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

StephenW

使用短期 HBV 特异性 TCR 表达的 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#1、赵金芳#1、Anthony Tanoto Tan#2、胡伟1、王思雨1、金洁华1、胡娟1、李媛媛1、石磊1、傅俊良1、于双杰1 , Yingjuan Shen 1 , Limin Liu 1 , Junqing Luan 1 , Ming Shi 1 , Yunbo Xie 1 , Chun-Bao Zhou 1 , Regina Wanju Wong 3 , Wai Lu-En 3 4 , Sarene Koh 3 4 , Antonio Bertoletti 2 4 ,王婷婷 5 , 张继元 6 , 王福生 7
隶属关系
隶属关系

    1
    中国北京西四环100号，中国人民解放军总医院第五医学中心，国家传染病临床研究中心，高级传染病科，北京，100039。
    2
    新加坡新加坡杜克-新加坡国立大学医学院新兴传染病。
    3
    狮子 TCR 私人有限公司Ltd, 77 Ayer Rajah Crescent, #01-29, Singapore, 139954, Singapore。
    4
    新加坡免疫学网络，科学技术局 (A*STAR)，新加坡，新加坡。
    5
    狮子 TCR 私人有限公司Ltd, 77 Ayer Rajah Crescent, #01-29, Singapore, 139954, Singapore。 [email protected]。
    6
    中国北京西四环100号，中国人民解放军总医院第五医学中心，国家传染病临床研究中心，高级传染病科，北京，100039。 [email protected]。
    7
    中国北京西四环100号，中国人民解放军总医院第五医学中心，国家传染病临床研究中心，高级传染病科，北京，100039。 [email protected]。

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同等贡献。

    PMID：34850325 DOI：10.1007/s12072-021-10250-2

抽象的

背景和目的：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）评估抗肿瘤反应和总生存期来评估 HBV-TCR-T 细胞疗法的疗效。

结果：在纳入的 8 名患者中，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 剂量后出现 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：本研究已在 ClinicalTrials.gov (NCT03899415) 上注册。

关键词：慢性乙型肝炎；临床试验;乙肝病毒； HBV-TCR-T 细胞；肝细胞癌；免疫疗法；总生存期；阶段1;安全;进度时间。

© 2021。作者。

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 #  1 , Jinfang Zhao #  1 , Anthony Tanoto Tan #  2 , Wei Hu  1 , Si-Yu Wang  1 , Jiehua Jin  1 , Juan Wu  1 , Yuanyuan Li  1 , Lei Shi  1 , Jun-Liang Fu  1 , Shuangjie Yu  1 , Yingjuan Shen  1 , Limin Liu  1 , Junqing Luan  1 , Ming Shi  1 , Yunbo Xie  1 , Chun-Bao Zhou  1 , Regina Wanju Wong  3 , Wai Lu-En  3   4 , Sarene Koh  3   4 , Antonio Bertoletti  2   4 , Tingting Wang  5 , Ji-Yuan Zhang  6 , Fu-Sheng Wang  7
Affiliations
Affiliations

    1
    Senior Department of Infectious Diseases, The Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious Diseases, 100 Western 4th Ring Road, Beijing, 100039, China.
    2
    Emerging Infectious Diseases, Duke-NUS Medical School, Singapore, Singapore.
    3
    Lion TCR Pte. Ltd, 77 Ayer Rajah Crescent, #01-29, Singapore, 139954, Singapore.
    4
    Singapore Immunology Network, Agency for Science and Technology (A*STAR), Singapore, Singapore.
    5
    Lion TCR Pte. Ltd, 77 Ayer Rajah Crescent, #01-29, Singapore, 139954, Singapore. [email protected].
    6
    Senior Department of Infectious Diseases, The Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious Diseases, 100 Western 4th Ring Road, Beijing, 100039, China. [email protected].
    7
    Senior Department of Infectious Diseases, The Fifth Medical Center of Chinese PLA General Hospital, National Clinical Research Center for Infectious Diseases, 100 Western 4th Ring Road, Beijing, 100039, China. [email protected].

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Contributed equally.

    PMID: 34850325 DOI: 10.1007/s12072-021-10250-2

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).

Keywords: Chronic hepatitis B; Clinical trial; HBV; HBV-TCR-T cells; HCC; Immunotherapy; Overall survival; Phase 1; Safety; Time-to-progression.

© 2021. The Author(s).