Novel Treatments and Technologies Applied to the Cure of Neuroblastoma

Abstract

Neuroblastoma (NB) is the most common extracranial solid tumour in childhood, accounting for approximately 15% of all cancer-related deaths in the paediatric population1. It is characterised by heterogeneous clinical behaviour in neonates and often adverse outcomes in toddlers. The overall survival of children with high-risk disease is around 40-50% despite the aggressive treatment protocols consisting of intensive chemotherapy, surgery, radiation therapy and hematopoietic stem cell transplantation2,3. There is an ongoing research effort to increase NB's cellular and molecular biology knowledge to translate essential findings into novel treatment strategies. This review aims to address new therapeutic modalities emerging from preclinical studies offering a unique translational opportunity for NB treatment.

Keywords: Antibody-Drug Conjugates-Based Therapy; Drug-Loaded Nanoparticles; Monoclonal Antibodies; Neuroblastoma; Third-Generation Tyrosine Kinase Inhibitor; cellular immunotherapies; intra-operative treatments; radiation therapies; tumour vaccines.

Figure 1

Molecular targets in Neuroblastoma. The image shows 6 different targets: tyrosine kinases (TK); GD2; L1 cell adhesion molecule (L1 CAM); glypican-2 (GPC2); B7H3, and anaplastic lymphoma kinase (ALK). Molecules highlighted in red discussed in paragraph 2.

Figure 2

Mechanism of action of drug-loaded liposomes. Liposomes are loaded with anticancer agents and functionalised with peptides capable of recognising the cell of interest. Once the liposome fuses its lipid bilayers with other cell bilayers, the anticancer drugs are released from the liposome into the cancer cells, exhibiting their cytotoxic action.

Figure 3

Schematic representation of near-infrared photoimmunotherapy (NIR-PIT) mechanism of action. (A) Specific binding of the anti-GD2 monoclonal antibody (mAb) labelled with IRdye700DX (anti-GD2-IR700DX) to the cancer cell surface GD2 antigen (GD2). (B) Subsequent local exposure to near infrared (NIR) light. (C) The exposure turns on the photochemical “death” switch, resulting in the rapid and highly selective immunogenic cell death (ICD) of targeted cancer cells. (D) The rapid cell lysis leads to release of intra-cytoplasmatic antigens and damage associated molecular patterns (DAMPs) in the extracellular space, leading to the activation of the host immune system against the dying tumour cells.

Figure 4

Schematic representation of in-situ-sprayed immunotherapeutic fibrin gel. (A) The gel, which contains CaCO₃ nanoparticles encapsulated with the immunotherapeutic antibody, is sprayed on the tumour bed to be gradually released into the tissue. (B) CaCO₃ nanoparticles scavenge H+ in the surgical wound site, eliciting an immune-supportive tumour microenvironment after surgery. Cyclodextrins (CD) are used to improve the solubility, delivery, and bioavailability of different drugs, such as doxorubicin, leading to higher drug uptake by cells’ antiproliferative and apoptotic activity. Abbreviations: TAM, tumour-associated macrophage. oCD-NH2/DXR, doxorubicin administered in association with functionalised cyclodextrins.