x-ray lung cancer
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In a reversal to accepted theories, scientists have discovered the adding radiation to immunotherapy does not boost the immune system. It’s actually the reverse. Yet, in several cancers, the combination together shows improved treatment responses over either treatment alone. The reason may have more to do with the tumor’s aneuploidy status—the amount of extra chromosome gained or lost in a tumor. In a pair of papers published in Nature Cancer and Nature Genetics, scientists at the University of Chicago discovered that lung cancers with high aneuploidy responded better to simultaneous treatment with radiation and immunotherapy. They believe aneuploidy could be useful as a biomarker for identifying patients more or less likely to benefit from the combined approach.

The premise that radiation improves immunotherapy has been based on a large body of preclinical work that the dual treatment activates an immune response to super-charge the response to immune checkpoint blockade. More than 500 clinical trials have been initiated based on the idea that radiation positively stimulates the immune system, yet the majority of published trials show that almost none of them are conclusive for showing that interaction.

“A lot of people are sort of scratching their heads as to what’s going on and why is that the case,” said Sean Pitroda, MD, assistant professor of Radiation and Cellular Oncology at UChicago Medicine and the senior author of the paper whose lab has been among the strong proponents of that idea based on the preclinical evidence. To find supportive clinical data to prove the case of dual immunotherapy/radiation treatment, Pitroda’s team designed a trial in non-small cell lung cancer (NSCLC) combining immunotherapy—which is the standard of care in lung cancer—with radiation.

In the trial published in the group’s Nature Cancer paper, patients received radiation in addition to immunotherapy with ipilimumab plus nivolumab (ipi/nivo) to see if outcomes inmproved. The team first determined that it was safer to give both treatments concurrently rather than doing radiation first followed by immunotherapy. After studying tissue from surgical biopsies of the tumors both before and during therapy, they found a big surprise.

“What we found was really quite striking and contradictory to preclinical evidence,” said Pitroda. “The radiation did not activate the immune system; it actually suppressed the immune cells in the tumor, really killed a lot of them off.” However, the researchers observed this phenomena could be rescued and that the killing of the tumor could be amplified, with adding immunotherapy.

“This proved for the first time in patients that radiation was actually immune suppressive, not immunogenic and that combination of radiation and immunotherapy was better at killing tumors than radiation followed by immunotherapy,” added Pitroda.

In the next set of experiments, Pitroda wanted to identify which patients benefited most from the combination therapy. Having investigated standard biomarkers associated with immunotherapy response—like tumor mutational burden or PD-1 expression—none provided answers in this context.

Next, the researchers turned to a tumor’s degree of aneuploidy. Almost every tumor has some degree of aneuploidy, but it turns out the relative level of the aneuploidy is important.

“We discovered that if a tumor has very high aneuploidy, it turns out it is resistant to both immunotherapy and to radiation,” explained Pitroda. “But by combining the two therapies, you can better kill these highly aneuploid tumors and we found that those are the ones that actually benefited from adding the radiation onto the immunotherapy.” In lung cancer, the researchers discovered that at least 40% of the chromosomes in a tumor needed to have some level of aneuploidy to see this benefit of adding radiation to immunotherapy. “That’s a very large proportion. About half of patients exhibit that elevated aneuploidy,” he added

To validate their discovery, they team studied a dataset of 350 lung cancers that were treated only with immunotherapy to see which ones benefited. They found aneuploidy to be a very strong biomarker in patients who get immunotherapy with high aneuploidy associated with worse survival than low aneuploidy.

A second data set evaluated patients who got radiation and immunotherapy. They found that outcomes were similar in the low aneuploid patients, whether they got immunotherapy alone or any combination of radiation and immunotherapy. But in patients with high-end aneuploid tumors did much better if they got radiation with immunotherapy than if they only got immunotherapy.

In the Nature Genetics paper, the team wanted to see if this finding was broadly applicable beyond lung cancer because aneuploidy occurs in more than 95% of cancers. Looking at a large cohort of more than 1,600 patients who all received immunotherapy, the investigators looked to see the role of aneuploidy as a biomarker of immunotherapy response. “We found that across these 10 different tumor types, aneuploidy was a biomarker for immunotherapy response, again with high aneuploid responding less and having worse survival than low aneuploid,” said Pitroda. Not only was it strongly prognostic, but it also complemented and was independent of tumor mutation burden, which is a known predictor of immunotherapy response across multiple cancer types.

“When we put all of these insights together, we show that aneuploidy is a key determinant of immunotherapy response and that it complements other genomic biomarkers like tumor mutation burden,” Pitroda concluded. “The patients with the highest level of aneuploidy in their tumor don’t respond well to immunotherapy, but those are the ones where we can personalize therapy better and add radiation onto their existing immunotherapy treatment that potentially could improve their outcomes.”

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