Multiple Tumor Mutations Equivalent to Higher Success Rate of Cancer Immunotherapy Drugs


Credit: The New England Journal of Medicine

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  • This study clarifies the extent to which mutational burden affects the outcomes of immune checkpoint resistances in many different cancer strains.Click on Tweet
  • The number of DNA mutations in a tumor is a good predictor of whether it will respond to a class of cancer immunotherapy drugs known as checkpoint inhibitors.. – Click on Tweet

“Mutational burden,” or the number of mutations present in a tumor’s DNA, is a good predictor of whether that type of cancer will respond to a class of cancer immunotherapy drugs known as checkpoint inhibitors, a new study led Johns Hopkins Kimmel Cancer Center shown by the researchers. The find, published December 21 New England Journal of Medicine, can be used to guide future clinical trials for these drugs.

Checkpoint inhibitors are a new class of drug that helps the immune system detect cancer by interfering with the mechanisms used by cancer cells to hide from immune cells. As a result, the drugs cause the immune system’s resistance to cancer in the same way that it fights infection. These drugs have had surprising success in treating certain types of cancers that have historically had poor prognoses, such as advanced melanoma and lung cancer. However, these therapies have no effect on other deadly types of cancer, such as pancreatic cancer and glioblastoma.

The mutational burden of some tumor types has previously been suggested as an explanation as to why some cancers respond better than others to immune checkpoint resistances according to the study leader. Mark Yarchoan, MD, is the chief associate in medical oncology. It’s work Dung Le, MD, associate professor of oncology, and other researchers at the Johns Hopkins Kimmel Cancer Center and its Bloomberg ~ Kimmel Cancer Institute for Cancer Immunotherapy has been shown that colon cancers that carry a higher number of mutations are more likely to respond to checkpoint inhibitors than those with small mutations. However, exactly how much effect mutational burden has on the consequences of immune checkpoint resistances in many different cancer strains is unclear.

To investigate this question, Yarchoan and colleagues Alexander Hopkins, Ph.D., co -authored the research, and Elizabeth Jaffee, MD, co-director of the Skip Viragh Center for Pancreas Cancer Clinical Research and Patient Care and co -director of the Bloomberg ~ Kimmel Institute, reviewed the medical literature for the results of clinical trials using checkpoint inhibitors in various cancer strains. They combined these findings with mutational burden data on thousands of tumor samples from patients with different tumor types.

Analyzing 27 different cancer types for which the same information is available, the researchers found a strong correlation: the higher the mutation severity of a type of cancer, the higher many respond to checkpoints that prevent. More than half of the differences in how well cancers respond to immune checkpoint resistances may be explained by the mutational burden of that cancer.

“The idea is that a type of tumor with a lot of mutations can be more easily treated than one with a little bit of a contraindication. It’s one of those things that doesn’t sound right when you hear it,” he said. by Hopkins. “But with immunotherapy, the more changes you have, the more chance the immune system will detect the tumor.”

Although this finding is true for most of the cancer strains they study, there are some outliers in their analysis, according to Yarchoan. For example, Merkel cell cancer, a rare and severely aggressive skin cancer, has a high probability of a number of mutations but responds very well to inhibitory checkpoints. However, he explains, this type of cancer is often caused by a virus, which thus encourages strong immune resistance despite the slightest cancer severity. In contrast, the most common variant of colorectal cancer has a moderate mutational burden, although checkpoint inhibitors do not respond well for reasons that are not yet clear.

Yarchoan reported that these findings can help guide clinical trials to test checkpoints that prevent cancer types where these drugs have not yet been tested. Future studies may also focus on finding ways to induce cancers with short mutational loads to behave like those with higher mutational loads to better respond to it. therapies.

He and his colleagues plan to extend this line of research by investigating whether mutational burden can be a good predictor if individual patients ’cancers can respond well to this class. of immunotherapy drugs.

“The ultimate goal is the right medicine-to work out what’s real for many groups of patients to see if we can use this information to help any patient,” he said.

Yarchoan received funding from the Norman & Ruth Rales Foundation and Conquer Cancer Foundation.

Through a licensing agreement with Aduro Biotech, Jaffee has the potential to receive royalties in the future.



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