Immunotherapy of HCC metastases with autologous T cell receptor redirected T cells, targeting HBsAg in a liver transplant patient

Qasim, Waseem; Brunetto, Maurizia Rossana; Gehring, Adam J.; Xue, Shao-An; Schurich, Anna; Khakpoor, Atefeh; Zhan, Hong; Ciccorossi, P.; Gilmour, Kimberly; Cavallone, D.; Moriconi, F.; Farzhenah, F; Mazzoni, Alessandro; Chan, Lucas; Morris, Emma; Thrasher, Adrian J.; Maini, Mala K.; Bonino, Ferruccio; Stauss, Hans J.; Bertoletti, Antonio

doi:10.1016/j.jhep.2014.10.001

Cited by 173 publications

(150 citation statements)

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“…Our report 7 describes a unique clinical scenario with a much reduced risk of potential damage to normal liver tissue. This patient had a liver transplant and then presented with extrahepatic HCC metastasis with HBV-DNA integration producing only surface protein of HBV (HBsAg) while complete HBV-DNA, a sign of HBV replication was absent in blood and in the transplanted liver.…”

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confidence: 95%

T cell receptor-therapy in HBV-related hepatocellularcarcinoma

et al. 2015

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confidence: 95%

T cell receptor-therapy in HBV-related hepatocellularcarcinoma

et al. 2015

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“…Because HCC cells can express HBV-derived peptides, as well as oncofetal proteins and cancer-testis antigens, adoptive immunotherapy using T lymphocytes redirected with T-cell receptors (TCR) against these peptides represents an attractive possibility. Indeed, T cells expressing TCR anti-HBV envelope antigens are cytotoxic against HCC cell lines (14,15); infusion of such cells in a patient with HCC resulted in their in vivo expansion and a reduction in hepatitis B surface antigen (HBsAg) without apparent liver toxicity (16). A practical constraint of this approach is that TCRs must be tailored to the patient's HLA type, which may limit patient eligibility if HLA-matched TCRs are not available.…”

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confidence: 99%

Expanded and Activated Natural Killer Cells for Immunotherapy of Hepatocellular Carcinoma

Kamiya

Chang

Campana

2016

Cancer Immunology Research

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Viral infection of the liver is a major risk factor for hepatocellular carcinoma (HCC). Natural killer (NK) cells recognize virally infected and oncogenically transformed cells, suggesting a therapeutic role for NK-cell infusions in HCC. Using the K562-mb15-41BBL cell line as a stimulus, we obtained large numbers of activated NK cells from the peripheral blood of healthy donors. Expanded NK cells exerted remarkably high cytotoxicity against HCC cell lines, which was generally much higher than that of unstimulated or IL2-activated NK cells. In immunodeficient NOD/scid IL2RGnull mice engrafted with Hep3B, treatment with expanded NK cells markedly reduced tumor growth and improved overall survival. HCC cells exposed for 48 hours to 5 mmol/L of sorafenib, a kinase inhibitor currently used for HCC treatment, remained highly sensitive to expanded NK cells. HCC cell reductions of 39.2% to 53.8% caused by sorafenib in three cell lines further increased to 80.5% to 87.6% after 4 hours of culture with NK cells at a 1:1 effector-to-target ratio. NK-cell cytotoxicity persisted even in the presence of sorafenib. We found that NKG2D, an NK-cell-activating receptor, was an important mediator of anti-HCC activity. We therefore enhanced its signaling capacity with a chimeric NKG2D-CD3z-DAP10 receptor. This considerably increased the anti-HCC cytotoxicity of expanded NK cells in vitro and in immunodeficient mice. The NK expansion and activation method applied in this study has been adapted to clinical-grade conditions. Hence, these results warrant clinical testing of expanded NK-cell infusions in patients with HCC, possibly after genetic modification with NKG2D-CD3z-DAP10.

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“…The feasibility of using HBV-specific TCR-T cells for the treatment of HBV-HCC was first demonstrated in a compassionate therapy of a chronic HBV patient who has widespread extrahepatic HCC metastasis post-liver transplantation [40] . The combination of several clinical features of the patient makes him an ideal candidate for the first-in-man proof-of-concept therapy where an emphasis on safety is essential.…”

Section: First-in-man Proof-of-concept Tcr-t Cell Immunotherapy Of Hbmentioning

confidence: 99%

T cell immunotherapy in hepatitis B Virus related hepatocellular carcinoma

Hafezi¹,

Bertoletti²,

Tan³

2018

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Chronic hepatitis B virus (HBV) infection is a major risk factor for hepatocellular carcinoma (HCC). While multiple treatment modalities are available, liver transplantation remains the sole curative treatment for advanced stages of HCC, and hence new treatment approaches are required to fulfill this unmet need of curative HCC therapy. Our first-in-man proof-of-concept adoptive T-cell immunotherapy against HBV related hepatocellular carcinoma metastases has shown promising results. Here, we review the development of T-cell immunotherapy targeting HBV antigens for the treatment of HBV-HCC and discuss the practical considerations for the safe and effective use in clinics.

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Immunotherapy of HCC metastases with autologous T cell receptor redirected T cells, targeting HBsAg in a liver transplant patient

Cited by 173 publications

References 18 publications

T cell receptor-therapy in HBV-related hepatocellularcarcinoma

T cell receptor-therapy in HBV-related hepatocellularcarcinoma

Expanded and Activated Natural Killer Cells for Immunotherapy of Hepatocellular Carcinoma

T cell immunotherapy in hepatitis B Virus related hepatocellular carcinoma

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