Personalized T cell therapy against HBV related hepatocellular carcinoma

Dr. Thinesh Lee, Dr. Tan Anthony Tanoto, Prof. Antonio Bertoletti, A/Prof. Chow Wan Cheng

Abstract: The efficacy of cancer T-cell immunotherapy is increasingly recognized. We developed a method to select T-cell receptors (TCR) from HBV-specific T-cells of patients who resolved HBV infection and reintroduce them on lymphocytes of hepatocellular carcinoma (HCC) patients. Our objective was to test whether HBV-specific TCR-redirected T-cells recognize HCC with HBV-DNA integration and can be used in immunotherapy against HCC. We profiled the HBV transcripts in HCC with HBV-DNA integration in order to select the HBV-specific TCR able to redirect T-cells against them. These engineered T-cells lysed HCC cells in vitro and in animal models. The approach was then translated in a clinical setting. Primary HCC of a patient treated with liver transplantation was analyzed for HBV-transcript expression. We detected HBV-mRNA coding for a fragment of HBV-envelope containing an epitope recognized by a HLA-B58-restricted HBV-specific TCR. The patient (HLA-B58+) developed HCC relapses in the lung and was treated with multiple infusions of the HLA-B58-restricted TCR-redirected T-cells. An objective positive response was observed while new lesions in the lung or liver have not been detected till date. In conclusion, we demonstrate that immunotherapy of HBV-related HCC is possible and the HBV integration profile in HCC can guide personalized treatment of HCC patients.