Scientists Discover New Way to Predict Immunotherapy Responses

Immune checkpoint inhibitors like Keytruda offer new ways to treat cancer patients who might otherwise have no options. But the treatment has posed challenges to health care professionals when it comes to figuring out which tumors will respond to immunotherapy and which tumors won’t.

A research team at Memorial Sloan Kettering Cancer Center in New York City has recently uncovered a crucial piece of information that should allow clinicians to more accurately predict immunotherapy success. Their study, published in Nature Genetics, reveals that malignant cells with a large amount of DNA faults will likely respond well to immune checkpoint inhibitors (ICI).

The study looked at “tumor mutation burden (TMB), which involves counting the number of DNA faults, or errors in sequence, contained in a tumor. Luc Morris, MD, surgical oncologist at MSKCC, explains that although it’s been assumed that TMB can help to predict treatment response, very few studies have actually been done to explore this area.

Using a tool called MSK-IMPACT, the researchers looked at DNA from 1,662 patients with stage IV metastatic cancer who were treated with ICI drugs, and DNA from 5,371 patients with stage IV metastatic cancer who were not treated with ICI. The tool allowed them to see the number of mutations in each genome.

The team hoped to find out whether or not TMB could predict immunotherapy success in all cancers, or at least in a large number of them. The results showed that 20% of the cancer genes that contained the most mutations responded better to ICI than the genes with low numbers of mutations. But the correlation did not exist for brain tumors like gliomas. Breast cancer tumors also lacked concrete evidence, but it was noted that ICI is not commonly used to treat breast cancer at this time.

The reason behind the correlation between high TMB and better immunotherapy success is relatively mysterious, but the team does have one hypothesis: the more mutations a cell has, the more likely that cell is to create damaged proteins. Because these damaged proteins, called neoantigens, are highly abnormal, the immune system treats them as invaders and attacks them.

Although previous studies have been done on the concept of high TMB rates and immunotherapy success, this study is the largest and most inclusive to date. Other studies have focused on particular cancers like lung and melanoma, but this study looked at a large number of cancer types.

There are still some patients who have a high TMB, but don’t respond to ICI treatments. Researchers still have more to discover in this area, as it’s clear that high TMB is not a 100% universal way to predict treatment success. Morris hopes that the data discovered here will allow for future studies with more types of cancer.