Immunotherapy for Neuroblastoma

Introduction

Standard care for patients with high-risk neuroblastoma (NB) currently consists of aggressive multimodal therapy including high-dose chemotherapy, surgery, and radiotherapy . Immunotherapy utilizes mechanisms of action that are not cross-reactive with other antitumor modalities, and is thus, an attractive therapeutic option, particularly to eradicate minimal residual disease. Moreover, in the young children typically afflicted with NB, chemotherapy and radiotherapy, which have significant off-target effects on normal tissue, are associated with significant long-term morbidities. These include growth impairment and asymmetry, hearing deficits, learning difficulties, and secondary malignancies . Immunotherapy, by virtue of its specificity for identified tumor targets, has the potential to avoid or mitigate some of these toxicities. Indeed, NB is the only pediatric solid tumor for which immunotherapy is an established therapeutic modality given the approval of the anti-GD2 antibody dinutuximab for high-risk NB by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) in 2015 .

Targets for NB Immunotherapy

The properties for an ideal tumor antigen targetable by immunotherapy include specificity, role in oncogenesis, expression level, and immunogenicity, although none of the currently targeted antigens meet all criteria . In adults, the discovery of mutation-associated neoantigens has vastly expanded the pool of antigens that can be potentially used for immunotherapy . Most pediatric malignancies, including NB, have far fewer genetic mutations, thus restricting a strategy aimed at neoantigens . Immunotherapy for pediatric malignancies has mostly focused on targeting nonmutated antigens with a differential expression on malignant versus normal cells. Cell surface antigens, the most commonly targeted molecules in NB immunotherapy, are not major histocompatibility complex (MHC)-restricted and are optimal for targeting by monoclonal antibodies (MoAbs) or engineered immune effector cells. Intracellular tumor antigens usually require processing by antigen-presenting cells for presentation to cytotoxic lymphocytes and are MHC-restricted . MoAbs can target intracellular antigens if they internalize after binding. Tumor antigens targeted for immunotherapy in patients with NB thus far are chiefly expressed on the cell surface, the ganglioside GD2 being the most common ( Table 9.1 ). Other cell surface antigens include L1CAM and B7H3 . The intracellular cancer-testis antigens MAGE and NY-ESO-1 have also been clinically investigated ( Table 9.2 ).

Effectors of Immunotherapy for NB

NB can be potentially targeted by all the major effector cells and proteins of the immune system ( Fig. 9.1 ). Innate immune system components including complement, MoAbs, macrophages, polymorphonuclear leukocytes, and natural killer cells have been recruited for passive anti-NB immunotherapy in the clinic. Natural killer T cells (NKT) and γδ T cells can play roles as both innate and adaptive components and are being studied in the early phase trials. The adaptive immune system requires direct activation through antigen presentation by antigen-presenting cells (APCs). Upon antigen presentation and activation, antigen-specific T and B cells are generated. B-cell activation can generate humoral immunity against NB . However, expression of human leukocyte antigen (HLA) and PD-L-1 is absent or low in NB, limiting the effect of potent T-cell-mediated active immunotherapy. Strategies to redirect and harness T-cells in NB immunotherapy include MHC-independent approaches such as chimeric antigen receptor-transduced T-cells and bispecific MoAbs .

Cytokines

MoAb-based NB cell lysis involves recognition and binding to the tumor cell, followed by recruitment of immune effectors, which then release cytotoxic molecules for NB cell destruction . However, effector function, particularly antibody-dependent cellular cytotoxicity (ADCC), is often compromised in cancer patients due to immune suppression from both the underlying disease and the myelosuppressive treatment regimens . Cytokines can augment effector cell function and enhance ADCC . In general, these immunomodulators stimulate a broad range of immune cells, including T and B lymphocytes, monocytes, macrophages, and NK cells. The cytokines interleukin-2 (IL-2) and granulocyte macrophage colony stimulating factor (GM-CSF) have been used extensively for NB immunotherapy in conjunction with MoAbs. Other cytokines have the potential to be more effective but have not yet been tested in patients with NB.

Monoclonal Antibodies