Targets and Antibody Formats for Immunotherapy of Neuroblastoma

Abstract

Neuroblastoma (NB) is a malignant embryonal tumor of the sympathetic nervous system that is most commonly diagnosed in the abdomen, often presenting with signs and symptoms of metastatic spread. Three decades ago, high-risk NB metastatic to bone and bone marrow in children was not curable. Today, with multimodality treatment, 50% of these patients will survive, but most suffer from debilitating treatment-related complications. Novel targeted therapies to improve cure rates while minimizing toxicities are urgently needed. Recent molecular discoveries in oncology have spawned the development of an impressive array of targeted therapies for adult cancers, yet the paucity of recurrent somatic mutations or activated oncogenes in pediatric cancers poses a major challenge to the evolving paradigm of personalized medicine. Although low tumor mutational burden is a major hurdle for immune checkpoint inhibitors, an immature or impaired immune system and inhibitory tumor microenvironment can further complicate the prospects for successful immunotherapy. In this regard, despite the poor immunogenic properties of NB, the success of antibody-based immunotherapy and radioimmunotherapy directed at single targets (eg, GD2 and B7-H3) is both encouraging and surprising, given that most solid tumor antibodies that use Fc-dependent mechanisms or radioimmunotargeting have largely failed. Here, we summarize the current information on the immunologic properties of this tumor, its potential immunotherapeutic targets, and novel antibody-based strategies on the horizon.

Anti-GD2-IRDye800CW as a targeted probe for fluorescence-guided surgery in neuroblastoma

“…Importantly, although we observed heterogeneous expression of GD2, with some patients only expressing intermediate or even low expression levels, experiments with patient-derived organoid lines reflecting these expression levels, showed that TBRs of subsequent xenografted tumors were still sufficiently high to discriminate tumor from healthy tissue, even for low expressing organoid lines. Finally, anti-GD2 is increasingly used for immunotherapy in high-risk NB 36 . Currently, after surgery, but ongoing trials will assess the advantage of neoadjuvant treatment 37 , 38 .…”

The immune landscape of neuroblastoma: Challenges and opportunities for novel therapeutic strategies in pediatric oncology

“…Although neuroblastoma has been considered to be an immunologically 'cold' tumour [19,20], multiple studies have demonstrated the presence of TIL, including T cells and NK cells, in human neuroblastoma tumours (Table 1 and Fig. 1) [21e42].…”

Immunotherapeutic Strategies for Neuroblastoma: Present, Past and Future

“…Similarly to other pediatric solid tumors, NB shows intrinsic immunological properties that render often ineffective therapies based on recruitment of cellular components of the immune system or the reactivation of them [ 30 ]. NB is poorly immunogenic as witnessed by (i) low expression of HLA class I molecules, (ii) defects in antigen-processing machinery, (iii) down-regulation of molecules that activate T and natural killer (NK) cells (i.e., PD-1L, NKG2DL, MIC-A and –B, ULBP-1, ULBP-2, ULBP-3 and DNAM-1 ligand), (iv) membrane expression and release of soluble HLA-G and –E, (v) release of exosomes containing immune-suppressive molecules (i.e., B7-H3) and (vi) secretion of immunomodulatory cytokines (e.g., IL-10 and TGF-β1) [ 31 , 32 , 33 , 34 , 35 , 36 ].…”

“…These Abs showed similar clinical impact and toxicities mainly manifested as neuropathic pain, fever and allergic reactions. However some differences have been reported probably due to their different half life [ 30 , 53 ].…”