A variant of the CTLA-4 gene associated with autoimmune disease has been found to be more common in patients with non-small cell lung cancer (NSCLC) who have shown an exceptionally high response to anti-inflammatory immunotherapy. PD-1 and immune system-related side effects higher than in a comparable cohort of lung cancer patients and healthy individuals, according to data presented at the 2022 AACR Annual Meeting, which was held from April 8 to 13.
“PD-1/PD-L1 immune checkpoint protein inhibitors have transformed the landscape of cancer treatment. However, there remains great variability in response and unpredictable adverse events, including autoimmune reactions, in NSCLC patients undergoing this therapy,” said presenter India Allen, BSc, of the Garvan Institute of Medical Research, St Vincent’s Medical School, UNSW, Australia. “There are currently limited biomarkers to effectively predict this variability, and the extent to which a patient’s genetic makeup contributes to response is not well understood. »
The occurrence of immune system-related adverse events (irAEs) – side effects that occur in response to immune system activation by immunotherapy – are known to be correlated with a higher response to anti-PD-1 treatment and better outcomes in patients with NSCLC.
Additionally, Allen explained, blocking PD-1 and a second immune checkpoint protein, such as CTLA-4, in combination often results in better treatment outcomes, but at the cost of increased irAE, including autoimmunity.
“This suggests a shared mechanism behind the susceptibility that drives autoimmunity and a better response to cancer immunotherapy,” Allen said. “We hypothesized that patients who show an increased response may harbor genetic mutations in the CTLA-4 gene linked to autoimmunity, and that these might work to achieve better outcomes. »
To test this hypothesis, the authors of this study performed whole genome sequencing of germline DNA from 35 NSCLC patients with an exceptional response to anti-PD-1 treatment, defined as a progression-free survival of at least two years and one or more AEs of grade 2 or higher. In these patients, the frequency of certain single nucleotide polymorphisms (SNPs) in the genetic region encompassing the CTLA-4 gene was analyzed and compared to that of patients with lung cancer within the PCAWG (Pan-Cancer Analysis of Whole Genomes) publicly available. and elderly people without cancer or dementia included in the Medical Genome Reference Bank (MGRB).
Allen and colleagues identified several SNPs that were more common in exceptional responders compared to the other two cohorts. In particular, an SNP was present in 15.7% of exceptional responders and was twice as common as in patients in the PCAWG cohort and nearly four times as common as those in the MGRB cohort.
“This SNP has been reported to impact 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 enrichment of this variant in our cohort suggests a mechanism by which it could
confer an increased response to treatment. As such, this CTLA-4 variant could be used to identify patients who would benefit from anti-PD-1 treatment. »
According to Allen, the identification of this genetic variant by genomic sequencing could be used alongside existing biomarkers to help select NSCLC patients likely to respond better to anti-PD1/PD-L1 therapy and those at risk for side effects. more severe autoimmunes.
The authors are currently extending the search for genetic response biomarkers to other genes related to autoimmunity, including CTLA-4 neighboring genes such as CD28 and ICOS.
“Further analysis of the immunological impact of these genetic variants could also help us better understand the mechanisms underlying the current variability in response and why some patients develop more severe autoimmune side effects after therapy with immune checkpoint,” Allen said. “Understanding the mechanisms of response to these drugs is essential to broaden their potential clinical benefit. »
An important limitation of this study was the lack of direct comparison with nonresponders, who are currently being recruited and sequenced for future analysis. Additionally, as Allen noted, the costs associated with whole genome sequencing and the paucity of patients with an exceptional immunotherapeutic response severely limited sample size. Other limitations include differences in patient demographics, including gender, age, and smoking status, and differences in the recruitment process between the exceptional responder cohort and comparison cohorts (MGRB and PCAWG ), although these differences were taken into account in the comparisons.