Strategies for Potentiating NK-Mediated Neuroblastoma Surveillance in Autologous or HLA-Haploidentical Hematopoietic Stem Cell Transplants

SIMPLE SUMMARY: High-risk neuroblastomas (HR-NB) are malignant tumors of childhood that are treated with a very aggressive and life-threatening approach; this includes autologous hemopoietic stem cell transplantation (HSCT) and the infusion of a mAb targeting the GD2 tumor-associated antigen. Although the current treatment provided benefits, the 5-year overall survival remains below 50% due to relapses and refractoriness to therapy. Thus, there is an urgent need to ameliorate the standard therapeutic protocol, particularly improving the immune-mediated anti-tumor responses. Our review aims at summarizing and critically discussing novel immunotherapeutic strategies in HR-NB, including NK cell-based therapies and HLA-haploidentical HSCT from patients’ family. ABSTRACT: High-risk neuroblastomas (HR-NB) still have an unacceptable 5-year overall survival despite the aggressive therapy. This includes standardized immunotherapy combining autologous hemopoietic stem cell transplantation (HSCT) and the anti-GD2 mAb. The treatment did not significantly change for more than one decade, apart from the abandonment of IL-2, which demonstrated unacceptable toxicity. Of note, immunotherapy is a promising therapeutic option in cancer and could be optimized by several strategies. These include the HLA-haploidentical αβT/B-depleted HSCT, and the antibody targeting of novel NB-associated antigens such as B7-H3, and PD1. Other approaches could limit the immunoregulatory role of tumor-derived exosomes and potentiate the low antibody-dependent cell cytotoxicity of CD16 dim/neg NK cells, abundant in the early phase post-transplant. The latter effect could be obtained using multi-specific tools engaging activating NK receptors and tumor antigens, and possibly holding immunostimulatory cytokines in their construct. Finally, treatments also consider the infusion of novel engineered cytokines with scarce side effects, and cell effectors engineered with chimeric antigen receptors (CARs). Our review aims to discuss several promising strategies that could be successfully exploited to potentiate the NK-mediated surveillance of neuroblastoma, particularly in the HSCT setting. Many of these approaches are safe, feasible, and effective at pre-clinical and clinical levels.