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To reduce the risk of transplant rejection in liver cancer patients, A*STAR scientists have engineered T cells that temporarily resist immunosuppresive drugs and attack liver cancer cells.

Fortifying T cells that fight liver cancer

14 Dec 2021

Researchers engineer specialized T cells that can transiently and effectively attack liver cancer cells even in the presence of immunosuppressive drugs.

If the immune system were an army, T cells would be the armored soldiers engaging in active combat against enemy cells. For patients with hepatocellular carcinoma (HCC), a form of liver cancer associated with hepatitis B virus (HBV) infections, these T cells could be a key to a decisive victory.

By designing T cell receptor (TCR) therapies targeting HBV-infected cells, scientists can specifically recognize and kill HBV-HCC cells, but not the surrounding healthy cells. “HBV-TCR T cells are T cells from the patients engineered to recognize liver cancer cells expressing HBV antigen fragments,” explained Antonio Bertoletti, Professor at Duke-NUS Medical School and Principal Investigator at A*STAR’s Singapore Immunology Network (SIgN).

But while TCR therapies may appear like the shot in the arm needed to beat HCC, it can get tricky at advanced stages of the disease, where patients typically receive liver transplants from healthy donors to replace their ailing organ.

The problem is that the immunosuppressive drugs taken by HCC patients act as a double-edged sword—resisting organ rejection, but inactivating therapeutic T cells and blocking their ability to attack cancer cells. To overcome this challenge, Bertoletti and colleagues sought to engineer HBV-TCR T cells that could function even in immunosuppressive conditions.

The researchers first studied the effects of two immunosuppressants, namely tacrolimus and mycophelonate mofetil, on the cancer-killing potential of HBV-TCR cells. Unsurprisingly, the medications significantly disrupted the T cells’ effectiveness.

Through mRNA electroporation, the team then engineered HBV-TCRs with selected genes that allowed the cells to resist immunosuppressive drugs. Called Immunosuppressive Drug-Resistant Armored (IDRA) TCR T cells, in vitro experiments revealed that these cells could transiently escape the immunosuppressive drugs and destroy malignant cells for up to four days.

“For the HBV-TCR T cells to recognize and kill HBV-HCC cells, their function has to be maintained in the presence of the immunosuppression,” said Bertoletti. “But permanent resistance to immunosuppression carries an increased risk of rejection of the transplanted liver.  This is why we engineered HBV-TCR T cells that are only resistant for a couple of days, after which they become sensitive to the immunosuppression again.”

According to Bertoletti, IDRA TCR T cells have robust clinical potential as they are tough on cancer cells but gentle on donor tissues. “In this way, the treatment is designed to target only the cancer cells and reduce adverse events against the transplanted liver.”

The team plans to expand the application scope of these armored T cell therapies beyond HCC to tackle other conditions faced by transplant patients taking immunosuppressive drugs, including the reactivation of dormant viral infections. As the next steps, the scientists are collaborating with industry partners to manufacture clinical-grade IDRA-TCR T cells for use in future human trials.

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References

Hafezi, M., Lin, M., Chia, A., Chua, A., Ho, Z.Z. et al. Immunosuppressive drug resistant armored TCR T cells for immune therapy of HCC in liver transplant patients. Hepatology74(1), 200-213 (2020) | article

About the Researcher

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Antonio Bertoletti

Adjunct Principal Investigator

Singapore Immunology Network
Antonio Bertoletti trained as a specialist in infectious diseases at the Scripps Research Institute, US, and the University of Parma, Italy, where he was the first to characterize hepatitis B virus (HBV)-specific CD8+ T cells. Subsequently, he moved to University College of London in 1997 where he pioneered the use of HLA-tetramers to characterize the role of HBV-specific T cells in viral control and disease pathogenesis. In 2006, he became the Director of the Infection and Immunity Program at A*STAR’s Singapore Institute for Clinical Sciences before joining Duke-NUS Medical School in 2013.

This article was made for A*STAR Research by Wildtype Media Group