MaltSci 麦伴科研

Appearance

文献精选 > 高引权威"CAR-T疗法"文献

Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. ​

文献信息 ​

DOI10.1056/NEJMoa1215134
PMID23527958
期刊The New England journal of medicine
影响因子78.5
JCR 分区Q1
发表年份2013
被引次数1855
关键词嵌合抗原受体, 急性淋巴细胞白血病, 细胞因子释放综合症
文献类型Case Reports, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't
ISSN0028-4793
页码1509-1518
期号368(16)
作者Stephan A Grupp, Michael Kalos, David Barrett, Richard Aplenc, David L Porter, Susan R Rheingold, David T Teachey, Anne Chew, Bernd Hauck, J Fraser Wright, Michael C Milone, Bruce L Levine, Carl H June

一句话小结 ​

本研究探讨了针对CD19的嵌合抗原受体（CAR）T细胞在复发难治性前B细胞急性淋巴细胞白血病（ALL）儿童中的临床应用，结果显示两名患者均实现完全缓解，其中一名患者在11个月后仍保持缓解。研究发现CAR T细胞在体内扩增显著，但也出现了细胞因子释放综合症和B细胞缺失，提示未来治疗可能需要针对其他分子以应对白血病细胞逃逸。

在麦伴科研 (maltsci.com) 搜索更多文献 ​

嵌合抗原受体 · 急性淋巴细胞白血病 · 细胞因子释放综合症

摘要 ​

带有针对CD19特异性的嵌合抗原受体（CAR）改造T细胞在治疗慢性淋巴细胞白血病（CLL）方面显示出良好的前景。然而，尚需确定嵌合抗原受体T细胞在急性淋巴细胞白血病（ALL）中的临床活性。两名复发且难治的前B细胞急性淋巴细胞白血病儿童接受了转导有抗CD19抗体和T细胞信号分子（CTL019嵌合抗原受体T细胞）的T细胞输注，剂量为每千克体重1.4×10^6至1.2×10^7个CTL019细胞。两名患者的CTL019 T细胞扩增至初始移植水平的1000倍以上，并在骨髓中被检测到。此外，嵌合抗原受体T细胞在脑脊液中也被观察到，并且在至少6个月内保持在高水平。共观察到8例3级或4级不良事件。两名患者均出现了细胞因子释放综合症和B细胞缺失。在一名儿童中，细胞因子释放综合症严重；使用依那西普和托珠单抗进行细胞因子阻断有效逆转了该综合症，并且没有阻止嵌合抗原受体T细胞的扩增或降低抗白血病疗效。两名患者均观察到完全缓解，其中一名患者在治疗后11个月仍在持续缓解。另一名患者在治疗后约2个月出现复发，白血病细胞不再表达CD19。嵌合抗原受体改造T细胞能够在体内杀死即使是侵袭性、难治的急性白血病细胞。肿瘤细胞不再表达靶标的出现表明，在某些ALL患者中，需要靶向除CD19以外的其他分子。

英文摘要 ​

Chimeric antigen receptor-modified T cells with specificity for CD19 have shown promise in the treatment of chronic lymphocytic leukemia (CLL). It remains to be established whether chimeric antigen receptor T cells have clinical activity in acute lymphoblastic leukemia (ALL). Two children with relapsed and refractory pre-B-cell ALL received infusions of T cells transduced with anti-CD19 antibody and a T-cell signaling molecule (CTL019 chimeric antigen receptor T cells), at a dose of 1.4×10(6) to 1.2×10(7) CTL019 cells per kilogram of body weight. In both patients, CTL019 T cells expanded to a level that was more than 1000 times as high as the initial engraftment level, and the cells were identified in bone marrow. In addition, the chimeric antigen receptor T cells were observed in the cerebrospinal fluid (CSF), where they persisted at high levels for at least 6 months. Eight grade 3 or 4 adverse events were noted. The cytokine-release syndrome and B-cell aplasia developed in both patients. In one child, the cytokine-release syndrome was severe; cytokine blockade with etanercept and tocilizumab was effective in reversing the syndrome and did not prevent expansion of chimeric antigen receptor T cells or reduce antileukemic efficacy. Complete remission was observed in both patients and is ongoing in one patient at 11 months after treatment. The other patient had a relapse, with blast cells that no longer expressed CD19, approximately 2 months after treatment. Chimeric antigen receptor-modified T cells are capable of killing even aggressive, treatment-refractory acute leukemia cells in vivo. The emergence of tumor cells that no longer express the target indicates a need to target other molecules in addition to CD19 in some patients with ALL.

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. 在急性淋巴细胞白血病的治疗中，除了CD19，是否有其他潜在的靶点可以考虑？
  2. CTL019细胞在骨髓和脑脊液中的持久性对患者的长期预后有何影响？
  3. 针对细胞因子释放综合征的管理，是否有其他有效的治疗策略可以结合使用？
  4. 在急性淋巴细胞白血病的临床试验中，如何评估CAR-T细胞的长期疗效和安全性？
  5. 患者在接受CTL019治疗后复发的机制是什么，如何预防此类复发？

核心洞察 ​

研究背景和目的 ​

急性淋巴细胞白血病（ALL）是一种儿童常见的血液肿瘤，尽管已有多种治疗手段，但对于复发和难治性病例的预后仍然较差。本研究旨在评估改造的嵌合抗原受体（CAR）T细胞（CTL019）在复发性和难治性前B细胞ALL中的安全性和有效性。

主要方法/材料/实验设计 ​

本研究为一项临床试验，涉及两名患有复发和难治性前B细胞ALL的儿童。患者接受了经过抗CD19抗体和T细胞信号分子转导的CTL019 T细胞输注。具体实验设计如下：

Mermaid diagram
  • 患者招募与筛选：选取符合条件的复发和难治性前B细胞ALL患者。
  • PBMCs收集与T细胞扩增：通过单采技术收集外周血单核细胞（PBMCs）。
  • CTL019 T细胞转导与扩增：使用慢病毒载体技术转导T细胞以表达抗CD19 CAR。
  • CTL019 T细胞输注：将扩增后的CTL019 T细胞输注给患者。
  • 监测T细胞扩增与疗效：通过流式细胞术和分子检测监测T细胞在外周血、骨髓和脑脊液中的扩增情况。
  • 评估不良事件与生存情况：记录患者的副作用和临床反应。

关键结果和发现 ​

  • 疗效：两名患者均实现完全缓解，其中一名患者在治疗11个月后持续缓解，而另一名患者在治疗2个月后复发，复发细胞不再表达CD19。
  • T细胞扩增：CTL019 T细胞在输注后扩增至初始水平的1000倍以上，并在骨髓和脑脊液中被检测到。
  • 不良事件：两名患者均出现3级或4级不良事件，包括细胞因子释放综合症和B细胞缺失。

主要结论/意义/创新性 ​

本研究表明，CTL019 CAR T细胞在治疗复发和难治性前B细胞ALL中具有显著的抗肿瘤活性和良好的耐受性。尤其是在难治性病例中，CAR T细胞显示出强大的治疗潜力。然而，复发病例中CD19阴性细胞的出现提示需要开发针对其他靶点的治疗策略。

研究局限性和未来方向 ​

  • 局限性：样本量小，仅涉及两名患者，结果的普遍性尚需进一步验证。
  • 未来方向：建议未来研究应探索结合其他靶点的CAR T细胞治疗，以降低CD19阴性逃逸变异体的风险，并评估长期疗效和安全性。

参考文献 ​

  1. In childhood acute lymphoblastic leukemia, blasts at different stages of immunophenotypic maturation have stem cell properties. - Christoph le Viseur;Marc Hotfilder;Simon Bomken;Kerrie Wilson;Silja Röttgers;André Schrauder;Annegret Rosemann;Julie Irving;Ronald W Stam;Leonard D Shultz;Jochen Harbott;Heribert Jürgens;Martin Schrappe;Rob Pieters;Josef Vormoor - Cancer cell (2008)
  2. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. - David L Porter;Bruce L Levine;Michael Kalos;Adam Bagg;Carl H June - The New England journal of medicine (2011)
  3. T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. - Michael Kalos;Bruce L Levine;David L Porter;Sharyn Katz;Stephan A Grupp;Adam Bagg;Carl H June - Science translational medicine (2011)
  4. Safety and persistence of adoptively transferred autologous CD19-targeted T cells in patients with relapsed or chemotherapy refractory B-cell leukemias. - Renier J Brentjens;Isabelle Rivière;Jae H Park;Marco L Davila;Xiuyan Wang;Jolanta Stefanski;Clare Taylor;Raymond Yeh;Shirley Bartido;Oriana Borquez-Ojeda;Malgorzata Olszewska;Yvette Bernal;Hollie Pegram;Mark Przybylowski;Daniel Hollyman;Yelena Usachenko;Domenick Pirraglia;James Hosey;Elmer Santos;Elizabeth Halton;Peter Maslak;David Scheinberg;Joseph Jurcic;Mark Heaney;Glenn Heller;Mark Frattini;Michel Sadelain - Blood (2011)
  5. Tumor regression in cancer patients by very low doses of a T cell-engaging antibody. - Ralf Bargou;Eugen Leo;Gerhard Zugmaier;Matthias Klinger;Mariele Goebeler;Stefan Knop;Richard Noppeney;Andreas Viardot;Georg Hess;Martin Schuler;Hermann Einsele;Christian Brandl;Andreas Wolf;Petra Kirchinger;Petra Klappers;Margit Schmidt;Gert Riethmüller;Carsten Reinhardt;Patrick A Baeuerle;Peter Kufer - Science (New York, N.Y.) (2008)
  6. Interleukin-6 modulates graft-versus-host responses after experimental allogeneic bone marrow transplantation. - Isao Tawara;Motoko Koyama;Chen Liu;Tomomi Toubai;Dafydd Thomas;Rebecca Evers;Peter Chockley;Evelyn Nieves;Yaping Sun;Kathleen P Lowler;Chelsea Malter;Norihiro Nishimoto;Geoffrey R Hill;Pavan Reddy - Clinical cancer research : an official journal of the American Association for Cancer Research (2011)
  7. B-cell depletion and remissions of malignancy along with cytokine-associated toxicity in a clinical trial of anti-CD19 chimeric-antigen-receptor-transduced T cells. - James N Kochenderfer;Mark E Dudley;Steven A Feldman;Wyndham H Wilson;David E Spaner;Irina Maric;Maryalice Stetler-Stevenson;Giao Q Phan;Marybeth S Hughes;Richard M Sherry;James C Yang;Udai S Kammula;Laura Devillier;Robert Carpenter;Debbie-Ann N Nathan;Richard A Morgan;Carolyn Laurencot;Steven A Rosenberg - Blood (2012)
  8. Graft-versus-leukemia effect of donor lymphocyte transfusions in marrow grafted patients. - H J Kolb;A Schattenberg;J M Goldman;B Hertenstein;N Jacobsen;W Arcese;P Ljungman;A Ferrant;L Verdonck;D Niederwieser;F van Rhee;J Mittermueller;T de Witte;E Holler;H Ansari; - Blood (1995)
  9. IL-6 blockade attenuates the development of murine sclerodermatous chronic graft-versus-host disease. - Doanh Le Huu;Takashi Matsushita;Guihua Jin;Yasuhito Hamaguchi;Minoru Hasegawa;Kazuhiko Takehara;Manabu Fujimoto - The Journal of investigative dermatology (2012)
  10. Salvage therapy for refractory or relapsed acute lymphocytic leukemia. - G Garcia-Manero;D A Thomas - Hematology/oncology clinics of North America (2001)

引用本文的文献 ​

  1. Zoom Zoom: racing CARs for multiple myeloma. - Marcela V Maus;Carl H June - Clinical cancer research : an official journal of the American Association for Cancer Research (2013)
  2. Advanced targeted, cell and gene-therapy approaches for pediatric hematological malignancies: results and future perspectives. - Chiara F Magnani;Sarah Tettamanti;Francesca Maltese;Nice Turazzi;Andrea Biondi;Ettore Biagi - Frontiers in oncology (2013)
  3. Cytokine release syndrome after blinatumomab treatment related to abnormal macrophage activation and ameliorated with cytokine-directed therapy. - David T Teachey;Susan R Rheingold;Shannon L Maude;Gerhard Zugmaier;David M Barrett;Alix E Seif;Kim E Nichols;Erica K Suppa;Michael Kalos;Robert A Berg;Julie C Fitzgerald;Richard Aplenc;Lia Gore;Stephan A Grupp - Blood (2013)
  4. Young T Cells Age During a Redirected Anti-Tumor Attack: Chimeric Antigen Receptor-Provided Dual Costimulation is Half the Battle. - Andreas A Hombach;Hinrich Abken - Frontiers in immunology (2013)
  5. Cardiovascular toxicity and titin cross-reactivity of affinity-enhanced T cells in myeloma and melanoma. - Gerald P Linette;Edward A Stadtmauer;Marcela V Maus;Aaron P Rapoport;Bruce L Levine;Lyndsey Emery;Leslie Litzky;Adam Bagg;Beatriz M Carreno;Patrick J Cimino;Gwendolyn K Binder-Scholl;Dominic P Smethurst;Andrew B Gerry;Nick J Pumphrey;Alan D Bennett;Joanna E Brewer;Joseph Dukes;Jane Harper;Helen K Tayton-Martin;Bent K Jakobsen;Namir J Hassan;Michael Kalos;Carl H June - Blood (2013)
  6. Cellular immunotherapy for refractory hematological malignancies. - John L Reagan;Loren D Fast;Howard Safran;Martha Nevola;Eric S Winer;Jorge J Castillo;James N Butera;Matthew I Quesenberry;Carolyn T Young;Peter J Quesenberry - Journal of translational medicine (2013)
  7. Perspective: assembly line immunotherapy. - Bruce L Levine;Carl H June - Nature (2013)
  8. Evolutionary dynamics of cancer in response to targeted combination therapy. - Ivana Bozic;Johannes G Reiter;Benjamin Allen;Tibor Antal;Krishnendu Chatterjee;Preya Shah;Yo Sup Moon;Amin Yaqubie;Nicole Kelly;Dung T Le;Evan J Lipson;Paul B Chapman;Luis A Diaz;Bert Vogelstein;Martin A Nowak - eLife (2013)
  9. Chimeric antigen receptor-engineered T cells for cancer immunotherapy: progress and challenges. - Ethan Q Han;Xiu-ling Li;Chun-rong Wang;Tian-fang Li;Shuang-yin Han - Journal of hematology & oncology (2013)
  10. Generation of tumor antigen-specific T cell lines from pediatric patients with acute lymphoblastic leukemia--implications for immunotherapy. - Gerrit Weber;Ignazio Caruana;Rayne H Rouce;A John Barrett;Ulrike Gerdemann;Ann M Leen;Karen R Rabin;Catherine M Bollard - Clinical cancer research : an official journal of the American Association for Cancer Research (2013)

... (1845 更多 篇文献)

© 2025 MaltSci 麦伴科研 - 我们用人工智能技术重塑科研