1. May, Brandon

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Greater diversity and variation in human leukocyte antigen (HLA) genes is associated with a better response to immune checkpoint blockade (ICB), and this association appears to be consistent across several different types of cancer, according to a recent study published in Science (2017; doi:10.1126/science.aao4572).

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Genetic Diversity & Therapy Response

"One important finding from this study was that a statistical correlation was demonstrated between the number of mutations in the tumor and how the body would respond to ICB," said study author Diego Chowell, PhD, Research Fellow at the Memorial Sloan Kettering Cancer Center, New York, N.Y. "The underlying hypothesis for this observation is that mutations can create new antigens that are recognized by the immune system when receiving ICB."


Very few studies have explored the role of patient-specific genetic characteristics in terms of response to ICB therapies. In this study, researchers examined these characteristics-namely HLA-with response to anti-PD-1 or anti-CTLA-4 ICBs. The HLA class I (HLA-I) genotype has been consistently associated with immune responses in autoimmune disease and even HIV (Curr Genomics 2007;8(7):453-465; Science 2010;330(6010):1551-1557), making this study a novel addition to the current oncology-related literature.


Variation in HLA-I molecules are located in the peptide-binding region, and these molecules tend to bind particular peptides for presentation on CD8+ T-cell surfaces (Proc Natl Acad Sci USA 2015;112(14):E1754-1762). Primarily, the CD8+ T cell, HLA class I-dependent immunity is the depending factor associated with ICBs' anti-tumor activity (Nature 2014;515(7528):577-581; N Engl J Med 2016;375(23):2255-2262).


Study Methods & Findings

Investigators evaluated two patient cohorts that consisted of cancer patients who were treated with ICB (n=1,535). The first cohort was comprised of patients with advanced melanoma (n=269) and advanced non-small cell lung cancer (NSCLC) (n=100) who were treated with anti-CTLA-4 or anti-PD-1 therapy.


In the second cohort (n=1,166), patients with melanoma and NSCLC were treated with therapies targeting PD-1/PD-L1, CTLA-4, or both. Exome sequencing and targeted next-generation sequencing (MSK-IMPACT) were performed for cohort 1 and cohort 2, respectively. Additionally, each patient underwent high-resolution HLA-I genotyping with the use of DNA sequencing data or an HLA typing assay, and researchers assessed the variation of HLA-I of the HLA-A, HLA-B, and HLA-C genes in both patient groups.


In this patient population, there was no difference between homozygous and heterozygous patients in regard to the number of tumor-related somatic mutations. Patients in cohort 1 experienced a significantly reduced survival if there was HLA-I homozygosity in >=1 locus (p=0.036, HR=1.40, 95% CI 1.02-1.9), an association that was confirmed in the second cohort (p=0.028, HR=1.31, 95% CI 1.03-1.70). This association remained consistent when researchers adjusted for age, drug class, tumor stage, and mutation load (cohort 1: p=0.02, HR=1.50, 95% CI 1.07-2.10 and cohort 2: p=0.028, HR=1.31, 95% CI 1.03-1.67).


In addition, HLA-I homozygosity in >=1 locus (HLA-A, HLA-B, or HLA-C) correlated with significantly reduced overall survival (OS) among 1,535 patients from both cohorts (p=0.003, HR=1.38, 95% CI 1.11-1.70). The association was found most strongly with the HLA-B (p=0.052, HR=1.66, 95% CI 0.93-2.94) and HLA-C (p=0.004, HR=1.60, 95% CI 1.16-2.21) genes. According to the investigators, a potential explanation for this association may be due to the fact that HLA-B is often expressed at higher levels on the cell surface and binds to more diverse peptides in comparison to HLA-A and HLA-C.


Reduced survival was also observed among patients experiencing loss of heterozygosity (LOH) of HLA-I (p=0.05, HR=1.60, 95% CI 1.03-2.43). Low tumor-related mutation load was associated with a greater survival impact related to LOH of HLA-I (p=0.0006, HR=3.68, 95% CI 1.64-8.23). Additionally, reduced survival was also observed in patients with HLA class II homozygosity at HLA-DP (p=0.018, HR=1.45, 95% CI 1.06-2.00). The investigators also noticed decreased survival among patients with homozygosity at the HLA-DPB locus (p=0.04, HR=1.37, 95% CI 1.07-1.87).


Better survival was found in patients with B44 superfamily alleles (p=0.01, HR=0.61, 95% CI 0.42-0.89). The presence of HLA-B*18:01, HLA-B*44:02, HLA-B*44:03, HLA-B*44:05, and HLA-B*50:01 represented the primary driving force behind this association (p=0.001, HR=0.49, 95% CI 0.32-0.76). Based on a univariate analysis, patients with melanoma and the B44 "supertype" alleles who were treated with anti-PD-1 or anti-CTLA-4 also demonstrated better OS (p=0.054, HR=0.32, 95% CI 0.09-1.1). Conversely, the presence of B62 alleles was associated with worse survival (p=0.0007, HR=2.29, 95% CI 1.40-3.74) in this cohort.


Putting the Findings Into Context

As demonstrated by this study, the clinical importance of genetic diversity on ICB response can't be ignored. "HLA genes are critical for helping the immune system recognize the antigen," commented Chowell. "The immune system recognizes HLA as these are small fragments of the patient's own self-mutated proteins." He explained that each person in the world has six HLA variations, but not all of these genes or alleles are different. "Out of all those six, maybe only five, or four, or two are different."


The greater diversity in specific genes, Chowell explained, translates into a greater response to ICB therapy. "These specific HLA genes are critical for the immune system to recognize the antigen presented, and this study highlights the importance of the patient's genetic diversity," which may assist in risk stratification irrespective of cancer type.


"Just as tumors with a greater number of genetic changes are more recognizable to immune cells, having more-diverse HLA genes means the immune system has a greater ability to recognize what doesn't belong inside the body," according to senior study investigator, Timothy A. Chan, MD, PhD, Radiation Oncologist at Memorial Sloan Kettering Cancer Center. "While the HLA genes that people are born with can't be changed, learning more about how the immune system recognizes novel proteins can help with the development of new cancer treatments, such as vaccines that could be used on their own or in combination with checkpoint inhibitors."


Implications for Clinical Practice

"We found statistical associations of particular variations of HLA genes-in two cohorts, some particular HLA alleles were associated with response to ICB," Chowell noted. "This is the first study showing an association." He added that disease progression appears to be much faster in patients with less diversity and stressed that future randomized, prospective studies are needed to determine whether genetic diversity leads to slower progression in cancer patients receiving ICB.


Overall, the findings from this study demonstrate the potential utility of genetic assessment for risk identification among cancer patients receiving ICB. "This can be used as a biomarker to help make treatment decisions," Chowell noted, "and these findings should encourage scientists to identify new ways of immunotherapy to overcome the effect of the diversity of certain patients."


Brandon May is a contributing writer.