A study by a multidisciplinary team of researchers from The Saban Research Institute of Children's Hospital Los Angeles sheds further light on the role of the cytokine TGFβ1 in the growth of neuroblastoma, and suggests the possibility for a small molecule drug/antibody combinatorial therapy to treat this cancer. Their data has been published online by the journal Clinical Cancer Research.
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 TGFβ1 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.
This work was supported in part by grants 5P01 CA81403-15 and 1R01CA182633-01 from the National Cancer Institute of the National Institutes of Health (NIH, and from the Nautica Malibu Triathlon and the T.J. Martell Foundation.
Article: TGFβR1 Blockade with Galunisertib (LY2157299) Enhances Anti-Neuroblastoma Activity of Anti-GD2 Antibody Dinutuximab (ch14.18) with Natural Killer Cells, Robert C Seeger, Hung C Tran, Zesheng Wan, Michael A. Sheard, Jianping Sun, Jeremy R Jackson, Jemily Malvar, Yibing Xu, Larry Wang, Richard Sposto, Eugene S. Kim and Shahab Asgharzadeh, Clinical Cancer Research, doi: 10.1158/1078-0432.CCR-16-1743, published 10 October 2016.