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
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However, in patients with non-small cell lung cancer receiving this treatment, response and unpredictable adverse events (including autoimmune reactions) ) remains largely variable
.
" "Currently, there are limited biomarkers that can effectively predict this variation, and the extent to which a patient's genetic makeup affects response is not well understood
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The occurrence of immune-related adverse events (irAEs), i.
e.
side effects produced when immunotherapy activates the immune system, is known to be associated with higher responses to anti-PD-1 therapy and improved outcomes in NSCLC patients
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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
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"This suggests that there is a shared mechanism behind driving autoimmunity and susceptibility to better responses to cancer immunotherapy," Allen said
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"We hypothesized that patients who exhibit enhanced responses may harbor the autoimmune-linked gene CTLA.
-4 genetic mutations, these may lead to better outcomes
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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
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In these patients, the researchers analyzed the frequency of certain single nucleotide polymorphisms (SNPs) in the genetic region where the CTLA-4 gene resides and compared them with the publicly accessible Pan-Cancer Analysis of Genome-Wide (PCAWG) cohort The frequencies of lung cancer patients and older adults without cancer and dementia included in the Medical Genome Reference Bank (MGRB)
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Allen and colleagues found several more frequent SNPs in special responders compared to the other two groups
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In particular, one SNP was present in 15.
7% of abnormal responders, twice as frequently as in the pcag group and almost four times as high as in the MGRB group
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"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
.
"In our cohort, the enrichment of this variant suggests a possible mechanism
Improve response to treatment
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Therefore, this CTLA-4 variant can be used to identify patients who benefit from anti-PD-1 therapy
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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
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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
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"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
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The mechanism of response of these drugs is critical in extending their potential clinical benefit
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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
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In addition, as Allen points out, the costs associated with whole-genome sequencing and rare immunotherapy-responsive patients greatly limit sample size
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Other limitations included differences in patient demographics, including gender, age, and smoking status, and differences in the recruitment process between the exception-responder cohort and the comparison cohort (MGRB and PCAWG), although these differences were taken into account in the comparison
.
