Immunotherapeutic Strategies for Neuroblastoma: Present, Past and Future

Abstract

Neuroblastoma is the most common extracranial pediatric solid tumor with a heterogeneous clinical course, ranging from spontaneous regression to metastatic disease and death, irrespective of intensive chemotherapeutic regimen. On the basis of several parameters, children affected by neuroblastoma are stratified into low, intermediate and high risk. At present, more than 50% of high-risk patients with metastatic spread display an overall poor long-term outcome also complicated by devastating long-term morbidities. Thus, novel and more effective therapies are desperately needed to improve lifespan of high-risk patients. In this regard, adoptive cell therapy holds great promise and several clinical trials are ongoing, demonstrating safety and tolerability, with no toxicities. Starting from the immunological and clinical features of neuroblastoma, we here discuss the immunotherapeutic approaches currently adopted for high-risk patients and different innovative therapeutic strategies currently under investigation. The latter are based on the infusion of natural killer (NK) cells, as support of consolidation therapy in addition to standard treatments, or chimeric antigen receptor (CAR) T cells directed against neuroblastoma associated antigens (e.g., disialoganglioside GD2). Finally, future perspectives of adoptive cell therapies represented by γδ T lymphocyes and CAR NK cells are envisaged.

Keywords: CAR; NK; antibodies; immunotherapy; neuroblastoma; γδ T cells.

Figure 1

NB immunotherapy based on antibodies and mechanisms of action. The figure describes mechanisms of action of antibodies currently used in clinical settings. These antibodies specific for NB-associated antigens may induce direct cell death, complement-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC). In addition, cytokines such as IL-2 and GM-CSF may increase the anti-tumor activity exerted by these antibodies.

Figure 2

Current adoptive cell therapies in the clinical setting of neuroblastoma (NB) treatment. This figure describes different adoptive cell therapy approaches currently investigated for immunotherapy of high-risk NB patients. This includes CAR T cells and NK cells as adjuvant therapy, used alone or in combination with cytokines. Cytokines may also be used to expand NK cells before infusion.