Biomarker May Identify Neuroblastoma Patients Most Likely to Benefit from Immunotherapy

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​WASHINGTON — Among patients with high-risk neuroblastoma, those who had a certain combination of genotypes gained substantial benefit from adding immunotherapy to isotretinoin treatment, while it is uncertain whether those who lacked the combination gained benefit from immunotherapy, according to results from a randomized phase III clinical trial presented here at the AACR Annual Meeting 2017, April 1-5.

Previously reported data from the phase III clinical trial, which involved 226 patients, showed that adding immunotherapy, in the form of dinutuximab (Unituxin), aldesleukin, and sargramostim, to isotretinoin significantly improved event-free and overall survival for patients with high-risk neuroblastoma. These data led to a U.S. Food and Drug Administration approval for this dinutuximab regimen in this indication.

However, not all patients who received immunotherapy had a response and many had significant adverse events.

“We wanted to determine if certain genotypes that are related to immune cells called NK cells—KIR/KIR-ligand genotypes—could be predictive of how patients with high-risk neuroblastoma respond to immunotherapy,” said Amy K. Erbe, PhD, an associate scientist in the Department of Human Oncology at the University of Wisconsin School of Medicine and Public Health in Madison. “Identifying biomarkers of response to immunotherapy may allow us to personalize therapy for patients in the future, helping to spare those unlikely to respond from the potential of adverse events.

“Our data show that a certain combination of KIR/KIR-ligand genotypes may be predictive of benefit from immunotherapy” continued Erbe. “However, these findings need to be validated before we can consider making clinical decisions for patients with high-risk neuroblastoma based on KIR/KIR-ligand genotype.”

Erbe and colleagues determined the KIR/KIR-ligand genotypes of the 174 patients from the phase III trial for whom sufficient DNA was available for analysis. They then assessed whether certain genotypes were associated with event-free and overall survival.

Among the 49 patients who were positive for both the KIR2DL2/HLA-C1 genotype and the KIR3DL1/HLA-Bw4 genotype, 23 had received isotretinoin plus immunotherapy and 26 had received isotretinoin only. The researchers found that those who received immunotherapy and isotretinoin had significantly improved event-free and overall survival; at five years, the addition of immunotherapy improved event-free survival from 27 percent to 61 percent and overall survival from 34 percent to 91 percent for this group.

Among the 125 patients who were not positive for both the KIR2DL2/HLA-C1 genotype and the KIR3DL1/HLA-Bw4 genotype, 65 had received isotretinoin plus immunotherapy and 60 had received isotretinoin only. There was no significant difference in either event-free or overall survival between the two treatment groups; at five years, event-free survival was 57 percent for those receiving immunotherapy and isotretinoin versus 53 percent for those receiving only isotretinoin and overall survival was 68 percent for both treatments.

“Our data not only identify KIR/KIR-ligand genotypes associated with differences in outcome following treatment with immunotherapy but also indicate that the immune cells that are regulated by KIR/KIR-ligand interactions, namely NK cells, play a major role in mediating the anticancer effects of this immunotherapy treatment,” said Erbe. “It is important to show that NK cells are involved because this helps us to understand the therapy and provides clues as to how we might improve it.”

According to Erbe, the main limitation of this study is that the number of patients in the two treatment groups was relatively small, and the subgroups with the different KIR/KIR-ligand genotypes were even smaller. Thus, the conclusions from this single study cannot be viewed as definitive and need to be validated, she explained.

This study was funded in part by Hyundai Hope on Wheels Grant, Midwest Athletes Against Childhood Cancer, Stand Up To Cancer, The St. Baldrick’s Foundation, the American Association of Cancer Research (AACR), the University of Wisconsin Carbone Cancer Center, and Public Health Service Grants from the National Cancer Institute. Erbe declares no conflicts of interest.

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