Lung cancer patients with genetic variants linked to autoimmune disease may respond better to immunotherapy

Non-small cell lung cancer (NSCLC) patients in whom a variant CTLA-4 gene associated with autoimmune disease was found to be more frequent experienced abnormally high responses to anti-PD-1 immunotherapy and several side effects, higher than comparable Lung cancer patients and healthy people

"Inhibitors of the immune checkpoint proteins PD-1/PD-L1 have changed the landscape of cancer treatment

The occurrence of immune-related adverse events (irAEs), i.

In addition, Allen explained that combined blockade of PD-1 and a second immune checkpoint protein such as CTLA-4 often results in better therapeutic outcomes, but at the cost of increased irae, including autoimmunity

"This suggests that there is a shared mechanism behind driving autoimmunity and susceptibility to better responses to cancer immunotherapy," Allen said

To test this hypothesis, the authors of this study performed whole-genome sequencing of germline DNA from 35 NSCLC patients who exhibited abnormal responses to anti-PD-1 therapy, defined as at least 2-year progression-free survival and one or more 2 grade or higher iae

Allen and colleagues found several more frequent SNPs in special responders compared to the other two groups

"This SNP has been reported to affect the function of the CTLA-4 immune checkpoint protein, thereby increasing susceptibility to autoimmune diseases such as type 1 diabetes and rheumatoid arthritis," comments Allen

Improve response to treatment

According to Allen, the identification of this genetic variant by genome sequencing could be used in conjunction with existing biomarkers to help select NSCLC patients who are likely to respond better to anti-PD1/PD-L1 checkpoint therapy, as well as those Patients at risk for more severe autoimmune side effects

Currently, the authors are expanding the search for gene-responsive biomarkers to other autoimmunity-related genes, including CTLA-4's neighbors, such as CD28 and ICOS

"Further analysis of the impact of this genetic variant on immunity could also help us better understand the mechanisms underlying the current response variant and why some patients experience more severe autoimmune side effects following immune checkpoint therapy," Allen said

An important limitation of this study is the lack of direct comparisons with non-responders, who are currently being recruited and sequenced for future analysis