How targeting a genetic signature of cellular stress may boost cancer immunotherapy

MD Anderson Cancer Center
A genetic signature could help doctors predict which patients are most likely to respond to cancer immunotherapy, and inducing this marker with drugs may potentially sensitize other patients to checkpoint inhibitors, scientists at MD Anderson found. (MD Anderson Cancer Center)

Immune checkpoint inhibitors have become the new standard of care for many cancer types, but only a subset of patients have robust responses to these treatments. A research team from MD Anderson Cancer Center has found a genetic signature that could not only help doctors select the right patients for these treatments, but also open the door to sensitizing other patients to immunotherapy.

The genetic signature signals deficiencies in a cellular process called the replication stress response (RSR). By studying 12 cohorts of patients with low-mutated tumors spanning seven cancer types, the MD Anderson team showed that the biomarker could predict response to PD-1/L1 checkpoint inhibitors. Inducing RSR defects improved survival in mice treated with checkpoint inhibitors, they reported in Science Translational Medicine.

In normal cells, replication stress response slows DNA replication to allow for repair. Deficiencies in RSR can give rise to early cancer cells, allowing the rogue cells to escape death.

 But because RSR function can’t be derived from patient samples, the MD Anderson researchers developed a gene-expression signature of defective RSR, Daniel McGrail, Ph.D., the study’s first author, explained in an email. In RSR-deficient cancer cells, the team discovered high amounts of a type of DNA that activates immune-stimulating pathways.

Because PD-1/L1 inhibitors leverage the body’s immune response to target cancer, the researchers hypothesized that these immunotherapies might work better in tumors with high RSR deficiencies (RSRDs).

 Indeed, across five mouse models bearing breast cancer with different RSRD scores, checkpoint inhibitors failed to improve survival in two RSRD-low models but extended life in all three RSRD-high models. As the RSRD score got higher, the treatment outcome appeared better, the team found.

Further analysis linked RSRD-high breast cancers with increased infiltration of cancer-fighting dendritic cells and T cells in the tumors.

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The researchers went on to determine whether their findings might translate to people. They examined data from several studies of checkpoint inhibitors in multiple tumor types and found that RSRD scores robustly predicted clinical responses to immune checkpoint blockade among patients with low-mutated tumors, the team reported. On a measurement that asks, “how much better is this predictor than random chance?” the genetic signature was a nearly perfect predictor, McGrail said. By contrast, the known biomarker of tumor mutation burden in over 20 cohorts returned a much lower score, he noted.

The team also observed some survival benefits among patients with high RSRD. For example, in a Nature Medicine study that evaluated Merck's PD-1 blocker Keytruda in glioblastoma, patients with high RSRD scores had a 77% lower risk of death compared with those with low RSRD score when they got the PD-1 inhibitor before surgery, the MD Anderson team found.

To boost RSRD, the MD Anderson team turned to inhibitors of ATR and CHK1, which are key regulators of RSR. Combining Eli Lilly’s experimental CHK1 inhibitor prexasertib with checkpoint inhibitor significantly improved survival over either drug alone in mice with RSRD-low breast cancer tumors, the study showed.

Several other ATR and CHK1 inhibitors are in clinical testing. MD Anderson is evaluating Pfizer and Merck KGaA’s PD-L1 inhibitor Bavencio alongside the German Merck’s ATR inhibitor berzosertib. Bayer is pairing its ATR blocker BAY1895344 with Keytruda. AstraZeneca’s AZD6738 is also an ATR inhibitor.

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The MD Anderson study relied upon existing data, so clinical studies would be needed to validate the findings, the researchers said. 

And while the RSR defect is promising as a biomarker to help identify which patients may benefit from checkpoint inhibition, the promise of helping immunotherapy non-responders is even greater, McGrail noted.

“We found the ability to pharmacologically induce RSR defects and sensitize otherwise resistant tumor models to [checkpoint blockade] equally or even more exciting, as this approach may provide benefit for the remaining 70-90% of patients with cancer” who are not helped by the drug, he said.