HLA-A*03: A predictive biomarker for immune checkpoint inhibition response in advanced cancers

25 Feb 2022

Human leukocyte antigen (HLA) molecule plays a vital role in protective immunity and deleterious immune reactivity.1 Multiple diseases have been linked to the genetic variations in the HLA region; a repertoire for biomarker study.2,3 Research from Mary Carrington’s team from the National Cancer Institute, the United States, showed the association of HLA-A*03 with poor outcomes in cancer patients who received immune checkpoint inhibitor (ICI) therapy.3

Although ICI treatment has successfully decreased measurable tumor burden (objective response) promoting better overall survival (OS) in various types of cancer, only less than 50% of patients benefit from this type of treatment.3 Previously, it has been identified that responses to ICI therapy varied based on the patient’s HLA genotype. Therefore, Mary Carrington’s team investigated HLA class-I amino acids in patients who received ICI therapy.3

The investigators studied OS, progression-free survival (PFS) and objective response rate (ORR) in 8 cohorts of patients (N=3,335) and post ICI treatment.3 The 8 cohorts included 3 observational cohorts of patients with advanced cancer of different types: 1) The Memorial Sloan Kettering Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) cohort; 2) The Dana-Farber Cancer Institute (DFCI) Profile cohort; 3) The Cancer Genome Atlas (TCGA) and patients from 5 clinical trials; 4) JAVELIN Solid Tumour (advanced bladder cancer) and patients with renal cancer; 5) CheckMate009; 6) CheckMate-010; 7) CheckMate-025; and 8) JAVELIN Renal 101.3 These patients (N=3,335) were treated with ICIs comprising of anti-programmed cell death protein 1 (PD-1), anti-programmed death-ligand 1 (PD-L1), and anti- cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) inhibitors, while 10,917 patients were treated with non-ICI therapy.3

Carriage of HLA-A*03 allele caused decreased OS after ICI treatment in the MSK-IMPACT cohort (HR=1.48 per HLA-A*03 allele; 95% CI: 1.20-1.82; p=0.00022), the DFCI Profile cohort (HR=1.22 per HLA-A*03 allele, 1.05-1.42; p=0.0097), and in the JAVELIN Solid Tumour clinical trial (HR=1.36 per HLA-A*03 allele, 1.01-1.85; p=0.047).3 This effect was found to trend only in patients (with HLA-A*03) who were treated with ICI agents. However, it was clearly not observed in patients treated with non-ICI agents.3


Similarly, in the pooled population of patients (with HLA-A*03) from 3 CheckMate clinical trials of nivolumab, a decreased PFS was observed (HR=1.31, 1.01-1.71; p=0.044), however, it was not observed in the control group who received everolimus.3 Likewise, all ICI-treated patients carrying HLA-A*03 allele showed no objective response [compared with 59 of 222 HLA-A*03 non-carriers (26.6%), and 13 of 76 HLA-A*03 heterozygotes (17.1%)].3

In the JAVELIN Renal 101 trial, patients carrying HLA-A*03 allele showed decreased PFS after ICI treatment (avelumab + axitinib; HR=1.59 per HLA-A*03 allele, 1.16-2.16; p=0.0036) when compared with the control group who received sunitinib.3 Among these patients, objective responses were observed in 1 of 8 HLA-A*03 homozygotes (12.5%) in the ICI group [compared with 162 of 254 HLA-A*03 non-carriers (63.8%) and 40 of 72 HLA-A*03 heterozygotes (55.6%)].3 In meta-analysis of total ICI treated patients at genome-wide significance (p=2.01 × 10−8), HLA-A*03 carriage was associated with impaired outcome with no evidence of heterogeneity in effect (I2 0%; 95% CI: 0-0.76).3 However, the mechanism of HLA-A*03 effect has not yet been identified.3


The authors concluded, “HLA-A*03 is a predictive biomarker of poor response to ICIs. Further evaluation of HLA-A*03 is warranted in randomized trials.3 Given the common frequency of HLA-A*03 carriage (20%-30% in the cohort or trial populations studied), the magnitude of effect (such that even heterozygotes have substantially poorer responses to ICIs than individuals who do not carry HLA-A*03) and the rare objective responses accrued by HLA-A*03 homozygotes, formal HLA-A*03 testing is advisable when considering treatment decisions in cancer patients who are eligible for ICI therapy.”3

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