A variant of the CTLA-4 gene associated with autoimmune disease was found to be more frequent in patients with non–small cell lung cancer (NSCLC) who experienced an exceptionally high response to anti–PD-1 immunotherapy and a higher rate of immune-related side effects than in a comparable cohort of patients with lung cancer and healthy individuals, according to data presented by Allen et al during the American Association for Cancer Research (AACR) Annual Meeting 2022 (Abstract 665).
“Inhibitors of the immune checkpoint proteins PD-1/PD-L1 have transformed the cancer treatment landscape. However, there remains large variability in response and unpredictable adverse events, including autoimmune reactions, in [patients with] NSCLC who undergo this treatment,” said presenting author 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-related adverse events is known to correlate with higher response to anti–PD-1 therapy and improved outcomes in patients with NSCLC. In addition, Ms. Allen explained, combined blockade of PD-1 and a second immune checkpoint protein, such as CTLA-4, often results in better treatment outcomes—but at the cost of increased immune-related adverse events, including autoimmunity.
“This suggests a shared mechanism behind the predisposition that drives autoimmunity and better response to cancer immunotherapy,” said Ms. Allen. “We hypothesized that patients who exhibit increased response may be harboring genetic mutations within the autoimmune-linked gene CTLA-4, and that these might work to drive better outcomes.”
Whole-Genome Sequencing
To test this hypothesis, the authors of this study performed whole-genome sequencing on germline DNA from 35 patients with NSCLC exhibiting exceptional response to anti–PD-1 therapy, defined as progression-free survival of at least 2 years and one or more immune-related adverse events 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 publicly accessible Pan-Cancer Analysis of Whole Genomes (PCAWG) cohort, as well as to cancer- and dementia-free elderly individuals included in the Medical Genome Reference Bank (MGRB).
Results
Ms. Allen and colleagues identified several SNPs that were more frequent within the exceptional responders compared with the other two cohorts. In particular, one SNP was present in 15.7% of exceptional responders and was two times more frequent than in patients within the PCAWG cohort and almost four times more frequent than those in the MGRB cohort.
“This SNP has been reported to impact the function of the CTLA-4 immune checkpoint protein to drive increased susceptibility to autoimmune disease, such as type 1 diabetes and rheumatoid arthritis,” commented Ms. Allen. “The enrichment of this variant in our cohort suggests a mechanism by which it could be conferring increased response to treatment. As such, this CTLA-4 variant could be used to identify patients that would benefit from anti–PD-1 treatment.”
According to Ms. Allen, the identification of this genetic variant through genomic sequencing could be used alongside existing biomarkers to help select patients with NSCLC who may experience better response to anti–PD-1/PD-L1 checkpoint therapy and those at risk of more severe autoimmune side effects.
The authors are currently expanding the search for genetic response biomarkers to other autoimmune-linked genes, including neighboring 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,” said Ms. Allen. “Understanding the mechanisms of response to these drugs is paramount to broadening their potential clinical benefit.”
One important limitation of this study was the lack of direct comparison with nonresponders, who are currently being recruited and undergoing sequencing for future analysis. In addition, as noted by Ms. Allen, the costs associated with whole-genome sequencing and the rarity of patients with exceptional immunotherapy response greatly limited the sample size. Other limitations include the differences in patient demographics, including sex, age, and smoking status, and differences in the recruitment process between the exceptional responder cohort and the comparison cohorts (MGRB and PCAWG), although these differences were taken into consideration in the comparisons.
Disclosure: This study was funded by Bioplatforms Australia, The Kinghorn Foundation, and The Garvan Institute. For full disclosures of the study authors, visit abstractsonline.com.
