Form of HLA gene associated with shorter OS after immune checkpoint inhibitor therapy
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A form of the HLA-A gene appeared associated with shorter survival among patients treated with immune checkpoint inhibitors, according to a study published in The Lancet Oncology.
The gene, HLA-A*03, is found in 2% to 16% of the U.S. population, researchers noted.
Rationale and methods
“Although immune checkpoint inhibition is used to treat many cancers, for most cancer types fewer than 50% of patients respond to therapy. Therefore, identifying biomarkers of immune checkpoint inhibition response could allow greater precision in therapy selection,” Vivek Naranbhai, PhD, MB, ChB, clinical fellow in medicine at Dana-Farber Cancer Institute, told Healio. “The HLA genes are the most polymorphic loci in the human genome and encode HLA molecules responsible for presenting tumor antigens to T cells. In other immune-mediated disease processes, HLA genes have been disproportionately involved in affecting outcomes but in cancer findings have been inconsistent owing to small sample sizes. We were fortunate to be able to pool samples and data from across multiple academic and pharmaceutical partners from routine care, as well as clinical trials, to study this in detail.”
The epidemiological study compared outcomes of 3,335 patients treated with immune checkpoint inhibitors with those of 10,917 patients treated with nonimmune checkpoint inhibitor therapies. Researchers pooled data from three observational cohorts of patients with various advanced tumor types and five clinical trials of patients with advanced bladder cancer or renal cell carcinoma.
Researchers sought to determine the effect of HLA-A*03 as a biomarker for predicting response to immunotherapy.
Key findings
Results showed an association of HLA-A*03 with decreased OS after immune checkpoint inhibitor therapy among patients in the Memorial Sloan Kettering Integrated Mutation Profiling of Actional Cancer Targets cohort (HR = 1.48 per HLA-A*03 allele; 95% CI, 1.2-1.82), the validation Dana-Farber Cancer Institute Profile cohort (HR = 1.22 per HLA-A*03 allele; 95% CI, 1.05-1.42) and the JAVELIN Solid Tumor clinical trial for bladder cancer (HR = 1.36 per HLA-A*03 allele; 95% CI, 1.01-1.85).
Researchers observed the effect of HLA-A*03 across immune checkpoint inhibitor therapies and tumor types but not in patients treated with alternative agents. HLA-A*03 appeared associated with shorter PFS among those included in the three CheckMate trials of nivolumab (Opdivo, Bristol Myers Squibb) for renal cell carcinoma (HR = 1.31; 95% CI, 1.01-1.71) and in the JAVELIN Renal 101 randomized clinical trial of avelumab (Bavencio; EMD Serono, Pfizer) plus axitinib (Inlyta, Pfizer) for renal cell carcinoma (HR = 1.59 per HLA-A*03 allele; 95% CI, 1.16-2.16). Conversely, control therapies, including everolimus and sunitinib (Sutent, Pfizer), did not appear associated with shorter PFS.
“We had access to clinical trial data for patients with renal cell cancer that suggested HLA-A*03 homozygotes may not benefit from immune checkpoint inhibition and potentially do worse than if they were treated with other therapies,” Naranbhai said. “We discovered HLA-A*03 after searching for all possible HLA class I and class II residues that affect outcomes. This suggests this is the strongest finding.”
Implications
“Caution should be considered when treating patients who are HLA-A*03 carriers with immune checkpoint inhibitors when alternative therapeutic options exist,” Naranbhai said.
Clinical trials that stratify responses to the HLA-A*03 genotype are necessary, he added.
“Further replication of these findings would be helpful. Immunotherapy trials should consider reporting responses stratified by the HLA-A*03 genotype. We do not yet understand the mechanism behind the poor outcomes in HLA-A*03 carriers, but interrogation of blood and tumor biopsies in patients with HLA-A*03 and those without this allele may be useful,” Naranbhai said. “Specific focus on timepoints after immune checkpoint inhibitor therapy commencement will be necessary because HLA-A*03 predicts poor outcomes only in patients treated with immune checkpoint inhibitors but not those treated with other regimens such as chemotherapy, and the tumor environment appears similar prior to immune checkpoint inhibitor commencement in those with HLA-A*03 and those without.”
References:
Cancer immunotherapies don’t work for everyone: HLA gene may explain why. https://www.cancer.gov/news-events/cancer-currents-blog/2022/immunotherapy-cancer-biomarker-hla-gene. Published Jan. 27, 2022. Accessed March 4, 2022.
Naranbhai V, et al. Lancet Oncol. 2022;doi:10.1016/S1470-2045(21)00582-9.
For more information:
Vivek Naranbhai, PhD, MB, ChB, can be reached at Dana-Farber Cancer Institute, 450 Brookline Ave., Boston, MA 02215; email: vnaranbhai@partners.org.
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