title: Immunotherapy of HCC metastases with autologous T cell receptor redirected T cells, targeting HBsAg in a liver transplant patient.
abstract: HBV-DNA integration frequently occurs in HBV-related hepatocellular carcinoma (HCC), but whether HBV antigens are expressed in HCC cells and can be targeted by immune therapeutic strategies remains controversial. Here, we first characterized HBV antigen expression in HCC metastases, occurring in a patient who had undergone liver transplantation for HBV-related HCC. We then deployed for the first time in HCC autologous T cells, genetically modified to express an HBsAg specific T cell receptor, as therapy against chemoresistant extrahepatic metastases. We confirmed that HBV antigens were expressed in HCC metastases (but not in the donor liver) and demonstrated that tumour cells were recognized in vivo by lymphocytes, engineered to express an HBV-specific T cell receptor (TCR). Gene-modified T cells survived, expanded and mediated a reduction in HBsAg levels without exacerbation of liver inflammation or other toxicity. Whilst clinical efficacy was not established in this subject with end-stage metastatic disease, we confirm the feasibility of providing autologous TCR-redirected therapy against HCC and advocate this strategy as a novel therapeutic opportunity in hepatitis B-associated malignancies.
authors.affiliation: Institute of Child Health & Great Ormond Street Hospital, University College London, London, UK.
authors.forename: Waseem
authors.initials: W
authors.lastname: Qasim
authors.affiliation: Hepatology Unit, University Hospital of Pisa, Pisa, Italy.
authors.forename: Maurizia
authors.initials: M
authors.lastname: Brunetto
authors.affiliation: Singapore Institute for Clinical Sciences, A(∗)STAR, Singapore.
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Gehring
authors.affiliation: Division of Infection & Immunity, Institute of Immunity & Transplantation, University College London, UK.
authors.forename: Shao-An
authors.initials: SA
authors.lastname: Xue
authors.affiliation: Division of Infection & Immunity, Institute of Immunity & Transplantation, University College London, UK.
authors.forename: Anna
authors.initials: A
authors.lastname: Schurich
authors.affiliation: Program Emerging Infectious Diseases, Duke-NUS Medical School, Singapore.
authors.forename: Atefeh
authors.initials: A
authors.lastname: Khakpoor
authors.affiliation: Institute of Child Health & Great Ormond Street Hospital, University College London, London, UK.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhan
authors.affiliation: Hepatology Unit, University Hospital of Pisa, Pisa, Italy.
authors.forename: Pietro
authors.initials: P
authors.lastname: Ciccorossi
authors.affiliation: Institute of Child Health & Great Ormond Street Hospital, University College London, London, UK.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Gilmour
authors.affiliation: Hepatology Unit, University Hospital of Pisa, Pisa, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Cavallone
authors.affiliation: Hepatology Unit, University Hospital of Pisa, Pisa, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Moriconi
authors.affiliation: Rayne Cell Therapy Suite, Kings College, London, London, UK.
authors.forename: Farzin
authors.initials: F
authors.lastname: Farzhenah
authors.affiliation: Hepatology Unit, University Hospital of Pisa, Pisa, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Mazzoni
authors.affiliation: Rayne Cell Therapy Suite, Kings College, London, London, UK.
authors.forename: Lucas
authors.initials: L
authors.lastname: Chan
authors.affiliation: Division of Infection & Immunity, Institute of Immunity & Transplantation, University College London, UK.
authors.forename: Emma
authors.initials: E
authors.lastname: Morris
authors.affiliation: Institute of Child Health & Great Ormond Street Hospital, University College London, London, UK.
authors.forename: Adrian
authors.initials: A
authors.lastname: Thrasher
authors.affiliation: Division of Infection & Immunity, Institute of Immunity & Transplantation, University College London, UK.
authors.forename: Mala K
authors.initials: MK
authors.lastname: Maini
authors.affiliation: General Medicine, Liver and Digestive Disease Unit, University Hospital of Pisa, Pisa, Italy.
authors.forename: Ferruccio
authors.initials: F
authors.lastname: Bonino
authors.affiliation: Division of Infection & Immunity, Institute of Immunity & Transplantation, University College London, UK.
authors.forename: Hans
authors.initials: H
authors.lastname: Stauss
authors.affiliation: Singapore Institute for Clinical Sciences, A(∗)STAR, Singapore; Program Emerging Infectious Diseases, Duke-NUS Medical School, Singapore; School of Immunity and Infection, College of Medical and Dental Science, University of Birmingham, Edgbaston Birmingham, UK. Electronic address: antonio@duke-nus.edu.sg.
authors.forename: Antonio
authors.initials: A
authors.lastname: Bertoletti
mesh_terms: D000368:Aged; D006528:Carcinoma, Hepatocellular / Q000276:immunology / Q000556:secondary* / Q000628:therapy; D017809:Fatal Outcome; D005500:Follow-Up Studies; D006514:Hepatitis B Surface Antigens / Q000378:metabolism*; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D007167:Immunotherapy / Q000379:methods*; D008113:Liver Neoplasms / Q000276:immunology / Q000473:pathology* / Q000628:therapy; D008297:Male; D009362:Neoplasm Metastasis; D011948:Receptors, Antigen, T-Cell / Q000627:therapeutic use*; D016559:Tacrolimus / Q000627:therapeutic use*
chemical_list: D006514:Hepatitis B Surface Antigens; D007166:Immunosuppressive Agents; D011948:Receptors, Antigen, T-Cell; D016559:Tacrolimus
keywords: HBV-specific CD8 T cells; Liver cancer; T cell therapy