At the same time, radiotherapy and immunotherapy are beneficial in some lung cancer patients

In many types of cancer, cancer cells try to survive
by evading attacks by the immune system.
These cancer cells hijack a mechanism called immune checkpoints, which trick the immune system into thinking they are healthy cells
.
Recent advances in cancer treatment have focused on developing immune checkpoint blockers, which have revolutionized the treatment of many cancer patients, including metastatic non-small cell lung cancer (mNSCLC
).
Unfortunately, only a small percentage of patients benefit from this, and a large proportion of cancer patients still need better treatment
.
Many animal studies have shown that the addition of radiotherapy (RT) to immune checkpoint blockade (ICB) has produced positive results; However, this combination therapy has not been proven
in humans.
Now, the biggest clinical question is whether and how RT and ICB can produce positive outcomes
in patients with mNSCLC.

In a recently published Nature Cancer paper, researchers at the University of Chicago School of Medicine have discovered the first biomarker to predict response to combined RT and ICB therapy
.
Aneuploidy is a condition
in which tumor cells exhibit missing or extra chromosomes.
In the current study, it was found that patients with mNSCLC with high aneuploidy had significantly improved survival rates if RT was added to the ICB
.
In contrast, the addition of RT to ICB therapy had no benefit
for survival in hypoaneuploidy patients.
In addition, according to Sean Pitroda, MD, assistant professor of radiation and cellular oncology at the University of Chicago School of Medicine and senior author of the paper, the researchers demonstrated that concurrent metastatic radiotherapy at the ICB, rather than before or after the ICB, improved survival in patients with highly aneuploidy
tumors.

To assess differences in clinical and genomic parameters between sequential therapy (radiotherapy followed by ICB therapy) and concurrent therapy (radiotherapy followed by ICB therapy), 37 patients with mNSCLC were enrolled in a randomised Phase 1 clinical trial
.
Tumor tissue samples analyzed before and during treatment showed that radiotherapy alone was less effective at eliminating tumor cells than concurrent radiotherapy and immunotherapy
.

"A key observation is that radiotherapy alone leads to the depletion of important immune cells within the tumor, however, in the case of simultaneous treatment, the enrichment of immune cells and the elimination of tumor cells improves positive survival outcomes
for patients with mNSCLC," Pitroda said.

He describes that in synchronous therapy, immunotherapy stops immune cells and normally does not recognize cancer because cancer has a way to evade the immune system
.
Essentially, immunotherapy is all about lifting the veil on cancer cells and helping these immune cells lock on to tumors and fight cancer
.

"With radioimmunotherapy, we believe that radiation can help immune cells find damaged tumors that are dying, thereby killing tumor cells
more effectively," he said.
"Our findings highlight that radiation therapy alone is not sufficient to elicit a local immune response in small cell lung cancer, and that the timing of radiation and immunotherapy is critical
to this process," Pitroda said.

The concept of tumor aneuploidy has attracted increasing interest from researchers, and other work has shown a link between aneuploidy and the immune system, but exactly how it can be used to improve cancer treatment has not yet been determined
.
Liam Spurr, a current student at the University of Chicago's Pritzker School of Medicine and the first author of the studies, previously developed an algorithm that quantifies the extent
of aneuploidy in tumors as they undergo DNA sequencing.
Together, the researchers proposed the hypothesis that aneuploidy may help determine which tumors respond better
to immunotherapy.

Building on their findings in the Nature Cancer study, the team further tested whether aneuploidy could be used as a biomarker for predicting survival in another study published in Nature Genetics, which reanalyzed
1660 patients with various cancer types treated with immune checkpoint blockers.
Tumors with high aneuploidy have a poor prognosis because these patients do not respond to
immunotherapy alone.
In addition, tumor aneuploidy complements the tumor mutational burden (TMB)—a biomarker that has been identified in many cancers for immunotherapy response
.
Patients with high TMB usually respond well to immunotherapy, while patients with low TMB usually do not
.

"For low-TMB tumors, you need to look for another biomarker, such as aneuploidy, to improve your prediction
of response to immunotherapy.
The lowest survival rates after immunotherapy are patients with low TMB and high aneuploidy scores, who may need more than immunotherapy, such as radiotherapy, to improve their treatment response and outcomes," said Sean Pietroda
.

Immunotherapy has revolutionized the way
we treat many types of cancer.
Some cancers are fatal, especially when they metastasize, but now people can live a long time, and some of them can even be cured
with immunotherapy.
However, many patients do not respond to immunotherapy and better strategies are needed to improve outcomes, possibly combining
immunotherapy with other cancer treatments such as radiation or chemotherapy.
The current study found a completely new way to predict how patients will respond to immunotherapy and suggests that adding radiation therapy to those who do not respond to immunotherapy can improve outcomes
.

"We have the first approach to personalized treatment — choosing the right treatment for the right patient at the right time — using radiation and immunotherapy
," Pitroda said.

Original search:

Highly aneuploid non-small cell lung cancer shows enhanced responsiveness to concurrent radiation and immune checkpoint blockade: Nature Cancer

Liam F.
Spurr, Carlos A.
Martinez, Wenjun Kang, Mengjie Chen, Yuanyuan Zha, Robyn Hseu, Stanley I.
Gutiontov, William T.
Turchan, Connor M.
Lynch, Kelli B.
Pointer, Paul Chang, Septimiu Murgu, Aliya N.
Husain, Brittany Cody, Everett E.
Vokes, Christine M.
Bestvina, Thomas F.
Gajewski, Ralph R.
Weichselbaum, Steven J.
Chmura, and Sean P.
Pitroda from The University of Chicago; Jyoti D.
Patel from Northwestern University; Maximilian Diehn from Standford University.