TRBC1-CAR T cell therapy in peripheral T cell lymphoma: a phase 1/2 trial

IF 58.7 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Nature Medicine Pub Date : 2024-11-11 DOI:10.1038/s41591-024-03326-7
Kate Cwynarski, Gloria Iacoboni, Eleni Tholouli, Tobias Menne, David A. Irvine, Nivetha Balasubramaniam, Leigh Wood, Justin Shang, Eric Xue, Yiyun Zhang, Silvia Basilico, Margarida Neves, Meera Raymond, Ian Scott, Mohamed El-Kholy, Ram Jha, Heather Dainton-Smith, Rehan Hussain, William Day, Mathieu Ferrari, Simon Thomas, Koki Lilova, Wolfram Brugger, Teresa Marafioti, Pierre Lao-Sirieix, Paul Maciocia, Martin Pule
{"title":"TRBC1-CAR T cell therapy in peripheral T cell lymphoma: a phase 1/2 trial","authors":"Kate Cwynarski, Gloria Iacoboni, Eleni Tholouli, Tobias Menne, David A. Irvine, Nivetha Balasubramaniam, Leigh Wood, Justin Shang, Eric Xue, Yiyun Zhang, Silvia Basilico, Margarida Neves, Meera Raymond, Ian Scott, Mohamed El-Kholy, Ram Jha, Heather Dainton-Smith, Rehan Hussain, William Day, Mathieu Ferrari, Simon Thomas, Koki Lilova, Wolfram Brugger, Teresa Marafioti, Pierre Lao-Sirieix, Paul Maciocia, Martin Pule","doi":"10.1038/s41591-024-03326-7","DOIUrl":null,"url":null,"abstract":"<p>Relapsed/refractory peripheral T cell lymphomas (PTCLs) are aggressive tumors with a poor prognosis. Unlike B cell lymphomas, treatment of PTCL has not benefited from advances in immunotherapy. This is largely due to a lack of suitable target antigens that discriminate malignant from normal T cells, thus avoiding severe immunosuppression consequent to depletion of the entire T cell compartment. We recently described a targeting strategy based on the mutually exclusive expression of T cell antigen receptor beta-chain constant domain (TRBC) 1 and 2. Selective targeting of the T cell antigen receptor beta-chain expressed by the (clonal) malignancy spares normal T cells expressing the other chain. The LibraT1 study is an ongoing, multicenter, international, single-arm phase 1/2 study of TRBC1-directed autologous chimeric antigen receptor (CAR) T cells (AUTO4) in relapsed/refractory TRBC1-positive PTCL. Primary objectives were assessment of safety and tolerability of AUTO4 infusion. Key secondary endpoints included efficacy, CAR T cell expansion and persistence. Here we describe the findings from dose escalation in LibraT1 in the first ten patients, in a non-prespecified interim analysis. AUTO4 resulted in low frequency of severe immunotoxicity, with one of ten patients developing grade 3 cytokine release syndrome. Complete metabolic response was observed in four of ten evaluable patients, with remissions being durable beyond 1 year in two patients. While an absence of circulating CAR T cells was observed, CAR T cells were readily detected in lymph node biopsy samples from sites of original disease suggesting homing to tumor sites. These results support the continuing exploration of TRBC1 targeting in PTCL. ClinicalTrials.gov registration: NCT03590574.</p>","PeriodicalId":19037,"journal":{"name":"Nature Medicine","volume":null,"pages":null},"PeriodicalIF":58.7000,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Nature Medicine","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1038/s41591-024-03326-7","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0

Abstract

Relapsed/refractory peripheral T cell lymphomas (PTCLs) are aggressive tumors with a poor prognosis. Unlike B cell lymphomas, treatment of PTCL has not benefited from advances in immunotherapy. This is largely due to a lack of suitable target antigens that discriminate malignant from normal T cells, thus avoiding severe immunosuppression consequent to depletion of the entire T cell compartment. We recently described a targeting strategy based on the mutually exclusive expression of T cell antigen receptor beta-chain constant domain (TRBC) 1 and 2. Selective targeting of the T cell antigen receptor beta-chain expressed by the (clonal) malignancy spares normal T cells expressing the other chain. The LibraT1 study is an ongoing, multicenter, international, single-arm phase 1/2 study of TRBC1-directed autologous chimeric antigen receptor (CAR) T cells (AUTO4) in relapsed/refractory TRBC1-positive PTCL. Primary objectives were assessment of safety and tolerability of AUTO4 infusion. Key secondary endpoints included efficacy, CAR T cell expansion and persistence. Here we describe the findings from dose escalation in LibraT1 in the first ten patients, in a non-prespecified interim analysis. AUTO4 resulted in low frequency of severe immunotoxicity, with one of ten patients developing grade 3 cytokine release syndrome. Complete metabolic response was observed in four of ten evaluable patients, with remissions being durable beyond 1 year in two patients. While an absence of circulating CAR T cells was observed, CAR T cells were readily detected in lymph node biopsy samples from sites of original disease suggesting homing to tumor sites. These results support the continuing exploration of TRBC1 targeting in PTCL. ClinicalTrials.gov registration: NCT03590574.

Abstract Image

查看原文
分享 分享
微信好友 朋友圈 QQ好友 复制链接
本刊更多论文
外周 T 细胞淋巴瘤的 TRBC1-CAR T 细胞疗法:1/2 期试验
复发/难治性外周T细胞淋巴瘤(PTCL)是一种侵袭性肿瘤,预后较差。与 B 细胞淋巴瘤不同,PTCL 的治疗并未受益于免疫疗法的进步。这主要是由于缺乏合适的靶抗原来区分恶性和正常的T细胞,从而避免因整个T细胞群的耗竭而造成严重的免疫抑制。我们最近描述了一种基于 T 细胞抗原受体 beta 链恒定域(TRBC)1 和 2 相互排斥表达的靶向策略。选择性靶向由(克隆)恶性肿瘤表达的 T 细胞抗原受体 beta 链,可挽救表达另一条链的正常 T 细胞。LibraT1研究是一项正在进行的多中心、国际单臂1/2期研究,研究对象是复发/难治性TRBC1阳性PTCL的TRBC1定向自体嵌合抗原受体(CAR)T细胞(AUTO4)。首要目标是评估输注AUTO4的安全性和耐受性。主要次要终点包括疗效、CAR T细胞扩增和持续性。在此,我们将介绍在 LibraT1 中对首批 10 例患者进行剂量升级的结果,这是一项未作明确说明的中期分析。AUTO4 导致的严重免疫毒性发生率较低,10 例患者中有 1 例出现 3 级细胞因子释放综合征。在 10 例可评估的患者中,有 4 例观察到完全代谢反应,其中 2 例患者的缓解可持续 1 年以上。虽然没有观察到循环 CAR T 细胞,但在原发疾病部位的淋巴结活检样本中很容易检测到 CAR T 细胞,这表明它们在肿瘤部位归巢。这些结果支持继续探索 TRBC1 靶向治疗 PTCL。ClinicalTrials.gov 注册:NCT03590574。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 去求助
来源期刊
Nature Medicine
Nature Medicine 医学-生化与分子生物学
CiteScore
100.90
自引率
0.70%
发文量
525
审稿时长
1 months
期刊介绍: Nature Medicine is a monthly journal publishing original peer-reviewed research in all areas of medicine. The publication focuses on originality, timeliness, interdisciplinary interest, and the impact on improving human health. In addition to research articles, Nature Medicine also publishes commissioned content such as News, Reviews, and Perspectives. This content aims to provide context for the latest advances in translational and clinical research, reaching a wide audience of M.D. and Ph.D. readers. All editorial decisions for the journal are made by a team of full-time professional editors. Nature Medicine consider all types of clinical research, including: -Case-reports and small case series -Clinical trials, whether phase 1, 2, 3 or 4 -Observational studies -Meta-analyses -Biomarker studies -Public and global health studies Nature Medicine is also committed to facilitating communication between translational and clinical researchers. As such, we consider “hybrid” studies with preclinical and translational findings reported alongside data from clinical studies.
期刊最新文献
Seven-year performance of a clinical metagenomic next-generation sequencing test for diagnosis of central nervous system infections H5N1 from an infected dairy worker sheds light on viral transmission TRBC1-CAR T cell therapy in peripheral T cell lymphoma: a phase 1/2 trial Moving toward response-adapted trials in oncology Oncolytic immunotherapy with nivolumab in muscle-invasive bladder cancer: a phase 1b trial
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
已复制链接
已复制链接
快去分享给好友吧!
我知道了
×
扫码分享
扫码分享
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1