In brief

Reprogramming T cells to target acute myeloid leukaemia (AML) marker protein TIM-3 proves to be an effective strategy against one of the most aggressive types of cancer.

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Redirecting cancerous fates

14 Feb 2023

A T cell therapy innovation may offer new hope for acute myeloid leukemia patients who relapse after conventional treatment.

The immune system detects damaged cells and infectious invaders as if they were waving bright red flags. Cancer cells, however, can fly under the radar. By wielding their molecular armoury, tumours disguise themselves as healthy tissues to evade the immune system and resist chemotherapy. As a result, some cancer patients are prone to relapses after treatment.

This is especially true for people with acute myeloid leukemia (AML), a highly aggressive cancer of the white blood cells. About half of all AML patients experience a relapse after chemotherapy, causing their 5-year survival rates to plummet. According to Cheng-I Wang, a Senior Principal Investigator at A*STAR’s Singapore Immunology Network (SIgN), these poor clinical outcomes are likely a result of leukaemic stem cells (LSC) that persist even after chemotherapy.

Wang and colleagues are among cancer researchers that are designing approaches to reactivate the immune system to minimise the risk of relapse. These approaches include immunotherapies called chimeric antigen receptor-directed T lymphocytes (CAR-T) involve reprogramming T cells to express receptors that act like search and destroy missiles against tumours.

The problem is choosing the right tumour target. “It is difficult to target AML cells as their genetic background can be very diverse,” explained Wang, adding that their team selected an LSC marker called TIM-3 because it only appears on AML precursors, but not on healthy cells.

“Unlike many other druggable targets, TIM-3 is expressed by AML cells irrespective of the patients’ genetic characteristics and treatment course,” he said.

The team zapped T cells with tiny pulses of electricity to deliver the CAR genes to T cells in a process that Wang says is a safer alternative for mass-producing the potential AML treatment. “Anti-TIM-3 CAR produced by mRNA electroporation can ensure reduced toxicity to human bone marrow stem cells and endogenous TIM-3+ immune cells in the patients,” Wang explained.

They then successfully demonstrated the potency of their new CAR-Ts in a mouse model of AML, as well as in cells from patient donors grown in the lab. Most promisingly, AML mice treated with the new CAR-Ts had significantly fewer tumours in just two to three weeks. Furthermore, the CAR-Ts were highly selective towards the cancerous cells, leaving healthy cells that also express TIM-3 unscathed.

Spurred by these breakthrough results, the scientists have filed a patent for their CAR-T with hopes of advancing the cell therapy to further studies and clinical trials. Wang is hopeful that the treatment could one day help AML patients beat the odds. “Eradication of LSC by targeting TIM-3 may prevent AML recurrence and help achieve long-term remission in AML patients,” he concluded.

The A*STAR-affiliated researchers contributing to this research are from the Institute of Molecular and Cell Biology (IMCB) and Singapore Immunology Network (SIgN).

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Lee, W-H., Ye, Z., Cheung, A.M.S., Goh, Y.P.S., Oh, H.L.J., et al. Effective killing of acute myeloid leukemia by TIM-3 targeted chimeric antigen receptor T cells. Molecular Cancer Therapeutics 20, 1702–1712 (2021). | article

About the Researcher

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Cheng-I Wang

Principal Investigator

Singapore Immunology Network
Cheng-I Wang received a PhD degree in chemistry from Washington University and completed his postdoctoral training in the department of pharmaceutical chemistry at the University of California, San Francisco. Wang worked on drug discovery projects at biotechnology and pharmaceutical companies in the US before joining the A*STAR Singapore Immunology Network (SIgN) in 2009. As Head of the Human Monoclonal Antibody Technology Platform at SIgN, Wang works on the discovery and development of human antibodies against infection and immune disorders, using combinatorial approaches to incorporate novel functions into protein and antibody molecules.

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