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| Aneuploidy Identified As a Critical Biomarker For Radiation And Lmmunotherapy For Cancer |
Scientists have found that adding radiation to immunotherapy does not strengthen the immune system, contrary to widely held beliefs. Actually, the opposite is true. However, the combined therapy exhibits better therapeutic responses than either treatment alone in a number of malignancies. The tumor's aneuploidy status—the number of additional chromosomes it has acquired or lost—could be the primary factor. University of Chicago researchers found that combined radiation and immunotherapy treatment was more effective in treating lung tumors with high aneuploidy, as reported in two publications that appeared in Nature Cancer and Nature Genetics. They think aneuploidy may serve as a biomarker to help determine whether patients may benefit more or less from the combination strategy.
A substantial amount of preclinical research has supported the idea that radiation enhances immunotherapy by triggering an immunological response that amplifies the effect of immune checkpoint inhibition. On the theory that radiation favorably boosts the immune system, more than 500 clinical experiments have been started, however, the bulk of published trials reveal that nearly none of them are conclusive for demonstrating that interaction.
Senior author of the study and associate professor of radiation oncology and cellular oncology at the University of Chicago Medicine, Sean Pitroda, MD, whose laboratory has been one of the leading proponents of that theory based on the preclinical findings said: "A lot of people are sort of scratching their heads as to what's going on and why is that the case." Pitroda's team developed a study in non-small cell lung cancer (NSCLC) combining immunotherapy—which is the standard of care in lung cancer—with radiation in order to gather evidence from the clinical literature to support the case of combination immunotherapy/radiation treatment.
Patients underwent radiation treatment in conjunction with immunotherapy with ipilimumab plus nivolumab (ipi/nivo) in the experiment described in the group's Nature Cancer publication to examine if outcomes improved. First, the scientists found that administering both treatments simultaneously was safer than administering radiation first and then immunotherapy. They discovered a significant surprise after examining tissue from surgical biopsies of the malignancies both before and after treatment.
The combination of radiation and immunotherapy was more effective in killing cancers than radiation alone, Pitroda continued, "proving for the first time in patients that radiation was truly immunological suppressive, not immunogenic."
Pitroda's next round of tests aimed to determine which patients benefitted from the combo treatment the most. Having looked at common biomarkers for immunotherapy response, such as tumor mutational load or PD-1 expression, none offered solutions in this situation.
The researchers then focused on the aneuploidy level of a tumor. Nearly all tumors are aneuploid to some extent, but it turns out that the relative quantity of aneuploidy is crucial.
We discovered that a tumor with a very high aneuploidy level is resistant to both immunotherapy and radiation, according to Pitroda. But when you combine the two treatments, you can more effectively eradicate these highly aneuploid tumors, and we discovered that they were the ones who benefited from adding radiation to the immunotherapy. The advantage of adding radiation to immunotherapy in lung cancer was shown to require at least 40% of the chromosomes in a tumor to have some degree of aneuploidy. "That's a significant percentage. The high aneuploidy is seen in almost half of the individuals, he continued.
The scientists looked at a dataset of 350 lung cancer cases treated only with immunotherapy to see which ones benefited from the treatment in order to confirm their discovery. They discovered that aneuploidy is a highly powerful biomarker in immunotherapy patients, with higher aneuploidy being related to poorer survival than lower aneuploidy.
Patients who had radiation and immunotherapy were assessed using a second data set. They discovered that whether low aneuploid individuals received immunotherapy alone or any combination of radiotherapy and immunotherapy, results were comparable. However, individuals with high-end aneuploid tumors fared better with radiation combined with immunotherapy than with immunotherapy alone.
Because aneuploidy occurs in more than 95% of malignancies, the researchers intended to see whether this discovery was generally relevant beyond lung cancer in the Nature Genetics publication. The researchers examined a sizable cohort of more than 1,600 patients who had all undergone immunotherapy to determine the function of aneuploidy as a biomarker of immunotherapy response. With regard to these 10 different tumor types, Pitroda noted, "We found that aneuploidy was a biomarker for immunotherapy response, again with high aneuploid responding less and having shorter survival than low aneuploid.". It was not only highly predictive but also complimented tumor mutation load, a recognized predictor of immunotherapy response in a variety of cancer types, and it was independent of it.
Pitroda said, "When we combine all of these data, we demonstrate that aneuploidy is a critical driver of immunotherapy response and that it complements other genomic indicators like tumor mutation load. The patients with the greatest levels of aneuploidy in their tumors don't respond well to immunotherapy, but they are the ones for whom we may better customize therapy and add radiation to their current immunotherapy treatment, which may improve their results.
