Emergent and underexplored oncolytic viruses for treating pediatric central nervous system tumors

High-grade pediatric Central Nervous System (CNS) tumors are frequent, highly aggressive, and the most common cause of cancer-associated death in children. Due to their unique features, such as heterogeneous tumor molecular characteristics, distinct microenvironment, challenging anatomical localization and the presence of the blood brain barrier, brain tumors are especially difficult to treat and often present a poor response to standard therapies (surgery, radio and chemotherapy). Because of that, there is a need for investigating more effective therapeutic approaches and, within this context, Oncolytic Viruses (OVs) have emerged as a promising new class of immunotherapeutic agents. These viruses have a natural or artificial tropism for cancer cells and their central mechanism of action is the direct oncolytic effect followed by activation of the immune response. As a consequence, the OV therapy can be safer than traditional approaches, and its use may help overcome some pediatric CNS tumor treatment challenges. In this review, we initially examine the potential therapeutic advantages that are intrinsically related to OVs infection mechanism. Then, we address the surpassing resistance mechanisms of available treatments for pediatric brain tumors and present some challenges to be taken into consideration in clinical application. We next provide an overview of preclinical studies focusing on the mechanisms of infection and also in vitro and in vivo findings of emergent and underexplored OVs, namely Zika virus, Measles virus, Reovirus, Poliovirus, Seneca Valley virus, Vaccinia virus, Myxoma virus and Parvovirus. Finally, we summarize the latest clinical trials using these underexplored OVs against pediatric solid tumors.