Scientists step closer to unlocking new leukaemia treatments

Researchersfrom The Australian National University (ANU) and the Peter MacCallum Cancer Centrehave discovered how a type of blood cancer, known as acute myeloid leukaemia (AML), can "switch off" a proteinknown as MHC class II, causing the leukaemia to become invisible to the immune system.  

The molecular switchallows cancercells to evade recognition and prevents the immune system from destroying them.  

The researchers believe that drugs targeting this molecular switch could be used to turn MHC class II back on again. By restoring MHC class II to the surface of the AML cells,the canceris once again visible to the immune system and can be detected and eliminated.  

The findings, published in Cancer Cell, could unlock new and more effective therapies to treat AML patients who have relapsed after a bone marrow transplantation. It's hoped the principles of this research could serve as the foundation to treat a range of other cancers, including melanoma.  

AMLis a highly aggressive blood cancer that affects about 900 Australians every year.   

"For many AML patients, especially those with high-risk disease factors, bone marrow transplantationis the most effective way to treat theleukaemia," lead author Dr KahLok Chan, ahaematologist from Peter Mac, said.  

"Unfortunately,up to 50 per cent of AML patients can relapse after having a bone marrow transplant and these patients then have limited treatment options available to them." 

To carry out the research, the ANU and Peter Macscientists mimicked the growth of the aggressive AML cells in humans by growing them in the lab.  

Senior author Associate Professor Marian Burr, from ANU, said until now it was unknown how the leukaemia cells were able to switch off MHC class II and evade immune detection. 

"Using cutting-edge CRISPR gene editing technology, we were able to identify that a specific group of proteins, called the CtBP complex, were responsible for switching off MHC class II in AML and other cancers," Associate Professor Burr said. 

"Importantly, we found that inhibiting the CtBP complex using specific drugs restored MHC class II levels and enhanced the ability of immune system cells to destroy the tumour cells." 

Senior author Professor Mark Dawson, alsofrom Peter Mac, said: "This discovery reveals a potential new approach to treat patients who have relapsed after having a bone marrow transplant.   

"Specific inhibitors of the CtBP complex are widely available, although further research is needed to ensure they are safe for human trials and that our pre-clinical findings translate into meaningful improvements in patient outcomes." 

Associate Professor Burr, who is one of nine Snow Fellow researchers across the country, said the findings could also help treat patients with a range of other cancers.  

"Cancer immunotherapies have been extremely effective in many different types of cancer, although treatment resistance remains a fundamental issue for some patients," Associate Professor Burr said.  

"We hope that this work will help to improve the effectiveness of immunotherapy, especially for aggressive types of cancers." 

For background: 

The Snow Fellowship program awards up to $8 million over eight years to the best and brightest early- to mid-career researchers tackling some of the greatest health and medical challenges facing populations in Australia andglobally. Associate Professor Burr was awarded her fellowship in 2020.