HLA-A * 03 and response to immune checkpoint blockade in cancer: a study of epidemiological biomarkers

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Background

Predictive biomarkers may allow more precise use of immune checkpoint inhibitors (ICI) in the treatment of advanced cancers. Given the central role of HLA molecules in immunity, variation in HLA loci may affect the response to ICI differently. The aim of this epidemiological study was to determine the effect of HLA-A * 03 as a biomarker to predict response to immunotherapy.

Methods

In this epidemiological study, we investigated the clinical outcomes (overall survival, progression-free survival, and objective response rate) after treatment for advanced cancer in eight patient cohorts: three observational cohorts of patients with various types of advanced tumors (the Memorial Sloan Kettering Integrated mutation profile of exploitable cancer targets [MSK-IMPACT] cohort, the Dana-Farber Cancer Institute [DFCI] Profile cohort and The Cancer Genome Atlas) and five clinical trials involving patients with advanced bladder cancer (JAVELIN Solid Tumor) or renal cell carcinoma (CheckMate-009, CheckMate-010, CheckMate-025 and JAVELIN Renal 101). In total, these cohorts included 3,335 patients treated with various ICI agents (anti-PD-1, anti-PD-L1 and anti-CTLA-4 inhibitors) and 10,917 patients treated with non-ICI therapeutic approaches to cancer. We initially modeled the association of HLA amino acid variation with overall survival in the MSK-IMPACT Discovery Cohort, followed by a detailed analysis of the association between HLA-A * 03 and clinical outcomes in MSK-IMPACT, with replication in additional cohorts (two additional observational cohorts and five clinical trials).

Results

HLA-A * 03 was additively associated with reduced overall survival 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 validation cohort of the DFCI profile (HR 1.22 by HLA-A * 03 allele, 1.05-1.42; p = 0.0097), and in the JAVELIN Solid Tumor clinical trial for bladder cancer (HR 1.36 per HLA-A * 03 allele, 1.01-1.85; p = 0.047). the HLA-A * 03 the effect was seen across ICI agents and tumor types, but not in patients treated with alternative therapies. Patients with HLA-A * 03 had shorter progression-free survival in the pooled patient population of the three CheckMate clinical trials of nivolumab for renal cell carcinoma (HR 1.31, 1.01–1.71; p = 0.044), but not in those receiving control (everolimus) therapies. Objective responses were not observed in any of the eight HLA-A * 03 homozygous in the ICI group (compared to 59 [26·6%] from 222 HLA-A * 03 non-carriers and 13 (17.1%) out of 76 HLA-A * 03 heterozygous). HLA-A * 03 was associated with shorter progression-free survival in patients receiving ICI in the randomized clinical trial JAVELIN Renal 101 for renal carcinoma (avelumab plus axitinib; HR 1.59 per HLA-A * 03 allele, 1 · 16–2 · 16; p = 0.0036), but not in those receiving control treatment (sunitinib). Objective responses were recorded in one (12.5%) of the eight HLA-A * 03 homozygous in the ICI group (compared to 162 [63·8%] from 254 HLA-A * 03 non-carriers and 40 [55·6%] from 72 HLA-A * 03 heterozygous). HLA-A * 03 was associated with altered results in the meta-analysis of 3335 ICI-treated patients with genome-wide significance (p = 2.01 × 10-8) without proof of heterogeneity in force (I2 0%, 95% CI 0–0 76)

Interpretation

HLA-A * 03 is a predictive biomarker of a poor response to IBI. Further assessment of HLA-A * 03 is justified in randomized trials. HLA-A * 03 carriage could be taken into account in decisions to initiate IBI in cancer patients.

Funding

National Institutes of Health, Merck KGaA and Pfizer.


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