Current therapeutic approaches for high-risk neuroblastoma include dose-intensive chemotherapy, surgical and radiotherapeutic interventions that are associated with long- and short-term toxicities. Immunotherapy utilizes mechanisms of action that are not cross-reactive with other antitumor modalities and reduce exposure to cytotoxic agents, improving both the survival and quality of life in patients treated for high-risk neuroblastoma. In this chapter, we review antineuroblastoma immunotherapy strategies in clinical use and preclinical development. These include monoclonal antibodies and cytokines, immunoconjugates, chemoimmunotherapy, radioimmunotherapy, adoptive cell therapies, and cancer vaccines.
KeywordsAdoptive immunotherapy, Cancer vaccines, Chemoimmunotherapy, GD2, Immunotherapy, Monoclonal antibodies, Neuroblastoma, Radioimmunotherapy
We thank Joe Olechnowicz for editorial assistance.
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 ).
|Agent||Combination||Phase||Summary of Results||References|
|m3F8||barley- or yeast-derived-β-D- glucan||I|
|Dinutuximab||IL-2 + GM-CSF; CRA||Randomized III|
|Dinutuximab||I/T/GMCSF; temsirolimus||Randomized II|
|Dinutuximab-beta||SC IL-2||Randomized III|
|131 I- m3F8||I|
|131 I- m3F8||II|
|131 I- m3F8||Bevacizumab||I|
|131 I- m3F8 IO||I|
|Haploidentical NK cells + m3F8||Chemotherapy||I|
|Haploidentical NK cells + hu14.18K322 A||Myeloablative chemotherapy||Component of phase II|
|Haploidentical NK cells + hu14.18K322 A||Combination chemotherapy||Pilot|
|First generation CAR T-cells||Chemotherapy||I|
|Third generation CAR T-cells||Chemotherapy||I|
|Bivalent anti-GD2/GD3||KLH, OPT-821, yeast-derived-β-D- glucan||I|
|Antigen||Agent||Phase||Summary of Results||References|
|B7H3||Radioimmunoconjugate 131 I-omburtamab (8H9)||I/II|
|L1-CAM||Radioimmunoconjugate 131 I-chCE7||Imaging|
|MAGE-A1, MAGE-A3, NY ESO1+ decitabine||Dendritic cells||I|
|Various||Autologous tumor cells secreting IL-2 ± lymphotactin||I|
|Allogeneic tumor cells secreting IL-2||I|
|Dendritic cells pulsed with tumor RNA||I|