Adoptive Transfer of T cell Receptor-engineered T cells to treat hepAtocellular Carcinoma recurrence after liver Transplantation: a preclinical feasibility study

An increasing indication for liver transplantation (LTx) is hepatocellular
carcinoma (HCC). Despite LTx, HCC often recurs, after which prognosis is
dismal. From an immunological point of view the post-transplant setting is of a
particular interest since donor and recipient of the transplant liver have a
different Human Leukocyte Antigen (HLA)-background. The objective of this pilot
study is to isolate T cell receptors (TCR) that are highly specific for liver
antigen presented by recipient HLA expressed on residual tumor cells of
recipients of liver transplants.

Adoptive transfer of T cells gene-engineered with antigen-specific receptors
has proven its feasibility and therapeutic potential in the treatment of
cancer. Recently, T cells gene-engineered to express a HBV-specific TCR have
been described treating recurrent HBV-related HCC after liver transplantation.
However, in HBV-low endemic regions (e.g. Western society) targeting HBV
antigens to treat HCC will only have limited impact.

We hypothesize that gene-engineered TCRs recognizing liver-specific antigen in
the context of recipient HLA (LSARH) have a unique safety profile and are
suited for adoptive T cell therapy for all patients with HCC recurrence after
LTx, independent of the cause of the liver disease

To isolate and validate TCRs that exclusively recognize liver antigens
presented by specific (*recipient*) HLA-molecules (LSARH) on the surface of
tumor cells.

Expression of pre-selected non-secretory liver-specific antigens will be
validated ex vivo in healthy liver and HCC tissues. In silico predicted HLA
epitopes of the validated antigens will be tested in vitro for HLA binding and
immunogenicity to select peptides being most potent in inducing T cell
responses.

A cohort study in autoimmune hepatitis (AIH) patients (N=35) will be conducted
as these are highly likeable to have enhanced frequencies of circulating
LSARH-specific T cells. Peripheral blood mononuclear cells (PBMCs) from AIH
patients will be co-cultivated with the highest ranked peptides and T cell
supporting cytokines to enrich for LSARH-specific T cells. T cells harboring
peptide-HLA cognate TCRs and responding to peptide stimulation will be sorted
and TCRs will be sequenced. Obtained TCR genes will be cloned into viral
expression vectors to express TCR in lymphocytes by viral transduction. TCRs
will be tested in vitro for liver/tumour specificity and lack of
cross-reactivity.

Intervention: invasive measurement of 80mL of blood collected at the
out-patient clinic during regular check-ups. No benefit and negligible risk for
the patients are expected. Hopefully, the results of this study will benefit
HCC patients after liver transplantation in the future.