Abstract
Background & aimsImmunotherapy 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.MethodsWe 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.ResultsAdverse 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.ConclusionsThe 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 registrationThis study was registered at ClinicalTrials.gov (NCT03899415).
Highlights
Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide, and is characterized by rapid progression and poor prognosis with 5-year survival rates of less than 5% [1, 2]
Previous studies reported that hepatitis B virus (HBV)-T cell receptorengineered T-cell (TCR-T)-cell immunotherapy in HBVrelated hepatocellular carcinoma (HBV-HCC) patients after liver transplantation with disseminated HCC metastasis in lung, bones and neck or with HCC recurrence had no signs of acute toxicities and only had a largely unremarkable alteration of ALT levels
The safety of HBV-TCR-T-cell immunotherapy had not been evaluated in HBV-HCC patients who had not performed liver transplantation
Summary
Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide, and is characterized by rapid progression and poor prognosis with 5-year survival rates of less than 5% [1, 2]. Chemotherapy and radiotherapy are conventional treatments on HCC, but, in the end, most patients die from disease recurrence or metastasis Tyrosine kinase inhibitors, such as sorafenib, lenvatinib and cabozantinib, had been approved for HCC, but poor improvement in overall survival of advanced HCC patients was observed in the clinic [3,4,5]. 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). 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)
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