短寿命 HBV-TCR T 细胞免疫治疗后的免疫学改变与 HBV-HCC 的长期

StephenW

短寿命 HBV-TCR T 细胞免疫治疗后的免疫学改变与 HBV-HCC 的长期治疗反应相关
Anthony Tanoto Tan #1 , Fanping Meng #2 3 , Jiehua Jin #2 , Ji-Yuan Zhang 2 3 , Si-Yu Wang 2 , Lei Shi 2 , Ming Shi 2 3 , Yuanyuan Li 2 , Yunbo Xie 2 , Li-Min Liu 2 , Chun-Bao Zhou 2 , Alicia Chua 4 , Zi Zong Ho 4 , Junqing Luan 2 , Jinfang Zhao 2 , Jing Li 2 , Lu-En Wai 4 5 , Sarene Koh 4 5 , Tingting Wang 4 , Antonio Bertoletti 1 5 , 王福生 2 3
隶属关系
隶属关系

    1
    新加坡杜克-新加坡国立大学医学院新兴传染病。
    2
    中国人民解放军总医院第五医学中心传染病治疗研究中心，北京，中国。
    3
    中国人民解放军总医院第五医学中心国家临床研究中心，北京，中国。
    4
    Lion TCR 私人有限公司，新加坡。
    5
    新加坡免疫学网络，新加坡科学技术局 (A*STAR)。

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同等贡献。

    PMID：34935312 DOI：10.1002/hep4.1857

抽象的

乙型肝炎病毒 (HBV)-T 细胞受体 (TCR) T 细胞免疫疗法在 HBV 相关肝细胞癌 (HBV-HCC) 患者中的应用一直冷淡，因为正常 HBV 感染者均表达 HBV 抗原。具有 HBV-DNA 整合的肝细胞和 HCC 细胞会增加发生靶向肿瘤外严重肝脏炎症事件的风险。为了提高这种免疫治疗方法的安全性，我们开发了信使 RNA (mRNA) HBV-TCR 重定向的 T 细胞，由于 mRNA 的短暂性，这些 T 细胞在功能上寿命很短，可以逐渐增加剂量。这种方法的安全性及其对抗原发性 HBV-HCC 的临床潜力从未在人体试验中进行过分析；因此，我们研究了 8 名慢性 HBV 感染和弥漫性不可手术 HBV-HCC 患者的临床和免疫学参数，这些患者每周接受递增剂量（1 × 104、1 × 105、1 × 106 和 5 × 106 TCR+ T 细胞/ kg 体重）的 T 细胞用 HBV-TCR 编码 mRNA 修饰。治疗耐受性良好，在整个治疗过程中，在这些患者中没有观察到严重的全身炎症事件、细胞因子风暴或神经毒性。相反，我们在 8 名患者中的 3 名中观察到肿瘤病变的破坏或长期稳定的疾病。重要的是，没有临床相关 HCC 减少的患者没有表现出任何可检测的外周血免疫学改变。相比之下，在具有长期临床益处的患者中检测到暂时性局部肝脏炎症、T 细胞室激活和/或血清趋化因子（C-X-C 基序）配体 (CXCL) 9 和 CXCL10 水平升高的迹象。结论：我们表明，尽管体内半衰期缩短（3-4 天），但将 mRNA HBV-TCR T 细胞过继转移到 HBV-HCC 患者中显示出与瞬时免疫学改变相关的长期临床益处。

© 2021 作者。由 Wiley Periodicals LLC 代表美国肝病研究协会出版的 Hepatology Communications。

StephenW

Immunological alterations after immunotherapy with short lived HBV-TCR T cells associates with long-term treatment response in HBV-HCC
Anthony Tanoto Tan #  1 , Fanping Meng #  2   3 , Jiehua Jin #  2 , Ji-Yuan Zhang  2   3 , Si-Yu Wang  2 , Lei Shi  2 , Ming Shi  2   3 , Yuanyuan Li  2 , Yunbo Xie  2 , Li-Min Liu  2 , Chun-Bao Zhou  2 , Alicia Chua  4 , Zi Zong Ho  4 , Junqing Luan  2 , Jinfang Zhao  2 , Jing Li  2 , Lu-En Wai  4   5 , Sarene Koh  4   5 , Tingting Wang  4 , Antonio Bertoletti  1   5 , Fu-Sheng Wang  2   3
Affiliations
Affiliations

    1
    Emerging Infectious Diseases, Duke-NUS Medical School, Singapore.
    2
    Treatment and Research Center for Infectious Diseases, The Fifth Medical Center of PLA General Hospital, Beijing, China.
    3
    National Clinical Research Center, The Fifth Medical Center of PLA General Hospital, Beijing, China.
    4
    Lion TCR Pte Ltd., Singapore.
    5
    Singapore Immunology Network, Agency for Science and Technology (A*STAR), Singapore.

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Contributed equally.

    PMID: 34935312 DOI: 10.1002/hep4.1857

Abstract

The application of hepatitis B virus (HBV)-T-cell receptor (TCR) T-cell immunotherapy in patients with HBV-related hepatocellular carcinoma (HBV-HCC) has been apathetic, as the expression of HBV antigens by both normal HBV-infected hepatocytes and HCC cells with HBV-DNA integration increases the risk of on-target off-tumor severe liver inflammatory events. To increase the safety of this immunotherapeutic approach, we developed messenger RNA (mRNA) HBV-TCR-redirected T cells that-due to the transient nature of mRNA-are functionally short lived and can be infused in escalating doses. The safety of this approach and its clinical potential against primary HBV-HCC have never been analyzed in human trials; thus, we studied the clinical and immunological parameters of 8 patients with chronic HBV infection and diffuse nonoperable HBV-HCC treated at weekly intervals with escalating doses (1 × 104 , 1 × 105 , 1 × 106 , and 5 × 106 TCR+ T cells/kg body weight) of T cells modified with HBV-TCR encoding mRNA. The treatment was well tolerated with no severe systemic inflammatory events, cytokine storm, or neurotoxicity observed in any of these patients throughout treatment. Instead, we observed a destruction of the tumor lesion or a prolonged stable disease in 3 of 8 patients. Importantly, the patients without clinically relevant reductions of HCC did not display any detectable peripheral blood immunological alterations. In contrast, signs of transient localized liver inflammation, activation of the T-cell compartment, and/or elevations of serum chemokine (C-X-C motif) ligand (CXCL) 9 and CXCL10 levels were detected in patients with long-term clinical benefit. Conclusion: We show that despite the reduced in vivo half-life (3-4 days), adoptive transfer of mRNA HBV-TCR T cells into patients with HBV-HCC show long-term clinical benefit that was associated with transient immunological alterations.

© 2021 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.