Occurrence of immune-related adverse events (irAE)—side effects arising in response to the activation of the immune system by immunotherapy—are known to correlate with a higher response with anti-PD-1 therapy and improved outcomes in NSCLC patients.
In addition, explains Allen, a combination of PD-1 blockade and a second immune checkpoint protein, such as CTLA-4, often results in better treatment outcomes but at the expense of increased irAE, including autoimmunity.
“This suggests a shared mechanism behind the tendency to promote autoimmunity and better response to cancer immunotherapy.“, said Allen.
“We hypothesize that patients with hyperreactivity may be harboring genetic mutations in the autoimmune-associated gene CTLA-4, and that these diseases may work to provide a better outcome.. “
To test this hypothesis, the authors of this study performed whole-genome sequencing of germline DNA from 35 NSCLC patients with a specific response to anti-PD-1 therapy, defined as progression-free survival of at least two years and one or more irAEs of grade 2 or higher.
In these patients, the frequencies of certain single nucleotide polymorphisms (SNPs) in the genetic region including the CTLA-4 gene were analyzed and compared with the frequencies in patients with lung cancer in the group. The Pan-Cancer Analysis of Whole Genomes (PCAWG) cohort that is publicly accessible and for the elderly without cancer and dementia is included in the Medical Genome Reference Bank (MGRB).
Allen and colleagues identified some SNPs more frequently in ad hoc responders than in the other two groups.
In particular, an SNP was present in 15.7 percent of outliers and two times more frequently than in patients in the PCAWG group and almost four times more frequently in patients in the MGRB group.
“This SNP has been reported to affect the function of the immune checkpoint protein CTLA-4 to increase susceptibility to autoimmune diseases, such as type 1 diabetes and rheumatoid arthritis.“, commented Allen.
“The abundance of this variant in our cohort suggests a mechanism by which it may induce an increased response to treatment. Therefore, this variant of CTLA-4 can be used to identify patients who would benefit from anti-PD-1 therapy.. “
According to Allen, the identification of this genetic variant through gene sequencing can be used alongside existing biomarkers to help select NSCLC patients who may respond better to checkpoint therapy. resistant to PD1/PD-L1 and who are at higher risk for serious autoimmune side effects.
The authors are now expanding the search for genetic response biomarkers for other autoimmune-associated genes, including CTLA-4 neighboring genes such as CD28 and ICOS.
“Further analysis of the immunological effects of such genetic variants may also help us better understand the response mechanisms of the underlying current variation and why some patients develop more serious autoimmune side effects after immune checkpoint treatment“, said Allen.
“Understanding the response mechanisms to these drugs is paramount to extending their potential clinical benefits. “
An important limitation of this study is the lack of direct comparisons with non-responders who are currently recruited and undergoing sequencing for future analysis.
In addition, as Allen noted, the costs associated with whole-genome sequencing and the rarity of patients with a particular immunotherapy response have significantly limited sample size.
Other limitations included differences in patient demographics, including gender, age, smoking status, and differences in the recruitment process between the outlier and comparison groups. MGRB and PCAWG), although these differences were taken into account in the comparisons.
Source: Medindia
