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CD19 CAR-T cells of defined CD4+:CD8+ composition in adult B cell ALL patients. ​

文献信息 ​

PMID27111235
期刊The Journal of clinical investigation
影响因子13.6
JCR 分区Q1
发表年份2016
被引次数1162
关键词CD19 CAR-T细胞, B细胞急性淋巴细胞白血病, 细胞毒性, 免疫治疗, 生物标志物
文献类型Clinical Trial, Phase I, Clinical Trial, Phase II, Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural
ISSN0021-9738
页码2123-38
期号126(6)
作者Cameron J Turtle, Laïla-Aïcha Hanafi, Carolina Berger, Theodore A Gooley, Sindhu Cherian, Michael Hudecek, Daniel Sommermeyer, Katherine Melville, Barbara Pender, Tanya M Budiarto, Emily Robinson, Natalia N Steevens, Colette Chaney, Lorinda Soma, Xueyan Chen, Cecilia Yeung, Brent Wood, Daniel Li, Jianhong Cao, Shelly Heimfeld, Michael C Jensen, Stanley R Riddell, David G Maloney

一句话小结 ​

本研究探讨了特定CD4+和CD8+ T细胞亚群制备的CD19 CAR-T细胞在成人B细胞急性淋巴细胞白血病患者中的应用，结果显示93%的患者达成骨髓缓解，同时识别了与细胞扩展、持久性和毒性相关的关键因素。该研究为优化CAR-T细胞治疗策略提供了重要依据，有助于降低毒性并改善无病生存期。

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CD19 CAR-T细胞 · B细胞急性淋巴细胞白血病 · 细胞毒性 · 免疫治疗 · 生物标志物

摘要 ​

背景
经过修饰以表达CD19特异性嵌合抗原受体（CAR）的T细胞在B细胞恶性肿瘤中具有抗肿瘤活性；然而，在以未筛选的T细胞制备表型异质性的CAR-T细胞产品的先前研究中，识别决定这些T细胞毒性和疗效的因素一直存在挑战。

方法
我们进行了一项临床试验，评估从特定的CD4+和CD8+ T细胞亚群制造的CD19 CAR-T细胞，并在淋巴消耗化疗后按照特定的CD4+:CD8+组成给药于成人B细胞急性淋巴细胞白血病患者。

结果
该特定组成的产品显示出显著的疗效，29名患者中有27名（93%）通过流式细胞术确认达成骨髓缓解。我们确定高剂量的CAR-T细胞和肿瘤负担增加了严重细胞因子释放综合征和神经毒性的风险。此外，我们识别出允许在高风险毒性患者中测试早期干预策略的血清生物标志物。基于骨髓疾病负担的风险分层CAR-T细胞给药降低了毒性。在某些患者中，CD8+ T细胞介导的抗CAR转基因产品免疫反应在CAR-T细胞输注后发展，限制了CAR-T细胞的持续性，并增加了复发风险。将氟达拉滨加入淋巴消耗方案改善了CAR-T细胞的持久性和无病生存期。

结论
使用具有特定组成的CAR-T细胞产品的免疫疗法使得识别与CAR-T细胞扩展、持久性和毒性相关的因素成为可能，并促进了淋巴消耗和CAR-T细胞给药策略的设计，从而减轻了毒性并改善了无病生存期。

试验注册
ClinicalTrials.gov NCT01865617。

资助
R01-CA136551；生命科学发展基金；Juno Therapeutics；贝索斯家庭基金会。

英文摘要 ​

BACKGROUND T cells that have been modified to express a CD19-specific chimeric antigen receptor (CAR) have antitumor activity in B cell malignancies; however, identification of the factors that determine toxicity and efficacy of these T cells has been challenging in prior studies in which phenotypically heterogeneous CAR-T cell products were prepared from unselected T cells.

METHODS We conducted a clinical trial to evaluate CD19 CAR-T cells that were manufactured from defined CD4+ and CD8+ T cell subsets and administered in a defined CD4+:CD8+ composition to adults with B cell acute lymphoblastic leukemia after lymphodepletion chemotherapy.

RESULTS The defined composition product was remarkably potent, as 27 of 29 patients (93%) achieved BM remission, as determined by flow cytometry. We established that high CAR-T cell doses and tumor burden increase the risks of severe cytokine release syndrome and neurotoxicity. Moreover, we identified serum biomarkers that allow testing of early intervention strategies in patients at the highest risk of toxicity. Risk-stratified CAR-T cell dosing based on BM disease burden decreased toxicity. CD8+ T cell-mediated anti-CAR transgene product immune responses developed after CAR-T cell infusion in some patients, limited CAR-T cell persistence, and increased relapse risk. Addition of fludarabine to the lymphodepletion regimen improved CAR-T cell persistence and disease-free survival.

CONCLUSION Immunotherapy with a CAR-T cell product of defined composition enabled identification of factors that correlated with CAR-T cell expansion, persistence, and toxicity and facilitated design of lymphodepletion and CAR-T cell dosing strategies that mitigated toxicity and improved disease-free survival.

TRIAL REGISTRATION ClinicalTrials.gov NCT01865617.

FUNDING R01-CA136551; Life Science Development Fund; Juno Therapeutics; Bezos Family Foundation.

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主要研究问题 ​

  1. CD19 CAR-T细胞的定义CD4+:CD8+组成如何影响患者的长期生存率？
  2. 在CD19 CAR-T细胞治疗中，如何优化淋巴耗竭化疗以提高CAR-T细胞的持久性？
  3. 有哪些特定的血清生物标志物可以预测CAR-T细胞治疗的毒性风险？
  4. CD8+ T细胞介导的免疫反应对CAR-T细胞的持久性和复发风险有什么具体影响？
  5. 在成人B细胞急性淋巴细胞白血病患者中，如何根据骨髓疾病负担进行风险分层的CAR-T细胞剂量调整？

核心洞察 ​

研究背景和目的 ​

在B细胞恶性肿瘤中，表达CD19特异性嵌合抗原受体（CAR）的T细胞显示出抗肿瘤活性。然而，先前研究中，表型异质的CAR-T细胞产品使得确定这些T细胞的毒性和疗效的因素变得困难。因此，本研究旨在评估由特定CD4+和CD8+ T细胞亚群制备的CD19 CAR-T细胞，并在成人B细胞急性淋巴细胞白血病患者中使用。

主要方法/材料/实验设计 ​

本研究为一项临床试验，涉及以下关键步骤：

  1. 患者选择：选取经过淋巴耗竭化疗的成人B细胞急性淋巴细胞白血病患者。
  2. T细胞制备：从患者体内分离出特定的CD4+和CD8+ T细胞亚群，制备成CD19 CAR-T细胞。
  3. 给药方案：以特定的CD4+:CD8+比例给药。

以下是技术路线的流程图：

Mermaid diagram

关键结果和发现 ​

  • 27例患者（93%）在流式细胞术评估中达到骨髓缓解。
  • 高剂量CAR-T细胞和肿瘤负担增加了严重细胞因子释放综合征和神经毒性的风险。
  • 识别出可用于检测高风险毒性的血清生物标志物。
  • 基于骨髓疾病负担的风险分层CAR-T细胞给药策略减少了毒性。
  • 一些患者在CAR-T细胞输注后出现CD8+ T细胞介导的抗CAR转基因产品免疫反应，限制了CAR-T细胞的持久性并增加了复发风险。
  • 在淋巴耗竭方案中添加氟达拉滨改善了CAR-T细胞的持久性和无病生存期。

主要结论/意义/创新性 ​

本研究表明，使用特定组成的CAR-T细胞产品可以识别与CAR-T细胞扩展、持久性和毒性相关的因素，进而设计出减少毒性并改善无病生存期的淋巴耗竭和CAR-T细胞给药策略。这为未来的CAR-T细胞治疗提供了重要的理论依据和实践指导。

研究局限性和未来方向 ​

  • 本研究的局限性在于样本量相对较小，且仅限于特定类型的白血病患者，可能影响结果的广泛适用性。
  • 未来的研究可以扩展到其他类型的肿瘤以及更大规模的临床试验，以验证本研究的发现，并探索更优化的CAR-T细胞治疗方案。
研究要素细节
研究类型临床试验
患者群体成人B细胞急性淋巴细胞白血病患者
CAR-T细胞制备方式从特定CD4+和CD8+ T细胞亚群制备
关键发现高剂量和肿瘤负担增加毒性风险；CD8+ T细胞反应限制持久性
结论识别毒性因素并改善无病生存期的策略
未来方向扩大样本量，探索其他肿瘤类型的适用性

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引用本文的文献 ​

  1. Toxicities of chimeric antigen receptor T cells: recognition and management. - Jennifer N Brudno;James N Kochenderfer - Blood (2016)
  2. Generation of clinical-grade CD19-specific CAR-modified CD8+ memory stem cells for the treatment of human B-cell malignancies. - Marianna Sabatino;Jinhui Hu;Michele Sommariva;Sanjivan Gautam;Vicki Fellowes;James D Hocker;Sean Dougherty;Haiying Qin;Christopher A Klebanoff;Terry J Fry;Ronald E Gress;James N Kochenderfer;David F Stroncek;Yun Ji;Luca Gattinoni - Blood (2016)
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  6. Immunotherapy for opportunistic infections: Current status and future perspectives. - Shigeo Fuji;Jürgen Löffler;Hermann Einsele;Markus Kapp - Virulence (2016)
  7. Prospects for chimeric antigen receptor (CAR) γδ T cells: A potential game changer for adoptive T cell cancer immunotherapy. - Hamid Reza Mirzaei;Hamed Mirzaei;Sang Yun Lee;Jamshid Hadjati;Brian G Till - Cancer letters (2016)
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  10. Does it make sense to target one tumor cell chemotactic factor or its receptor when several chemotactic axes are involved in metastasis of the same cancer? - Mariusz Z Ratajczak;Malwina Suszynska;Magda Kucia - Clinical and translational medicine (2016)

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