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

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.

Fig. 1

Workflow and schematic of study design. a The Workflow of HBV-TCR-T-cell therapy. PBMCs are harvested, expanded, redirected short-lived mRNA HBV-Env-specific-TCR by electroporation and transferred back into the same patient. b The clinical protocol showing the overall study design included the infusion cycle, infusion dose and the main outcomes

Fig. 2

Characteristics of HBsAg-TCR-T cells. a Proliferation profiles of CD8 T cells from one HBV-HCC patient. Values in quadrant indicate percentage of CD8 T cells in cultured lymphocytes (gated on CD3 + T lymphocytes). b Electroporation efficiency. Values in quadrant indicate TCR-Vβ percentages expressed on T cells at different times after electroporation

Fig. 3

The alterations of ALT levels in B001 and B002 after TCR-T-cell infusion a B001 and b B002

Fig. 4

Disease response. a Median TTP for patients after infusions was 6.18 months n = 8, and b median OS for patients after infusions was 33.1 months (n = 8). c Outcome for evaluable patients by Swimmer plot

Fig. 5

Serum levels of HBsAg and HBV DNA before and after TCR-T-cells infusion. HBsAg and HBV DNA levels of every patient treated with HBV-TCR-T cells a B001; b B002; c B003; d B004; e B005; f B006; g B007 and h B008 before and after HBV-TCR-T-cell infusion. The numbers of HBV-TCR -T cells are indicated in black, HBsAg and HBV DNA levels are expressed in red and blue, respectively. The blue horizontal lines in b, e, f, g and h meant that the levels of HBV DNA levels were lower the limit of detectable levels