Hepatocellular carcinoma (HCC) is a deadly malignancy which occurs in the context of chronic liver inflammation. A major cause of HCC development is chronic hepatitis B virus (HBV) infection. Adoptive T cell therapy involving HBV-specific T cell receptor (TCR) redirecting T cells against HBV-associated HCC has demonstrated promising results. However, in patients who have undergone liver transplants (LT), the functions of these redirected T cells are curtailed due to the presence of immunosuppressive drugs such as tacrolimus and mycophenolate mofetil (MMF) which are given to prevent donor graft rejection. Therefore, in order to increase the clinical efficacy and application of HBV-TCR redirected T cells, we developed immunosuppressive drug-resistant armoured (IDRA) HBV-TCR T cells that can maintain their ability to lyse HBV-related HCC in the presence of immunosuppressive drugs. This expands the potential curative efficacy of the therapeutic T cells in patients who suffer from HCC relapses after liver transplant.

We further demonstrated that IDRA-HBV-TCR T cells can reduce the number of circulating tumour cells (CTCs) in whole blood in vitro. CTCs are responsible for HCC recurrence after LT and reduction of their numbers using prophylactic therapy can reduce the risk of recurrence. Thus, by modifying the ability of HBV-TCR T cells to be activated even in the presence of immunosuppressive drugs, we expand their use both as prophylactic therapy against HBV-HCC recurrence after LT and as a treatment for LT patients whose HBV-HCC has already recurred.