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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].
#
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). |
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