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

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.

CAR T cells redirected to B7-H3 for pediatric solid tumors: Current status and future perspectives

“…In contrast with low-level normal tissue expression, B7-H3 is highly expressed in pediatric solid tumors [ 4 , 11 , 19 , 21 , 39 , 40 ]. Pediatric sarcomas have particularly high B7-H3 expression, including osteosarcoma, Ewing sarcoma, rhabdomyosarcoma, and non-rhabdomyosarcoma soft tissue sarcomas [ 19 , 21 , 39 , 40 ].…”

“…B7-H3 (CD276) is an immunomodulatory protein that has emerged as an attractive target for immunotherapy, due to its expression on a range of malignancies including pediatric solid tumors [ 4 , 19 – 21 ]. Beyond antigen expression, CAR T cell therapy approaches for pediatric solid tumors must also overcome the challenges of localizing to and penetrating tumor sites, evading a hostile immune microenvironment, optimizing T cell dynamics, and avoiding antigen escape [ 11 , 12 ].…”

Monocyte and Macrophage in Neuroblastoma: Blocking Their Pro-Tumoral Functions and Strengthening Their Crosstalk with Natural Killer Cells

“…NB represents rare cancer with a very dismal prognosis, particularly in High Risk (HR) cases identified as children with metastatic disease and age > 18 months, or with localized MYC-N amplified tumors. These patients receive an aggressive combined standard therapy having a maintenance phase based on the infusion of a chimeric monoclonal antibody (mAb) targeting the GD2 antigen [ 36 , 37 ]. Immunotherapy aims at controlling the disease residual from the more conventional therapies (surgery, chemo, and radiotherapy) by killing tumor cells through complement activation and triggering the cytotoxicity of FcγRpos cells, such as macrophages and NK cells.…”

“…Unfortunately, however, the anti-GD2 immunotherapy does not cause long-lasting benefits and more than 50% of HR-NB patients fatally relapse within five years. Whether some properties of phagocytes and NK cells have been positively correlated with a better response, including the presence at genotypic levels of FcγRs polymorphism with different affinities [ 36 , 38 ], other “immune responsiveness signatures” are far from being identified. These could include the presence of specific macrophage and NK cell populations present at the tumor site.…”

Analysis of the mechanisms regulating soluble PD-1 production and function in human NK cells

“…However, during cancer progression, the transformed cells might decrease or even lose MHC expression increasing their susceptibility to NK cellmediated killing. In this context, NK cells are considered powerful weapons against tumors characterized by a very low or absent expression of HLA-I, such as Neuroblastoma (NB) (7)(8)(9). Nevertheless, neoplastic cells have developed different mechanisms which sharply dampen NK cell anti-tumour activity.…”