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Childhood leukaemia cannot hide from the immune system

St. Jude Children's Research Hospital scientists have evidence that children with acute lymphoblastic leukaemia mount a robust immune response to their cancer.

The findings, which appear today in the journal Science Translational Medicine, will likely aid development of immunotherapy for the most common childhood cancer.

Immunotherapy has revolutionised cancer treatment in the last decade, particularly for adults with melanoma, lung cancer and other solid tumours.

But immunotherapies for paediatric cancer have lagged.

Some immunotherapeutics, including immune checkpoint inhibitors, have worked best against high-mutation tumours and proved less effective against most paediatric cancer, which involve fewer mutations.

Researchers speculated that the immune system fails to recognise or respond to tumours with fewer mutations, including paediatric ALL.

"The results of this study flip that story on its head," said corresponding author Paul Thomas, Ph.D., a member of the St. Jude Department of Immunology.

"Using a variety of methods, we demonstrated that the tumour mutational burden does not necessarily determine the ability of tumour cells to be recognised by T cells or to elicit an immune response.

"The findings suggest that the immune system could be used to effectively target paediatric ALL," he said.

While more than 90 percent of children with ALL in the U.S. become long-term survivors, the outlook remains bleak for patients who relapse.

For this study, Thomas and his colleagues took a closer look at the immune response in children with paediatric ALL.

The scientists checked for specialised anti-tumour T cells (CD8 T cells) that recognise patient-specific mutant proteins.

The recognition launches the immune response that kills tumour cells.

Researchers found anti-tumour T cells that recognised 86% of the paediatric ALL mutations and specifically targeted 68% of the leukaemic cells.

That percentage is far greater than the 2% of solid tumour mutations that anti-tumour T cells are predicted to target.

"Given that we were able to identify tumour-reactive T cells that were functional suggests traditional immune checkpoint inhibitors may not be the best option for these patients," said first author Anthony Zamora, Ph.D., a postdoctoral fellow in Thomas' laboratory.

"Cellular-based approaches that allow patients' T cells to be modified to increase the specificity and magnitude of the anti-tumour response could show greater clinical efficacy."

Thomas and his colleagues made an analogy between viral and tumour immune responses as a possible explanation for the high levels of immune recognition in this study.

Large viruses, like high-mutation tumours, produce many possible immune targets.

During viral infections, a process called immunodominance leads to a focused immune response that includes production of T cells against a limited number of viral targets.

"The same process may be at work in tumours like paediatric ALL that have fewer mutations," Thomas said.

"As a result, the immune system might end up targeting a greater percentage of leukaemic mutations, including driver mutations that are responsible for the cancer."

Source: St. Jude Children's Research Hospital



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