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Messenger RNA electroporated hepatitis B virus (HBV) antigen-specific T cell receptor (TCR) redirected T cell therapy is well-tolerated in patients with recurrent HBV-related hepatocellular carcinoma post-liver transplantation: results from a phase I trial

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Abstract

Background and aims

Liver transplantation (LT) is the primary curative option for cirrhotic patients with early-stage hepatocellular carcinoma (HCC). However, tumor recurrence occurs in 15–20% of cases with unfavorable prognosis. We have developed a library of T cell receptors (TCRs) specific for different hepatitis B virus (HBV) antigens, restricted by different molecules of human leucocyte antigen (HLA)-class I, to redirect T cells against HBV antigens (Banu in Sci Rep 4:4166, 2014). We further demonstrated that these transiently functional T cells specific for HBV obtained through messenger RNA (mRNA) electroporation can eliminate HCC cells expressing HBV antigens in vitro and in vivo (Kah in J Clin Invest 127:3177–3188, 2017). A phase I clinical trial for patients with HCC recurrence post-liver transplant was conducted to assess the safety, tolerability, and anti-tumor efficacy of transiently functional HBV-TCR T cells. Here, we report the clinical findings with regard to the safety and anti-tumor efficacy of mRNA electroporated HBV-specific TCR-T cells. (ClinicalTrials.gov identifier: NCT02719782).

Patients and methods

A total of six patients with HBV-positive recurrent HCC post-liver transplant and HLA-matched to TCR targeting hepatitis B surface antigen (HBsAg) or hepatitis B core antigen (HBcAg) (HLA-A*02:01/HBsAg, HLA-A*11:01/HBcAg, HLA-B*58:01/HBsAg or HLA-C*08:01/HBsAg) were enrolled in this study. The primary objective was to assess the safety of short-lived mRNA electroporated HBV-TCR T cells based on the incidence and severity of the adverse event (AE) graded per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 4.0. The secondary objective was to determine the effectiveness of HBV-TCR T cells as per RECIST 1.1 criteria. Patients were followed up for survival for 2 years post-end of treatment.

Results

The median age of the six patients was 35.5 years (range: 28–47). The median number of HBV-TCR T cell infusions administered was 6.5 (range: 4–12). The treatment-related AE included grade 1 pyrexia. This study reported no cytokine release syndrome nor neurotoxicity. One patient remained alive and five were deceased at the time of the data cutoff (30 April 2020).

Conclusion

This study has demonstrated that multiple infusions of mRNA electroporated HBV-specific TCR T cells were well-tolerated in patients with HBV-positive recurrent HCC post-liver transplant.

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Data availability

Supporting data for this study are available from the corresponding authors and the first authors upon reasonable request.

Abbreviations

AE:

Adverse event

ACT:

Adoptive cell transfer

ALT:

Alanine transaminase

AST:

Aspartate transaminase

BW:

Body weight

BCLC:

Barcelona clinic liver cancer

CAR-T:

Chimeric antigen receptor-T

CIK:

Cytokine-induced killer

CnB:

Calcineurin B

CTCAE:

Common terminology criteria for adverse events

ECOG:

European cooperative oncology group

HBV:

Hepatitis B virus

HCC:

Hepatocellular carcinoma

HLA:

Human leukocyte antigen

HBcAg:

Hepatitis B core antigen

HBsAg:

Hepatitis B surface antigen

HBeAg:

Hepatitis B e antigen

IMPDH:

Inosine- 5′- monophosphate dehydrogenase

LT:

Liver transplantation

mRNA:

Messenger RNA

MMF:

Mycophenolate mofetil

MedDRA:

Medical dictionary for regulatory activities terminology

NCI:

National cancer institute

OS:

Overall survival

ORR:

Objective response rate

PD:

Progressive disease

PBMC:

Peripheral blood mononuclear cell

SD:

Stable disease

TAC:

Tacrolimus

TCR:

T cell receptor

TNM:

Tumor node metastasis

TTP:

Time to progression

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Acknowledgements

The authors would like to thank Antonio Bertoletti and Anthony T. Tan for their contribution to the development of the investigational HBV-TCR T cell product and clinical trial design. The authors would also like to thank the participants who contributed to this study.

Funding

This work was supported by a project funded by the National Natural Science Foundation of China (82260110, 81870449, 82170674, 51933011), China Postdoctoral Science Foundation (2019M653904XB), Natural Science Foundation of Xinjiang Uyghur Autonomous Region (2020D01C006). Science and Technology Projects in Guangzhou (202102010310).

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Author notes

  1. Fan Yang, Xiaofang Zheng and Sarene Koh have contributed equally to this study.

Authors and Affiliations

  1. Biotherapy Centre, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510630, China

    Fan Yang, Xiaofang Zheng, Jianxi Lu, Jintao Cheng, Panlong Li, Cong Du, Yunhao Chen, Xiaoyan Chen, Li Yang, Wanxin Chen, Qi Zhang & Wenjie Chen

  2. Department of Infectious Diseases, The First People’s Hospital of Kashi, The Kashi Affiliated Hospital, Sun Yat-Sen University, Kashi, 844000, China

    Fan Yang & Qi Zhang

  3. Lion TCR Pte Ltd, Singapore, Singapore

    Sarene Koh, Regina Wanju Wong, Lu‑En Wai & Tingting Wang

  4. Agency for Science and Technology (A*STAR), Singapore Immunology Network, Singapore, Singapore

    Sarene Koh & Lu‑En Wai

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  1. Fan Yang
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Contributions

LW and SK developed the investigational HBV-TCR T cell product. TW, QZ and WC designed and supervised the clinical trial. JL, XC, LY and WC contributed to the manufacturing of HBV-TCR T cells. FY, WC, JC, PL, CD and YC managed the patients. XZ, TW and RWW performed data analysis. RWW and FY wrote the manuscript. All authors approved the final manuscript.

Corresponding authors

Correspondence to Tingting Wang, Qi Zhang or Wenjie Chen.

Ethics declarations

Conflict of interest

Regina Wanju Wong, Lu-En Wai, Sarene Koh, and Tingting Wang are employees of Lion TCR Pte Ltd. Fan Yang, Xiaofang Zheng, Jianxi Lu, Jintao Cheng, Panlong Li, Cong Du, Yunhao Chen, Xiaoyan Chen, Li Yang, Wanxin Chen, Qi Zhang, and Wenjie Chen have no conflicts of interest to disclose.

Ethics approval and consent to participate

All participants provided informed consent, and the study was approved by the ethics committee of the third affiliated hospital of Sun Yat-sen University.

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Yang, F., Zheng, X., Koh, S. et al. Messenger RNA electroporated hepatitis B virus (HBV) antigen-specific T cell receptor (TCR) redirected T cell therapy is well-tolerated in patients with recurrent HBV-related hepatocellular carcinoma post-liver transplantation: results from a phase I trial. Hepatol Int 17, 850–859 (2023). https://doi.org/10.1007/s12072-023-10524-x

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