Simultaneous radiation beneficial for subset of lung cancer patients

CHICAGO: Cancer cells attempt to survive in many different cancers by avoiding immune system attacks. Immune checkpoints are methods that cancer cells use to deceive the immune system into believing they are healthy cells.

Immune checkpoint blockers, which have recently transformed treatment approaches for many cancer patients, especially those with metastatic non-small-cell cancer"lung cancer, are the focus of recent advancements in cancer treatment (mNSCLC).

Unfortunately, only a small percentage of patients have benefited, and a significant portion of cancer patients still require better care. Adding radiation therapy (RT) to immune checkpoint blockade (ICB) has produced excellent results in a number of studies in animals; however, this combination therapy has not been validated in people.

The main clinical question right now is whether and how combining RT and ICB can benefit patients with mNSCLC. Researchers from UChicago Medicine have discovered the first biomarker that predicts response to the RT and ICB treatment combination in a recent publication that appeared in Nature Cancer.

Tumour cells that are aneuploid will either have excess or missing chromosomes. In the current investigation, it was discovered that adding RT to ICB dramatically improved survival in mNSCLC patients with high tumour aneuploidy.

In contrast, adding RT to ICB therapy had no survival advantage for patients with minimal aneuploidy. Sean Pitroda, MD, Assistant Professor of Radiation and Cellular Oncology at UChicago Medicine and the paper's senior author, added that the researchers also showed that radiotherapy to metastatic sites concurrent with, but not before or after, ICB improves survival in patients with high aneuploidy tumours.

37 patients with mNSCLC were enrolled in a randomised phase 1 clinical trial to examine the differences in clinical and genomic characteristics between sequential (radiation therapy followed by ICB therapy) and concurrent (radiation therapy while ICB is on-board) therapies.

Analysis of tumour tissue samples taken both before and during treatment revealed radiation therapy alone is less successful at eliminating malignant cells than radiation combined with immunotherapy. "A key observation was that radiation therapy alone caused depletion of important immune cells within the tumour, however, with concurrent therapy there was enrichment of immune cells and improved elimination of tumour cells that led to positive survival outcomes in mNSCLC patients," Pitroda said.

He described that in concurrent treatment, immunotherapy takes the brakes off of the immune cells that would not normally recognize cancer because cancer has ways to hide from the immune system. Essentially, immunotherapy is unmasking cancer cells and helping those immune cells hone in on the tumour to fight cancer.

"By giving immunotherapy with radiation, we believe that radiation becomes more effective at killing tumour cells by helping immune cells find the damaged tumour that's dying off," he said.

"Our findings highlight that radiation therapy alone is not enough to trigger a localized immune response in mNSCLC and the timing of radiation and immunotherapy is critical to this process," said Pitroda.

Researchers have become increasingly interested in the idea of tumour aneuploidy, and other research has revealed a connection between aneuploidy and the immune system, but it is still unclear exactly how it may be used to enhance cancer treatments.

The initial author of these studies, Liam Spurr, a current medical student at the University of Chicago Pritzker School of Medicine, had previously created an algorithm that measures the degree of aneuploidy in patients' tumours after DNA sequencing.

The researchers proposed the idea that aneuploidy would be helpful in identifying which cancers might react better to immunotherapy. Based on their findings in the Nature Cancer study, the team went on to test whether aneuploidy could be useful as a biomarker for predicting survival in another study that was published in Nature Genetics.

This study re-analyzed data from a larger cohort of 1,660 patients who had received immune checkpoint blockade treatment for a variety of cancer types. The prognosis for tumours with a high aneuploidy level was poorer since immunotherapy alone did not work for these patients. Additionally, tumour aneuploidy complemented tumour mutational burden (TMB), a recognised biomarker for the efficacy of immunotherapy across a wide range of malignancies.

Patients who have high TMB frequently respond favourably to immunotherapy, while those who have low TMB typically do not. "For low TMB tumours, you look for another biomarker, like aneuploidy, to improve your prediction of immunotherapy response.

The ones that have the worst survival after immunotherapy are the ones that have low TMB and high aneuploidy scores and those are probably the patients that need something more than immunotherapy, like radiation, to improve their treatment response and outcomes," Sean Pitroda said.

The way we treat many different types of cancer has radically changed because of immunotherapy. Some cancers are fatal, particularly when they spread to other parts of the body, but today people can live a long time, and some tumours may even be treated with immunotherapy.

Better approaches are needed to enhance results, maybe by combining immunotherapies with other cancer treatments like radiation or chemotherapy, as many patients do not respond to immunotherapy.

The latest study suggested that adding radiation to patients who do not respond to immunotherapy alone can enhance outcomes and discovered a brand-new method for predicting patients' responses to immunotherapy. Pitroda said, "We have the first method to personalize therapy--to choose the right therapy for the right patient at the right time--employing radiation and immunotherapy."