Finding potential biomarkers to predict response to immunotherapy in nonhypermutated cancers

Scientists have discovered a potential biomarker that could more accurately identify which patients with non-hypermutated cancers will respond to specialized immunotherapy drugs called immune checkpoint inhibitors, according to findings published in Science Translational Medicine.

Amy Heimberger, MD, the Jean Malnati Miller Professor of Brain Tumor Research and a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, was a co-author of the study.

Immune checkpoint blockade (ICB) therapy has demonstrated significant clinical benefit for a subset of patients with hypermutated cancer types, such as melanoma or lung cancer.

ICB therapy utilizes immune checkpoint inhibitor drugs that block specific proteins on cancer and immune cells called checkpoints. These proteins keep the immune response from becoming too strong, but may also prevent T-cells from killing cancer cells.

Immune checkpoint inhibitors help reinvigorate T-cells, restoring their immune activity and helping them kill cancer cells more efficiently. For some cancers, however, T-cells become overstimulated or "exhausted," to the point where immune checkpoint inhibitors are unable to restore T-cell function at all.

"So, the real question is who benefits from an immune checkpoint inhibitor and who doesn’t benefit, because there can be toxicities associated with these drugs," said Heimberger, who is also a professor of Neurological Surgery and scientific director of the Lou and Jean Malnati Brain Tumor Institute of the Lurie Cancer Center.

Previous research has identified several biomarkers to help determine which patients with hypermutated cancers benefit from ICB therapy, with one of these biomarkers being tumor mutational burden, or the number of mutations in the DNA of cancer cells.

However, recent work, of which Heimberger was also a co-author, discovered that high tumor mutational burden does not accurately predict which patients with non-hypermutated cancers will best respond to ICB therapy. These findings established momentum for the current study, where Heimberger and collaborators aimed to identify biomarkers in non-hypermutated cancers that are predictive of ICB response.

In the study, investigators analyzed 12 cohorts of patients with non-hypermutated tumors across seven cancer types, including breast, prostate, kidney and brain cancer.

Cancer cells that expressed defects in the replication stress response (RSR) — when a cell's genome is exposed to stresses during DNA replication, resulting in compromising genetic mutations — were associated with ICB response in the 12 patient cohorts.

Next, using mouse models of breast cancer containing a low replication stress response signature, the investigators pharmacologically induced the replication stress response in the tumor cells, demonstrating that they could successfully modulate a response to ICB therapy.

The findings demonstrate that the RSR defect gene signature is a potential biomarker for identifying patients with non-hypermutated tumor types who may benefit from ICB therapy. More so, pharmacologically inducing RSR may also be a promising therapeutic approach to increase the number of patients who benefit from ICB therapy, but further research is still needed, according to the authors.

There are four key elements of an anti-tumor immune response: activation of the immune system, a target in the cancer that the immune system can go after, sufficient trafficking to that tumor's microenvironment and maintenance of that effect or response in the tumor microenvironment. What is required for us to get a definitive, clear biomarker for treatment response is a comprehensive biomarker that interrogates the entire system. This is a step in the right direction, but it’s not complete."

Amy Heimberger, MD, the Jean Malnati Miller Professor of Brain Tumor Research and a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University

"Though it would be extremely useful to identify the 10 to 20 percent of patients who may benefit from ICB, the ability to sensitize the remaining 80 to 90 percent that would otherwise be resistant to ICB has the potential to improve outcomes for much larger patient populations," said Daniel McGrail, PhD, a postdoctoral fellow at The University of Texas MD Anderson Cancer Center and first author of the study.

Source:
Journal reference:

Mcgrail, D.J., et al. (2021) Replication stress response defects are associated with response to immune checkpoint blockade in nonhypermutated cancers. Science Translational Medicine. doi.org/10.1126/scitranslmed.abe6201.

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