Neuroblastoma (NB) is a type of solid cancer that arises from nerve tissues. It is the most common type of childhood cancer with nearly half of its incidence in children under two years of age and accounts for 15 percent of all childhood cancer deaths. Currently available therapy involves the use of an antibody called dinutuximab which targets a type of modified carbohydrate sugar (GD2) found to be expressed at high levels in NB tumors. However, this antibody-based treatment is often not sufficient to prevent cancer relapse.
In addition to directly targeting molecules involved in disease, in many cases antibody-based therapy is thought to also involve the activation of natural killer (NK) cells. NK cells are a subset of immune cells that have a proven capacity to kill tumor cells upon activation by antibodies. Proteins such as TGFβ1 (transforming growth factor beta 1) have recently been shown to suppress the anti-cancer functions of NK cells in the tumor microenvironment.
TGFβ1, part of the superfamily of cytokines, is a secreted protein that performs many cellular functions including control of cell growth, proliferation, and cell death. The CHLA researchers demonstrate a unique mechanism for tackling NB by employing a combinatorial therapy involving dinutuximab and a small molecule drug, galunisertib, which inhibits TGFβ1. Grafting NB cell lines or tissue from a patient with neuroblastoma into immunodeficient mice, the authors demonstrate that galunisertib-mediated inhibition of TGFβ-1 allows dinutuximab and NK cells to effectively kill the NB tumors.
“The addition of galunisertib to adoptive cell therapy using natural killer cells in addition to the drug dinutuximab reduced tumor growth and increased the survival of mice injected with either neuroblastoma cell lines or patient-derived tumor tissue,” said principal investigator Robert Seeger, MD, of CHLA’s Center for Childhood Cancer and Blood Disease. Seeger is also a professor of pediatrics with the Keck School of Medicine of the University of Southern California (USC). He added that galunisertib reverses the TGFβ-1-induced suppression of cytotoxicity and may improve antibody-based immunotherapy for neuroblastoma.