使用短期 HBV 特异性 TCR 表达 T 细胞对 HBV 相关晚期肝细胞癌

StephenW

使用短期 HBV 特异性 TCR 表达 T 细胞对 HBV 相关晚期肝细胞癌进行免疫治疗：剂量递增的结果，I 期试验

    孟凡平、赵金芳、Anthony Tanoto Tan、胡伟、王思雨、金洁华、吴娟、李媛媛、石磊、傅俊良、俞双杰、沉颖娟、刘丽敏、栾俊清、石铭、谢云波、周春宝、Regina Wanju Wong、Wai Lu-En、Sarene Koh、Antonio Bertoletti、Tingting Wang、Ji-Yuan Zhang & Fu-Sheng Wang

Hepatology International 第 15 卷，第 1402–1412 页（2021 年）引用本文

    207 次访问

    1 替代指标

    指标详情

抽象的
背景与目标

据报道，肝移植后 HBV 相关肝细胞癌 (HBV-HCC) 患者使用乙型肝炎病毒 (HBV) 特异性 TCR 重定向 T (HBV-TCR-T) 细胞进行免疫治疗是安全的，并具有潜在的治疗效果。我们旨在研究 HBV-TCR-T 细胞免疫疗法在不符合肝移植标准的晚期 HBV-HCC 患者中的安全性。
方法

我们招募了 8 名晚期 HBV-HCC 患者，并过继转移了表达 HBV 特异性 TCR 的短寿命自体 T 细胞，以进行开放标签的 1 期剂量递增研究 (NCT03899415)。主要终点是根据美国国家癌症研究所不良事件通用术语标准（4.03 版）在剂量递增过程中评估 HBV-TCR-T 细胞治疗的安全性。次要终点是通过使用 RECIST 标准（1.1 版）和总生存率评估抗肿瘤反应来评估 HBV-TCR-T 细胞疗法的疗效。
结果

在登记的 8 名患者中，有两名参与者观察到不良事件。只有一名患者在接受 1 × 105 HBV-TCR-T 细胞/kg 的剂量后出现了 3 级肝脏相关不良事件，然后在没有免疫抑制剂干预的情况下恢复正常。在这些患者中，一名患者获得了持续 27.7 个月的部分缓解。重要的是，大多数患者在 HBV-TCR-T 细胞输注后表现出循环 HBsAg 和 HBV DNA 水平的降低或稳定，表明了靶向效应。
结论

将 HBV-TCR-T 细胞过继转移到晚期 HBV-HCC 患者中通常是安全且耐受良好的。临床疗效观察支持该治疗策略在晚期 HBV 相关 HCC 患者中的持续发展和最终应用。
临床试验注册

该研究已在 ClinicalTrials.gov (NCT03899415) 上注册。

StephenW

Immunotherapy of HBV-related advanced hepatocellular carcinoma with short-term HBV-specific TCR expressed T cells: results of dose escalation, phase I trial

    Fanping Meng, Jinfang Zhao, Anthony Tanoto Tan, Wei Hu, Si-Yu Wang, Jiehua Jin, Juan Wu, Yuanyuan Li, Lei Shi, Jun-Liang Fu, Shuangjie Yu, Yingjuan Shen, Limin Liu, Junqing Luan, Ming Shi, Yunbo Xie, Chun-Bao Zhou, Regina Wanju Wong, Wai Lu-En, Sarene Koh, Antonio Bertoletti, Tingting Wang, Ji-Yuan Zhang & Fu-Sheng Wang

Hepatology International volume 15, pages 1402–1412 (2021)Cite this article

    207 Accesses

    1 Altmetric

    Metrics details

Abstract
Background & aims

Immunotherapy with hepatitis B virus (HBV)-specific TCR redirected T (HBV-TCR-T) cells in HBV-related hepatocellular carcinoma (HBV-HCC) patients after liver transplantation was reported to be safe and had potential therapeutic efficacy. We aim to investigate the safety of HBV-TCR-T-cell immunotherapy in advanced HBV-HCC patients who had not met the criteria for liver transplantation.
Methods

We enrolled eight patients with advanced HBV-HCC and adoptively transferred short-lived autologous T cells expressing HBV-specific TCR to perform an open-label, phase 1 dose-escalation study (NCT03899415). The primary endpoint was to evaluate the safety of HBV-TCR-T-cell therapy according to National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.03) during the dose-escalation process. The secondary endpoint was to assess the efficacy of HBV-TCR-T-cell therapy by evaluating the anti-tumor responses using RECIST criteria (version 1.1) and the overall survival.
Results

Adverse events were observed in two participants among the 8 patients enrolled. Only one patient experienced a Grade 3 liver-related adverse event after receiving a dose of 1 × 105 HBV-TCR-T cells/kg, then normalized without interventions with immunosuppressive agents. Among the patients, one achieved a partial response lasting for 27.7 months. Importantly, most of the patients exhibited a reduction or stabilization of circulating HBsAg and HBV DNA levels after HBV-TCR-T-cell infusion, indicating the on-target effects.
Conclusions

The adoptive transfer of HBV-TCR-T cells into advanced HBV-HCC patients were generally safe and well-tolerated. Observations of clinical efficacy support the continued development and eventual application of this treatment strategy in patients with advanced HBV-related HCC.
Clinical trials registration

This study was registered at ClinicalTrials.gov (NCT03899415).

StephenW

https://link.springer.com/articl ... c_springer_20211208