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TRBC1-CAR T cell therapy in peripheral T cell lymphoma: a phase 1/2 trial
Nature Medicine ( IF 58.7 ) 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

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.



中文翻译:


外周 T 细胞淋巴瘤中的 TRBC1-CAR T 细胞疗法:一项 1/2 期试验



复发/难治性外周 T 细胞淋巴瘤 (PTCLs) 是预后不良的侵袭性肿瘤。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。这主要是由于缺乏区分恶性 T 细胞和正常 T 细胞的合适靶抗原,从而避免了因整个 T 细胞区室耗竭而导致的严重免疫抑制。我们最近描述了一种基于 T 细胞抗原受体 β 链恒定结构域 (TRBC) 1 和 2 互斥表达的靶向策略。选择性靶向(克隆性)恶性肿瘤表达的 T 细胞抗原受体 β 链,使表达另一条链的正常 T 细胞幸免于难。LibraT1 研究是一项持续的、多中心、国际的单臂 1/2 期研究,研究对象是 TRBC1 定向的自体嵌合抗原受体 (CAR) T 细胞 (AUTO4) 治疗复发/难治性 TRBC1 阳性 PTCL。主要目标是评估 AUTO4 输注的安全性和耐受性。关键次要终点包括疗效、 CAR T 细胞扩增和持久性。在这里,我们在非预先指定的中期分析中描述了前 10 名患者 LibraT1 剂量递增的结果。AUTO4 导致严重免疫毒性的频率较低,10 例患者中有 1 例发生 3 级细胞因子释放综合征。在 10 例可评估患者中有 4 例观察到完全代谢反应,2 例患者的缓解持续超过 1 年。虽然观察到不存在循环 CAR T 细胞,但在来自原始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 CAR T 细胞归巢到肿瘤部位。这些结果支持在 PTCL 中继续探索 TRBC1 靶向。ClinicalTrials.gov 注册:NCT03590574。

更新日期:2024-11-12
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