Immunotherapy for Neuroblastoma

Abstract

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.

Keywords

Adoptive immunotherapy, Cancer vaccines, Chemoimmunotherapy, GD2, Immunotherapy, Monoclonal antibodies, Neuroblastoma, Radioimmunotherapy

Acknowledgments

We thank Joe Olechnowicz for editorial assistance.

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 ).

Table 9.1

Selected Clinical Trials of GD2-Directed Immunotherapies With Published Results

Agent	Combination	Phase	Summary of Results
Murine Antibodies
m3F8	–	I	• Toxicity profile established: common toxicities included pain and allergic reactions
m3F8	SC GMCSF	II	• Activity against chemorefractory NB • Improved PFS and OS compared to historical data for patients in first and subsequent remissions • Improved outcomes when GMCSF given SC rather than IV • Biomarkers influencing outcome identified
m3F8	barley- or yeast-derived-β-D- glucan	I	• No additional toxicities of BG • Activity against chemorefractory NB
14.G2a		I	• Toxicity profile established: common toxicities included pain and allergic reactions
Chimeric Antibodies
Dinutuximab	–	I	• Toxicity profile established: common toxicities included pain and allergic reactions.
Dinutuximab	–	Randomized II/III	• 3-year EFS superior for immunotherapy group compared to maintenance chemotherapy or no therapy
Dinutuximab	IL-2 + GM-CSF; CRA	Randomized III	• 2-year EFS and OS superior for immunotherapy + CRA versus CRA
Dinutuximab	I/T/GMCSF; temsirolimus	Randomized II	• Superior response rate for dinutuximab + I/T/GMCSF compared to dinutuximab + temsirolimus
Dinutuximab-beta		I	• Toxicity profile and pharmacokinetics similar to dinutuximab
Dinutuximab-beta	SC IL-2	Randomized III	• Higher toxicities in IL-2 treated group • EFS and OS similar for intent-to-treat analysis but favorable trend for combination in patients completing planned therapy
Humanized Antibodies
hu14.18K322 A		I	• Toxicity profile similar to dinutuximab though higher doses tolerable
Naxitamab (hu3F8)	GM-CSF	I	• Toxicity profile similar to m3F8 though allergic reactions rare; higher doses tolerable compared to m3F8 • Anti-NB activity observed • Lower immunogenicity compared to m3F8
Immunocytokines
Hu14.18-IL-2		I/II	• Toxicity profile similar to dinutuximab + IL-2 • Responses observed in osteomedullary NB
Radioimmunoconjugates
¹³¹I- m3F8		I	• Myelosuppression requiring bone marrow rescue required in most patients • Dosimetry data obtained; radiation exposure was well below tolerable doses for all organs
¹³¹I- m3F8		II	• Patients received myeloablative doses after induction chemotherapy • Myelosuppression was reversible with autologous bone marrow rescue • Long-term EFS for HR-NB was 40%
¹³¹I- m3F8	Bevacizumab	I	• Myelosuppression requiring stem cell rescue required in most patients • Bevacizumab did not interfere with 3F8 targeting to tumor sites
¹³¹I- m3F8 IO		I	• Toxicity defined: headache, fever, vomiting • Recommended phase II dose established
Cell-Mediated Immunotherapy
Haploidentical NK cells + m3F8	Chemotherapy	I	• No unexpected toxicities (including GvHD) beyond those expected with chemotherapy and m3F8 • NK-cell dose-dependent anti-NB activity observed
Haploidentical NK cells + hu14.18K322 A	Myeloablative chemotherapy	Component of phase II	• Toxicities primarily related to chemotherapy and hu14.18K322 A
Haploidentical NK cells + hu14.18K322 A	Combination chemotherapy	Pilot	• Toxicities primarily related to chemotherapy and hu14.18K322 A • Anti-NB activity noted
First generation CAR T-cells	Chemotherapy	I	• Well-tolerated without neuropathic pain • Anti-NB activity noted • Persistence of CAR T cells for several years after infusion
Third generation CAR T-cells	Chemotherapy	I	• Well-tolerated without neuropathic pain
Vaccines
Anti-m3F8 antiidiotype	BCG	I	• Well tolerated; minimal toxicities
Anti-ch14.18 antiidiotype		I	• Well tolerated; minimal toxicities
Bivalent anti-GD2/GD3	KLH, OPT-821, yeast-derived-β-D- glucan	I	• Well tolerated; minimal toxicities • Prolonged EFS and OS for patients in second remission

BCG , Bacillus Calmette-Guerin; BG , β-glucan; CAR , Chimeric antigen receptors; CRA , cis-retinoic acid; EFS , Event-free survival; GM-CSF , Granulocyte macrophage colony stimulating factor; GvHD , Graft-versus-host disease; HR-NB , High-risk neuroblastoma; IL-2 , Interleukin-2; KLH , Keyhole limpet hemocyanin; NB , Neuroblastoma; NK-cell , Natural killer cell; OS , overall survival; PFS , Progression-free survival; SC , Subcutaneous

Table 9.2

Selected Clinical Trials of Immunotherapies Directed Against Targets Other Than GD2 With Published Results

Antigen	Agent	Phase	Summary of Results
B7H3	Radioimmunoconjugate ¹³¹I-omburtamab (8H9)	I/II	• Toxicity profile studied: myelosuppression was main toxicity • Recommended phase II dose for NB established • Improved survival in patients with CNS relapse of NB
L1-CAM	Radioimmunoconjugate ¹³¹I-chCE7	Imaging	• Radioimmunodetection of NB feasible
	CAR T-cells	I	• Toxicity mild • No significant anti-NB activity
MAGE-A1, MAGE-A3, NY ESO1+ decitabine	Dendritic cells	I	• Toxicity primarily related to decitabine
Various	Autologous tumor cells secreting IL-2 ± lymphotactin	I	• Toxicity mild • Anti-NB immune responses observed
	Allogeneic tumor cells secreting IL-2	I	• Toxicity mild • Immune responses suboptimal
	Dendritic cells pulsed with tumor RNA	I	• Toxicity mild • Modest anti-NB immune responses noted