T cell receptor-therapy in HBV-related hepatocellularcarcinoma

T cell immunotherapy in hepatitis B Virus related hepatocellular carcinoma

“…In chronic HBV patients, microgram quantities of HBV envelope antigens are circulating in the serum. These soluble HBV antigens can interfere with the function of HBV-envelope specific CAR-T cells by either blocking and sequestering of the cell surface CARs, or by the inappropriate activation of the CAR-T cells [32,37,38] . However, the obligate requirement for HLA presentation of T cell epitopes to TCRs would render the TCR-T cells insensitive to soluble HBV antigens in the serum [39] .…”

“…This integration results in either the expression of whole HBV antigens when the complete open reading frame is integrated, or the production of chimeric HBV-host proteins when only short fragments of HBV are integrated [36] . In any case, the integration process inadvertently marks the HBV-HCC cells with a foreign antigen through a mechanism that is highly hepatotropic as dictated by the infectivity of HBV [32] . This liver-specific marking would mean that the on-target off-tumour adverse events is largely predictable and would primarily be limited to the liver compartment, with little or no involvement of other organs [29] .…”

“…For instance, clinical trials from NCI and Adaptimmune has shown the unexpected binding of high affinity MAGE-A3 TCR to similar epitopes like MAGE-A12 and titin in the brain and heart respectively, resulting in severe off-tumour . Targeting overexpressed self-antigens in tumours might not be ideal due to potential off-tumour responses against normal cells [29,32] . Recently, the discovery of altered self-antigens in highly mutated tumours have sparked an interest in their use as a TAA for T-cell immunotherapy [33] .…”

“…In the natural history of chronic HBV infection, the virus integrates itself into the human genome, hence the HCC cells that eventually develop from chronically infected hepatocytes will carry these integrations and can be targeted by HBV-specific TCR T-cells [32,35] . This integration results in either the expression of whole HBV antigens when the complete open reading frame is integrated, or the production of chimeric HBV-host proteins when only short fragments of HBV are integrated [36] .…”

T-Cell-Associated Immunotherapy: A Promising Strategy for the Treatment of Hepatocellular Carcinoma

“…TCR redirected HBV-specific T cells derived from peripheral blood mononuclear cells (PBMCs) of chronic HBV and HBV-related HCC patients had the capabilities of recognizing HBV-infected cells and HCC tumor cells expressing viral antigens [15]. These reinfused HBV-TCR-T cells obviously decreased the level of HBsAg in the patient, while, unfortunately, no detectable reduction of the volume of the HCC metastasis [16]. Unlike TCRs, chimeric antigen receptors (CARs) armed T cells could get rid of the restriction of MHC.…”