Using data from a randomized phase III clinical trial of neuroblastoma patients (treated with or without immunotherapy) performed by the Children’s Oncology Group, researchers from the University of Wisconsin School of Medicine and Public Health found that a subset of patients, identified by the presence of a certain set of genes, were more likely to benefit from the immunotherapy than those patients that did not have that set of genes.
The trial, which involved 226 patients, was led by the Children’s Oncology Group, a coalition of research institutions across the country. The organization previously reported that the group of high-risk neuroblastoma patients that were treated with the immunotherapy regimen [dinutuximab (Unituxin), aldesleukin and sargramostim] in combination with isotretinoin had significantly improved event-free and overall survival as compared to patients that received isotretinoin alone.
Researchers at the University of Wisconsin-Madison, Amy Erbe and Wei Wang, in the lab of Dr. Paul Sondel, led an effort to determine if individual genetic differences could influence clinical response to this immunotherapy. Dinutuximab is a monoclonal antibody that can kill cancer cells by activating natural killer (NK) cells. Killer Immunoglobulin-like Receptors (KIRs), a family of certain proteins expressed by NK cells, have different genetic patterns that can influence how well the NK cells use dinituximab to kill cancer cells. Dr. Sondel’s research team received DNA from 174 of the 226 patients that were enrolled in the clinical trial, and assessed how the pattern of KIR genes in each patient influenced outcome.
The study found that patients with a certain combination of four genes – (genes that inhibit NK cells) had improved outcomes with the immunotherapy. In contrast those patients without that combination of those four genes did not seem to have improvement from the immunotherapy.
The study theorizes that this difference may reflect that NK cells that are inhibited (as hypothesized for the patients with these four genes) may need the extra stimulation of this immunotherapy, while those without these four genes may not be helped by the extra immune stimulation of this immunotherapy.
Erbe summarized the significance of this study.
“Our data show that a certain combination of KIR-related genes may be predictive of benefit from immunotherapy,” Erbe said. “However, these findings need to be validated before we can consider making clinical decisions for patients with high-risk neuroblastoma based on KIR-related genes.”
If these findings were validated, it could identify those who would best benefit from dinutuximab-based immunotherapy, potentially avoiding giving the somewhat toxic immunotherapy to patients who might not benefit from this regimen.
The study was published online today in the journal Clinical Cancer Research.
Financial support for the research came from the NCTN Operations Center Grant U10CA180886 and supported in part by National Public Health Service grants through the National Cancer Institute and National Institutes of Health (CA014520, CA166105, CA164132, CA197078), Stand Up 2 Cancer, the St. Baldrick’s Foundation, the University of Wisconsin Carbone Cancer Center, Midwest Athletes Against Childhood Cancer and Hyundai Hope on Wheels.
University of Wisconsin School of Medicine and Public Health