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文献精选 > 高引权威"CAR-T疗法"文献

CAR-T cell therapy: current limitations and potential strategies. ​

文献信息 ​

DOI10.1038/s41408-021-00459-7
PMID33824268
期刊Blood cancer journal
影响因子11.6
JCR 分区Q1
发表年份2021
被引次数1221
关键词CAR-T细胞疗法, 肿瘤微环境, 治疗限制
文献类型Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Review
ISSN2044-5385
页码69
期号11(4)
作者Robert C Sterner, Rosalie M Sterner

一句话小结 ​

嵌合抗原受体（CAR）T细胞疗法在治疗B细胞白血病和淋巴瘤中取得了显著效果，但在实体肿瘤和血液恶性肿瘤中面临着毒性、抗原逃逸及肿瘤微环境影响等多重挑战。本文综述了最近的创新策略，旨在增强CAR-T细胞的抗肿瘤活性并降低副作用，以改善其在这两类肿瘤中的临床应用。

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CAR-T细胞疗法 · 肿瘤微环境 · 治疗限制

摘要 ​

嵌合抗原受体（CAR）T细胞疗法是癌症治疗中的一项革命性新支柱。尽管CAR-T细胞治疗在某些亚型的B细胞白血病或淋巴瘤中产生了显著的临床反应，但许多挑战限制了CAR-T细胞在实体肿瘤和血液恶性肿瘤中的治疗效果。有效的CAR-T细胞疗法面临的障碍包括严重的危及生命的毒性、适度的抗肿瘤活性、抗原逃逸、运输受限以及肿瘤浸润有限。此外，宿主与肿瘤微环境与CAR-T细胞的相互作用会显著改变CAR-T细胞的功能。此外，开发和实施这些治疗需要一个复杂的工作团队。为了克服这些重大挑战，需要创新策略和方法来设计更强大的CAR-T细胞，以提高抗肿瘤活性并降低毒性。在本综述中，我们讨论了最近在CAR-T细胞工程方面的创新，以提高其在血液恶性肿瘤和实体肿瘤中的临床疗效，以及克服CAR-T细胞疗法在这两类肿瘤中局限性的策略。

英文摘要 ​

Chimeric antigen receptor (CAR)-T cell therapy is a revolutionary new pillar in cancer treatment. Although treatment with CAR-T cells has produced remarkable clinical responses with certain subsets of B cell leukemia or lymphoma, many challenges limit the therapeutic efficacy of CAR-T cells in solid tumors and hematological malignancies. Barriers to effective CAR-T cell therapy include severe life-threatening toxicities, modest anti-tumor activity, antigen escape, restricted trafficking, and limited tumor infiltration. In addition, the host and tumor microenvironment interactions with CAR-T cells critically alter CAR-T cell function. Furthermore, a complex workforce is required to develop and implement these treatments. In order to overcome these significant challenges, innovative strategies and approaches to engineer more powerful CAR-T cells with improved anti-tumor activity and decreased toxicity are necessary. In this review, we discuss recent innovations in CAR-T cell engineering to improve clinical efficacy in both hematological malignancy and solid tumors and strategies to overcome limitations of CAR-T cell therapy in both hematological malignancy and solid tumors.

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主要研究问题 ​

  1. 除了现有的CAR-T细胞工程创新，还有哪些新兴技术可能进一步提高其在实体肿瘤中的疗效？
  2. 针对CAR-T细胞治疗中的抗原逃逸现象，有哪些潜在的解决方案或策略？
  3. 在不同的肿瘤微环境中，CAR-T细胞的功能如何受到影响，是否有针对性的干预措施？
  4. 如何评估和管理CAR-T细胞治疗中出现的严重毒性反应，以提高患者的安全性？
  5. 针对CAR-T细胞在治疗血液恶性肿瘤和实体肿瘤中的不同表现，是否有特定的工程策略需要区别对待？

核心洞察 ​

研究背景和目的 ​

嵌合抗原受体（CAR）T细胞治疗是癌症治疗领域的一项革命性进展，尤其在某些B细胞白血病和淋巴瘤的治疗中取得了显著的临床效果。然而，该疗法在固体肿瘤和某些血液恶性肿瘤中的疗效受到严重限制，主要包括毒性反应、抗肿瘤活性不足、抗原逃逸、肿瘤浸润受限等问题。本文旨在探讨CAR-T细胞治疗的当前局限性及其潜在的解决策略。

主要方法/材料/实验设计 ​

本文采用文献综述的方式，分析了CAR-T细胞的结构、功能以及在不同肿瘤类型中的应用，同时总结了当前的技术进展和未来的研究方向。

Mermaid diagram

关键结果和发现 ​

  1. 抗原逃逸：许多患者在CAR-T细胞治疗后出现抗原表达下调或丧失，导致治疗失败。采用双抗原或串联CAR设计能够提高抗肿瘤效果。
  2. 毒性反应：CAR-T细胞治疗常伴随严重的细胞因子释放综合征（CRS）和神经毒性，可能导致生命危险。
  3. 肿瘤浸润受限：CAR-T细胞在固体肿瘤中的浸润能力受到肿瘤微环境和物理屏障的限制。
  4. 免疫抑制微环境：肿瘤微环境中的免疫抑制细胞（如MDSCs和Tregs）影响CAR-T细胞的持久性和功能。

主要结论/意义/创新性 ​

尽管CAR-T细胞治疗在某些血液恶性肿瘤中表现出色，但其在固体肿瘤中的应用仍面临诸多挑战。通过多靶点设计、局部给药和与其他免疫治疗结合，可能有效提升CAR-T细胞的疗效和安全性。未来的研究应集中在CAR结构的优化及对免疫微环境的调节上，以实现更广泛的临床应用。

研究局限性和未来方向 ​

  1. 局限性：文献综述未能涵盖所有最新的临床试验数据和技术进展。
  2. 未来方向：建议进一步探索CAR-T细胞的个性化设计、优化给药途径以及与其他治疗手段的联合应用，尤其是在固体肿瘤的治疗中，以提高患者的治疗反应和生存率。

参考文献 ​

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引用本文的文献 ​

  1. Adoptive Natural Killer Cell Immunotherapy for Canine Osteosarcoma. - William C Kisseberth;Dean A Lee - Frontiers in veterinary science (2021)
  2. CAR T cells: Building on the CD19 paradigm. - Anat Globerson Levin;Isabelle Rivière;Zelig Eshhar;Michel Sadelain - European journal of immunology (2021)
  3. The "Magic Bullet" Is Here? Cell-Based Immunotherapies for Hematological Malignancies in the Twilight of the Chemotherapy Era. - Nina Miazek-Zapala;Aleksander Slusarczyk;Aleksandra Kusowska;Piotr Zapala;Matylda Kubacz;Magdalena Winiarska;Malgorzata Bobrowicz - Cells (2021)
  4. In vitro selection of DNA aptamers against human osteosarcoma. - Khaliunsarnai Tsogtbaatar;Diana A Sousa;Debora Ferreira;Atakan Tevlek;Halil Murat Aydın;Eda Çelik;Ligia Rodrigues - Investigational new drugs (2022)
  5. The Promise of Personalized TCR-Based Cellular Immunotherapy for Cancer Patients. - Marion Arnaud;Sara Bobisse;Johanna Chiffelle;Alexandre Harari - Frontiers in immunology (2021)
  6. Structure-Dependent Stability of Lipid-Based Polymer Amphiphiles Inserted on Erythrocytes. - Chunsong Yu;Myunggi An;Meng Li;Charles Manke;Haipeng Liu - Membranes (2021)
  7. Nanoparticles Targeting Innate Immune Cells in Tumor Microenvironment. - Hochung Jang;Eun Hye Kim;Sung-Gil Chi;Sun Hwa Kim;Yoosoo Yang - International journal of molecular sciences (2021)
  8. Ubiquitination in T-Cell Activation and Checkpoint Inhibition: New Avenues for Targeted Cancer Immunotherapy. - Shubhangi Gavali;Jianing Liu;Xinyi Li;Magdalena Paolino - International journal of molecular sciences (2021)
  9. Improving CAR T-Cell Persistence. - Violena Pietrobon;Lauren Anne Todd;Anghsumala Goswami;Ofir Stefanson;Zhifen Yang;Francesco Marincola - International journal of molecular sciences (2021)
  10. Implications of Antigen Selection on T Cell-Based Immunotherapy. - Faye A Camp;Jill E Slansky - Pharmaceuticals (Basel, Switzerland) (2021)

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