A variant of the CTLA-4 gene associated with autoimmune disease may provide a biomarker for anti-PD-1 immunotherapy responses and adverse effects, Australian researchers have shown.
In findings presented at the AACR 2022 meeting, a team from the Garvan Institute of Medical Research, Sydney, showed that a single nucleotide polymorphism (SNPs) of the CTLA-4 gene was enriched in non-small cell lung cancer (NSCLC) patients who had an exceptionally high response to single agent anti-PD-1 immunotherapy and higher immune-related adverse effects (irAEs).
Study investigator India Allen said the study was based on observations that SNPs within and surrounding CTLA-4 were associated with autoimmune diseases such as rheumatoid arthritis and type 1 diabetes.
And since combined blockade of PD-1 and CTLA-4 often results in better treatment outcomes but at the cost of increased irAEs, there may be a shared mechanism.
“We hypothesised that patients who exhibit increased response may be harbouring genetic mutations within the autoimmune-linked gene CTLA-4, and that these might work to drive better outcomes,” she said.
To test this hypothesis, the Garvan team performed whole genome sequencing on germline DNA from 35 NSCLC patients exhibiting exceptional 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 frequency of certain SNPs in the genetic region encompassing the CTLA-4 gene was analysed and compared to that in patients with lung cancer within the publicly accessible Pan-Cancer Analysis of Whole Genomes (PCAWG) cohort and to healthy individuals included in the Medical Genome Reference Bank (MGRB).
Several non-coding SNPs were found to be enriched within the exceptional responders compared with control populations. One of them was present in 15.7% of exceptional responders; twice the frequency of comparable cases within the general lung cancer cohort and almost four times more than the healthy control group.
Since this non-coding SNP has been reported to exhibit differential enhancer activity and has been associated with RA and T1D, its enrichment within the exceptional responders suggested that the altered CTLA-4 function may cooperate with blockade of PD-1 to confer higher immune response, the researchers said.
Therefore, the identification of this genetic variant through genomic sequencing could be used alongside existing biomarkers to help select NSCLC patients who may experience better response to anti-PD-1/PD-L1 checkpoint therapy and those at risk of more severe autoimmune side effects, they suggested.
Ms Allen said the Garvan team are now expanding the search for genetic response biomarkers to other autoimmune-linked genes, including neighbouring genes of CTLA-4 such as CD28 and ICOS.
“Further analysis into the immunological impact of such genetic variants could also help us better understand the mechanisms underlying current variability in response and why some patients develop more severe autoimmune side effects following immune checkpoint therapy,” she said.
“Understanding the mechanisms of response to these drugs is paramount to broadening their potential clinical benefit.”
This study was funded by Bioplatforms Australia, the Kinghorn Foundation and Garvan Institute.