A new Massachusetts Institute of Technology (MIT) study has revealed a potential explanation as to why certain immunotherapies for cancerous tumours do not always work as predicted.

If validated in clinical trials, the findings could help doctors identify cancer patients who would benefit the most from drugs known as checkpoint blockade inhibitors.

Checkpoint blockade inhibitors work by stimulating immune cells to destroy tumours in the body’s T cell response.

In previous studies, findings have shown that these drugs work effectively in patients whose tumours have a large number of mutated proteins.

However, 50% of patients who received the US Food and Drug Administration-approved checkpoint blockade inhibitor, pembrolizumab, did not respond well or only showed short-lived responses, despite their tumours showing high mutational burden.

In a study of mice, the researchers revealed that measuring the diversity of mutations within a tumour generated a more accurate prediction as to whether immunotherapy treatment would succeed, compared to measuring the overall number of mutations.

In mouse models that closely mimicked the progression of high TMB tumours, the researchers found mutations in genes that drive cancer development did not respond well to pembrolizumab in mice with checkpoint blockade inhibitors.

After changing the heterogeneity of lung tumours in mice with clonal mutations, the researchers found that checkpoint blockade inhibitors were very effective. However, as the heterogeneity increased, the treatment became less effective.

"If you try to mutate an existing cancer, where you already have many cancer cells at the primary site and others that may have disseminated throughout the body, you’re going to create a super heterogeneous collection of cancer genomes," said Peter Westcott, former MIT postdoc in Jacks Lab and assistant professor at Cold Spring Harbor Laboratory.

The lack of T cell response occurs because they do not see enough of any cancerous protein or antigen to become activated, said the researchers.

Additionally, the team analysed data from two small clinical trials of people who had been treated with checkpoint inhibitors for colorectal or stomach cancer and found that patients whose tumours were more homogeneous responded better to the treatment.

Isidro Cortes-Ciriano, research group leader at EMBL’s European Bioinformatics Institute, said that "personalised medicine must take into account new research that is helping us understand why cancer treatments work for some patients but not all".

https://www.pmlive.com/pharma_news/mit_study_reveals_why_certain_immunotherapies_do_not_always_work_1500715