Yilong Wu;Pentao Liu;Duanqing Pei;Yao Yao;Peng Li - Oncoimmunology (2017)
  10. MUC1-C activates the TAK1 inflammatory pathway in colon cancer. - H Takahashi;C Jin;H Rajabi;S Pitroda;M Alam;R Ahmad;D Raina;M Hasegawa;Y Suzuki;A Tagde;R T Bronson;R Weichselbaum;D Kufe - Oncogene (2015)

引用本文的文献 ​

  1. MUC1 as a target for CAR-T therapy in head and neck squamous cell carinoma. - Zi Mei;Kai Zhang;Alfred King-Yin Lam;Junwen Huang;Feng Qiu;Bin Qiao;Yi Zhang - Cancer medicine (2020)
  2. Antibodies specific for disease-associated antigens (DAA) expressed in non-malignant diseases reveal potential new tumor-associated antigens (TAA) for immunotherapy or immunoprevention. - Camille Jacqueline;Olivera J Finn - Seminars in immunology (2020)
  3. Gene modification strategies for next-generation CAR T cells against solid cancers. - Yonggui Tian;Yilu Li;Yupei Shao;Yi Zhang - Journal of hematology & oncology (2020)
  4. Insights into Nanomedicine for Immunotherapeutics in Squamous Cell Carcinoma of the head and neck. - Qiang Xu;Meiyu Fang;Jing Zhu;Haoru Dong;Jun Cao;Lin Yan;Fransisca Leonard;Felix Oppel;Holger Sudhoff;Andreas M Kaufmann;Andreas E Albers;Xu Qian - International journal of biological sciences (2020)
  5. Adoptive Cell Therapy in Hepatocellular Carcinoma: Biological Rationale and First Results in Early Phase Clinical Trials. - Philippe Rochigneux;Brice Chanez;Bernadette De Rauglaudre;Emmanuel Mitry;Christian Chabannon;Marine Gilabert - Cancers (2021)
  6. Anti-mucin 1 chimeric antigen receptor T cells for adoptive T cell therapy of cholangiocarcinoma. - Kamonlapat Supimon;Thanich Sangsuwannukul;Jatuporn Sujjitjoon;Nattaporn Phanthaphol;Thaweesak Chieochansin;Naravat Poungvarin;Sopit Wongkham;Mutita Junking;Pa-Thai Yenchitsomanus - Scientific reports (2021)
  7. Immune Checkpoints Pathways in Head and Neck Squamous Cell Carcinoma. - Florencia Veigas;Yamil D Mahmoud;Joaquin Merlo;Adriana Rinflerch;Gabriel Adrian Rabinovich;María Romina Girotti - Cancers (2021)
  8. Immune deserts in head and neck squamous cell carcinoma: A review of challenges and opportunities for modulating the tumor immune microenvironment. - Janice L Farlow;J Chad Brenner;Yu L Lei;Steven B Chinn - Oral oncology (2021)
  9. A Systematic Review on PD-1 Blockade and PD-1 Gene-Editing of CAR-T Cells for Glioma Therapy: From Deciphering to Personalized Medicine. - Mahdi Abdoli Shadbad;Nima Hemmat;Vahid Khaze Shahgoli;Afshin Derakhshani;Farzad Baradaran;Oronzo Brunetti;Rossella Fasano;Renato Bernardini;Nicola Silvestris;Behzad Baradaran - Frontiers in immunology (2021)
  10. Novel Cellular Therapies for Hepatocellular Carcinoma. - Harriet Roddy;Tim Meyer;Claire Roddie - Cancers (2022)

... (51 更多 篇文献)

© 2025 MaltSci 麦伴科研 - 我们用人工智能技术重塑科研