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).
