Biomarkers Associated with Immune-Related Adverse Events under Checkpoint Inhibitors in Metastatic Melanoma

Abstract

Immune checkpoint inhibitors (ICI) have revolutionized the therapeutic landscape of metastatic melanoma. However, ICI are often associated with immune-related adverse events (IRAE) such as colitis, hepatitis, pancreatitis, hypophysitis, pneumonitis, thyroiditis, exanthema, nephritis, myositis, encephalitis, or myocarditis. Biomarkers associated with the occurrence of IRAE would be desirable. In the literature, there is only little data available and furthermore mostly speculative, especially in view of genetic alterations. Our major aim was to check for possible associations between NGS-based genetic alterations and IRAE. We therefore analyzed 95 melanoma patients with ICI and evaluated their NGS results. We checked the data in view of potential associations between copy number variations (CNVs), small variations (VARs), human leucocyte antigen (HLA), sex, blood count parameters, pre-existing autoimmune diseases and the occurrence of IRAE. We conducted a literature research on genetic alterations hypothesized to be associated with the occurrence of IRAE. In total, we identified 39 genes that have been discussed as hypothetical biomarkers. We compared the list of these 39 genes with the tumor panel that our patients had received and focused our study on those 16 genes that were also included in the tumor panel used for NGS. Therefore, we focused our analyses on the following genes: AIRE, TERT, SH2B3, LRRK2, IKZF1, SMAD3, JAK2, PRDM1, CTLA4, TSHR, FAN1, SLCO1B1, PDCD1, IL1RN, CD274, UNG. We obtained relevant results: female sex was significantly associated with the development of hepatitis, combined immunotherapy with colitis, increased total and relative monocytes at therapy initiation were significantly associated with the development of pancreatitis, the same, pre-existing autoimmune diseases. Further significant associations were as follows: HLA homozygosity (hepatitis), and VARs on SMAD3 (pancreatitis). Regarding CNVs, significant markers included PRDM1 deletions and IL1RN (IRAE), CD274 duplications and SLCO1B1 (hepatitis), PRDM1 and CD274 (encephalitis), and PRDM1, CD274, TSHR, and FAN1 (myositis). Myositis and encephalitis, both, were associated with alterations of PRDM1 and CD274, which might explain their joined appearance in clinical practice. The association between HLA homozygosity and IRAE was clarified by finding HLA-A homozygosity as determining factor. We identified several genetic alterations hypothesized in the literature to be associated with the development of IRAE and found significant results concerning pre-existing autoimmune diseases and specific blood count parameters. Our findings can help to better understand the development of IRAE in melanoma patients. NGS might be a useful screening tool, however, our findings have yet to be confirmed in larger studies.

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“…One study found an association between increased leukocytes and absolute number of neutrophils at the start of immunotherapy with the occurrence of irAEs. Additionally, there was also an association with HLA-I and HLA-A homozygosity and the occurrence of irAEs [12 ▪ ].…”

Type 3 autoimmune pancreatitis (immune checkpoint inhibitor-induced pancreatitis)

“…Studies have demonstrated that combination therapy with anti-PD-1 and anti-CTLA4 poses a higher risk of frequency and severity of irAEs compared with monotherapy. Melanoma and genitourinary cancers appear to confer an increased risk of irAEs, which is highly suggestive of the role of tumor biology in the development of drug-related toxicity [8][9][10]11 ICI-PI is infrequent, and hence knowledge of its biological and physiopathological aspects is limited. A vast majority of patients with ICI-PI present with an asymptomatic elevation of pancreatic enzymes.…”

“…]. Caucasian men in the sixth decade of life with advanced stage of cancer are at higher risk of developing irAEs [10,12].…”

“…Studies have demonstrated that combination therapy with anti-PD-1 and anti-CTLA4 poses a higher risk of frequency and severity of irAEs compared with monotherapy. Melanoma and genitourinary cancers appear to confer an increased risk of irAEs, which is highly suggestive of the role of tumor biology in the development of drug-related toxicity [8–10,11 ▪ ]. Caucasian men in the sixth decade of life with advanced stage of cancer are at higher risk of developing irAEs [10,12].…”

“…Melanoma and genitourinary cancers appear to confer an increased risk of irAEs, which is highly suggestive of the role of tumor biology in the development of drug-related toxicity [8–10,11 ▪ ]. Caucasian men in the sixth decade of life with advanced stage of cancer are at higher risk of developing irAEs [10,12].…”