Checkpoint inhibitors in the treatment of pediatric solid tumors (Geoerger et al., 2020)
One of the functions of our immune system is to get rid of aberrant or damaged cells, like cancer cells. Immunotherapy utilizes this aspect, and has become a very important new way of treating cancer. Checkpoint inhibitors are immunotherapeutic agents that have been highly successful in melanoma and several other types of cancer in adults.
Tumor cells often have special proteins on their cell surface, so-called immune checkpoints, which they use to put a brake on the immune system. Checkpoint inhibitors remove this brake, enabling the T cells in our body, a type of immune cells, to recognize, attack and kill the tumor cells. Atezolizumab, nivolumab and pembrolizumab are such checkpoint inhibitors, blocking the checkpoint proteins PD-1 or PD-L1. Researchers from the Princess Máxima Center, among whom prof. dr. Michel Zwaan, evaluated the safety and efficacy of atezolizumab in children. They did this in collaboration with researchers from the European partnership ITCC (Innovative Therapies for Children with Cancer). The results have been published in the scientific journal The Lancet Oncology.
PD-L1 is present on the surface of tumor cells in approximately 9% of children with solid tumors (such as neuroblastoma) or lymphomas. This allows the tumor cells to escape immune surveillance. In this study the researchers determined whether inhibition of PD-L1 with atezolizumab is a safe and effective treatment for children with various types of solid tumors or lymphomas who experienced a relapse or did not respond sufficiently (refractory) to previous treatments.
Atezolizumab was well tolerated by the children, although they often experienced fever and fatigue as adverse events. However, contrary to what was expected, atezolizumab had limited clinical activity. This was consistent with other studies using nivolumab and pembrolizumab, which demonstrated that these checkpoint inhibitors had little effect in children as well. Possibly pediatric tumors have fewer target sites for T cells to act upon, or different checkpoints may be active in pediatric tumors compared to adult tumors.
An exception is that checkpoint inhibitors do have clinical activity in two specific groups of pediatric tumors: in Hodgkin lymphoma, and in tumors with quite a few genetic aberrations. That can sometimes be caused by an underlying defect in DNA repair mechanisms, but may also occur as an isolated event in tumor cells. This is actively being investigated in the iTHER 2.0 study, now ongoing at the Princess Máxima Center, in which we search for targets for the treatment of children with relapsed disease.