Analysis of Human Leukocyte Antigen DR Alleles, Immune-Related Adverse Events, and Survival Associated With Immune Checkpoint Inhibitor Use Among Patients With Advanced Malignant Melanoma

Abstract

ImportanceTreatment with immune checkpoint inhibitors (ICIs) has increased survival in patients with advanced malignant melanoma but can be associated with a wide range of immune-related adverse events (irAEs). The role of human leukocyte antigen (HLA)–DR alleles in conferring irAE risk has not been well studied.ObjectiveTo evaluate the association between irAEs and treatment response, survival, and the presence of HLA-DR alleles after ICI therapy in advanced melanoma.Design, Setting, and ParticipantsThis case-control study used the patient registry and biobanked samples from the tertiary referral University of Colorado Cancer Center. Specimens and clinical data were collected between January 1, 2010, and December 31, 2021. Patients with advanced (stage III unresectable and stage IV) melanoma who received ICI therapy (n = 132) were included in the analysis.ExposuresImmune checkpoint inhibitors (anti–cytotoxic T-lymphocyte antigen 4, anti–programmed cell death protein 1 or its ligand, or the combination) for the treatment of advanced melanoma.Main Outcomes and MeasuresThe association between irAEs and response to therapy, survival, and HLA-DR alleles.ResultsAmong the cohort of 132 patients with advanced melanoma (mean [SD] age, 63.4 [7.2] years; 85 men [64%] and 47 women [36%]) treated with ICIs, 73 patients had at least 1 irAE and 59 did not have an irAE. Compared with patients without an irAE, patients with an irAE had higher treatment response rates (50 of 72 [69%] vs 28 of 57 [49%]; P = .02) and increased survival (median, 4.8 [IQR, 0.2-9.6] vs 3.2 [IQR, 0.1-9.2] years; P = .02). Specific HLA-DR alleles were associated with the type of irAE that developed: 7 of 10 patients (70%) who developed type 1 diabetes had DR4; 6 of 12 (50%) who developed hypothyroidism had DR8; 5 of 8 (63%) who developed hypophysitis had DR15; 3 of 5 (60%) who developed pneumonitis had DR1; and 8 of 15 (53%) who developed hepatitis had DR4.Conclusions and RelevanceThese findings suggest that IrAEs are associated with treatment response rates and increased survival after ICI therapy for advanced melanoma. Because distinct HLA-DR alleles are associated with given adverse events, HLA genotyping before ICI therapy may aid in identifying risk for specific irAEs that could develop with such treatment.

Amino acid polymorphisms in human histocompatibility leukocyte antigen class II and proinsulin epitope have impacts on type 1 diabetes mellitus induced by immune-checkpoint inhibitors

“…In comparison with our previous study (5), the current study was conducted on a larger scale with confirmation of HLA-DPB1*05:01 predominance in ICI-T1DM than those of general controls and ICIcontrols with the same ethnic background. Current study may also support other reports describing that HLA-DR4 alleles are increased in patients with ICI-T1DM in the United States (21,22), although these studies are not at the detailed allelic levels. Based on the conditional multiple regression analysis, in addition to HLA-DPB1*05:01 allele, alleles of HLA-DRB1*04:05 and DQB1*04:01, and HLA-DRB1*04:05-DQB1*04:01 haplotype were found to be susceptible to ICI-T1DM (Tables 2A-E) .…”

Incidence and risk factors of immune‐related adverse events induced by immune checkpoint inhibitors among older adults with non‐small cell lung cancer

“…According to recent studies, patients' human leukocyte antigen (HLA) expression may be predictive of their risk and severity of irAEs. Future studies should incorporate genomic test data to assess the association between HLA status and the development of irAE for older patients 53–55 . There is also a lack of data about irAE severity (e.g., Common Terminology Criteria for Adverse Events grading) in the SEER‐Medicare linked database.…”

“…Future studies should incorporate genomic test data to assess the association between HLA status and the development of irAE for older patients. 53 , 54 , 55 There is also a lack of data about irAE severity (e.g., Common Terminology Criteria for Adverse Events grading) in the SEER‐Medicare linked database. It is also necessary to conduct future studies to assess the incidence and risk factors associated with severe irAEs.…”

Autoimmunity in immune checkpoint inhibitor‐induced immune‐related adverse events: A focus on autoimmune skin toxicity and pneumonitis

“…Examples include pruritus and atopic dermatitis, 73,74 colitis and inflammatory bowel diseases, 75 thyroiditis and Grave's disease, 76,77 and arthritis 78 . A summary of the HLA alleles associated with ICI‐induced irAEs identified by us and others and found in Table 1 79–87 . These findings will require larger genome‐wide association studies to confirm the identified associations.…”

“…78 A summary of the HLA alleles associated with ICI-induced irAEs identified by us and others and found in Table 1. [79][80][81][82][83][84][85][86][87] These findings will require larger genome-wide association studies to confirm the identified associations.…”