Aller au contenu

HLA-A*03 alleles linked to poor ICI therapy response

By Lynda Williams, medwireNews Reporter

Carriage of a specific human leukocyte antigen (HLA) allele is associated with a poor response to immune checkpoint inhibitor (ICI) therapy in patients with a range of tumour types, suggests research published in The Lancet Oncology.

Mary Carrington (National Cancer Institute, Bethesda, Maryland, USA) and co-authors assessed the impact of one or two HLA-A*03 alleles on the overall survival (OS) of 3335 ICI-treated patients in three observational cohorts of advanced tumours and five clinical trials of patients with advanced bladder cancer or renal cell carcinoma (RCC).

Among 1166 participants of the MSK-IMPACT pan-cancer cohort, each HLA-A*03 allele conferred a significant increased risk of death after receipt of a PD-1, PD-L1 or CTLA-4 inhibitor (hazard ratio [HR]=1.48).

A similar significant relationship was also identified among 1326 patients in the pan-tumour DFCI Profile study (HR=1.22 per HLA-A*03 allele) and the researchers emphasize that HLA-A*03 alleles in these two studies had a negative impact on survival regardless of tumour type or class of ICI received.

By contrast, no relationship between HLA-A*03 carriage and outcome was found among participants of The Cancer Genome Atlas study who were given non-ICI treatments for bladder cancer, RCC, non-small-cell lung cancer, melanoma and other tumour types.

The JAVELIN Solid Tumor study of the PD-L1 inhibitor avelumab for bladder cancer patients showed a significant correlation between poor OS and HLA-A*03 (HR=1.36 per allele).

Among RCC patients participating in three CheckMate trials, individuals with an HLA-A*03 allele had significantly poorer OS than those without when they received the PD-1 inhibitor nivolumab (HR=1.31 per allele) but not if they were given the mTOR inhibitor everolimus.

And among patients in the JAVELIN Renal 101 trial, participants with a HLA-A*03 allele who received avelumab plus axitinib had significantly poorer progression-free survival than those who did not (HR for progression or death=1.59 per allele) but no such discrepancy by allele was found among patients given sunitinib.

Meta-analysis of data for all eight studies showed a significant genome-wide correlation between HLA-A*03 carriage and poor outcome from immunotherapy, without evidence of heterogeneity, the researchers emphasize.

Recommending further investigation into this association, the team suggests “[c]aution in treating patients who are HLA-A*03 carriers with immune checkpoint inhibitors” when other types of treatment are available.

“The magnitude of effect is such that HLA-A*03 homozygotes might even have potential harm from ICI therapy”, Carrington et al conclude.

News stories are provided by medwireNews, which is an independent medical news service provided by Springer Healthcare Ltd. © 2021 Springer Healthcare Ltd, part of the Springer Nature Group

Lancet Oncol 2021; doi: 10.1016/S1470-2045(21)00582-9