Higher mutational burdens in tumours linked to greater immunotherapy success, study finds

pharmafile | December 21, 2017 | News story | Research and Development Cancer, Johns Hopkins Kimmel Cancer Center, checkpoint inhibitors, mutational burden, pharma 

New research from the Johns Hopkins Kimmel Cancer Center and its Bloomberg-Kimmel Cancer Institute for Cancer Immunotherapy has indicated that the mutational burden (the number of mutations present in tumour DNA) can provide a strong indicator as to whether a cancer will respond to checkpoint inhibitor immunotherapy drugs.

Immunotherapy treatments, which enable the immune system to recognise and fight cancer cells by neutralising their ability to hide, have seen great success in areas such as advanced melanoma and lung cancer, but have had little effect on others, such as pancreatic tumours and glioblastoma.

Past efforts by Associate Professor of Oncology Dung Le and his team has demonstrated that colon cancers with high mutational burdens were more likely to respond to checkpoint inhibitor treatments, but exactly how influential this is on outcomes across a range of cancer types was not fully determined.

In this most recent study, study leader and Chief Medical Oncology Fellow Mark Yarchoan and his colleagues Alexander Hopkins and Elizabeth Jaffee, co-Director of the Skip Viragh Center for Pancreas Cancer Clinical Research and Patient Care and associate director of the Bloomberg-Kimmel Institute, combined efficacy data of checkpoint inhibitors on various cancer types with mutational burden data of thousands of tumour samples from a range of cancers. There were 27 cancer types for which both pieces of evidence were available.

The team found that there was a strong correlation between higher mutational burdens and checkpoint inhibitor success rates; more than 50% of efficacy differences could be explained using the cancer’s mutational burden. This is thought to be due to the fact that the immune system has more chances to recognise a cancer if it has more mutations.

However, a few aberrations came to light. The rare and aggressive Merkel cell cancer was seen to respond very well to checkpoint inhibitor drugs, yet usually only has a moderate mutational burden. Yarchoan theorises that this is because Merkel cell cancer is caused by a virus. On the opposite end of the spectrum, the most common colorectal cancer type responded poorly to this class of therapy, despite a similar level of mutations.

Yarchoan notes that this research could inform future clinical trials of checkpoint inhibitors in as-yet untested cancer types, or could help to uncover ways to make non-responsive cancers behave more like their counterparts with high mutational burdens, improving success rates of treatment. The team now plans to expand their research to determine whether mutational burden is a good indicator of whether individual patient cancers will respond to checkpoint inhibitors.

Matt Fellows

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