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

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
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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.

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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。
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