High-Risk Neuroblastoma Challenges and Opportunities for Antibody-Based Cellular Immunotherapy

Abstract

Immunotherapy has emerged as an attractive option for patients with relapsed or refractory high-risk neuroblastoma (HRNB). Neuroblastoma (NB), a sympathetic nervous system cancer arising from an embryonic neural crest cell, is heterogeneous clinically, with outcomes ranging from an isolated abdominal mass that spontaneously regresses to a widely metastatic disease with cure rates of about 50% despite intensive multimodal treatment. Risk group stratification and stage-adapted therapy to achieve cure with minimal toxicities have accomplished major milestones. Targeted immunotherapeutic approaches including monoclonal antibodies, vaccines, adoptive cellular therapies, their combinations, and their integration into standard of care are attractive therapeutic options, although curative challenges and toxicity concerns remain. In this review, we provide an overview of immune approaches to NB and the tumor microenvironment (TME) within the clinical translational framework. We propose a novel T cell-based therapeutic approach that leverages the unique properties of tumor surface antigens such as ganglioside GD2, incorporating specific monoclonal antibodies and recent advancements in adoptive cell therapy.

Keywords: adoptive cellular therapy; ex vivo armed T cell with bispecific antibody (EAT); high-risk neuroblastoma.

Figure 1

Antibody-based adoptive cellular therapy. Ex vivo armed T cells with BsAb (EATs) are manufactured as follows: (1) lymphocyte harvest, (2) T cell expansion over 10–14 days, (3) T cell arming with BsAb (efficiency of ≥98% versus transduction efficiency of 80% with hu3F8CAR) [58], (4) cryopreservation, and (5) thawing before infusion (without lymphodepletion). EATs home to tumors to engage GD2, whereby they become activated, form synapses with NB, and release cytolytic granules (perforin PFN, granzyme GzmB) plus cytokines (interferon gamma, IFN-ϒ and tumor necrosis factor alpha, TNF-α), effecting tumor kill.