Immunotherapy in Neuroblastoma: Mini-review of Novel Directions and Challenges

Neuroblastoma (NB) is the most frequent pediatric extracranial solid tumor that derives from neural crest cells, driven by aberrant expression and regulation of developmental proteins. The core regulatory circuitry driving NB consists of normal human proteins that are expressed in embryonic development but largely turned off postnatally in normal tissues. The adaptive immune system is thought to be unable to target these oncofetal antigens because high-affinity self-reactive T cells are deleted during thymopoiesis. Current treatment standard in patients with HR-NB consists of an intense treatment protocol with induction chemotherapy, surgical tumor resection, consolidation therapy with autologous bone marrow transplantation, followed by retinoid as differentiating therapy, significantly increasing survival rates to about 50%. Immunotherapy further improved survival rates that included monoclonal antibody (Anti-GD2 MoAb/Dinutuximab) and cytokines (ie, IL-2 and GM-CSF, [33-37]). CAR T cells are made from autologous T cells that engineered genetically to express a CAR. In vitro engineering methods have been developed to create antigen-specific T cells without the need for isolation from tumor tissues. Leukapheresis is used to separate unspecific T cells from the patient's peripheral blood, then genetically modified with a tumor-specific recognition construct (eg, tumor-specific TCR, CAR), expanded, and enriched in culture in the presence of cytokines under good manufacturing practice (GMP) conditions, and transduced with a vector. This allowed them to produce a CAR that targets a tumor-specific antigen. Following preparatory chemotherapy, the CAR T cell product is administered into the patient.