09 July 2019

Children with acute lymphoblastic leukaemia (ALL) mount an unexpectedly robust immune response to their cancer, according to a new USA study.

Scientists at the St. Jude Children's Research Hospital in Memphis, Tennessee, hope their findings could play a part in the development of new immunotherapies for the disease.

Although immunotherapy has revolutionised cancer treatment in adults, progress has not been so rapid in paediatric cancers. Some immunotherapeutics, like checkpoint inhibitors, have worked best against high-mutation tumours and proved less effective against most paediatric cancer, which often involve fewer mutations.  Researchers have speculated that the immune system fails to recognise or respond to tumours with fewer mutations, including paediatric ALL.

However, Dr Paul Thomas, of the St. Jude Department of Immunology, said their results “flip that story on its head”, and suggest that the immune system could be used to effectively target paediatric ALL – including relapsed ALL, for which the outlook still remains bleak.

Dr Thomas and his colleagues examined the immune response in children with paediatric ALL, checking 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.

In laboratory experiments with T cells donated by patients, the team found that overall, anti-tumour T cells recognised 86% of the paediatric ALL mutant proteins – far greater than the 2% of mutant proteins targeted by T cells in solid tumours. In addition, the anti-tumour T cells specifically targeted 68% of the leukaemic cells carrying fragments of these mutant proteins.

Dr Anthony Zamora, first author of the study published in Science Translational Medicine, said: “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.

“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.”

Source: Zamora, A.E., Crawford, J.C., Allen, E.K., Guo, X.J., Bakke, J., Carter, R.A., Abdelsamed, H.A., Moustaki, A., Li, Y., Chang, T.C., Awad, W., Dallas, M.H., Mullighan, C.G., Downing, J.R., Geiger, T.L., Chen, T., Green, D.R., Youngblood, B.A., Zhang, J., Thomas, P.G. (2019) “Pediatric patients with acute lymphoblastic leukemia generate abundant and functional neoantigen-specific CD8+ T cell responses”, Science Translational Medicine, available from doi: 10.1126/scitranslmed.aat8549


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