The management of patients with neuroblastoma is highly complex, especially when it is a high-risk case, more than 50% of all neuroblastomas at presentation. A multidisciplinary approach is required in all cases and few centers can provide all super-specialized disciplines that are required to aim for the best cure rates. SJD Barcelona Children's Hospital offers all treatment modalities that patients may need in order to find the best strategy based on a broad experience of clinical care and research that started more than 15 years ago.
The cure of high-risk neuroblastoma patients remains a significant challenge worldwide. Current treatment approaches within the major international cooperative groups comprise a backbone of intensive induction chemotherapy, consolidation with high-dose chemotherapy and autologous stem cell transplant (ASCT), and dinutuximab-based immunotherapy plus cis-retinoic acid (cis-RA). Long-term survival rates for children with high-risk neuroblastoma are currently 40 - 55% in large cooperative group studies.
More recently, anti-GD2 based immunotherapy was introduced in the treatment backbone and is now part of the standard of care for high-risk neuroblastoma. In 2010 the results of the COG ANBL0032 trial were published demonstrating that the 2-year event-free-survival and overall survival of patients with high-risk neuroblastoma achieving major responses (after standard induction and consolidation -including autologous stem cell transplant-) and receiving anti-GD2 immunotherapy (dinutuximab and cytokines: GM-CSF and IL-2) in addition to isotretinoin were significantly higher (2 years event-free survival 66 ± 5% and overall survival 86 ± 4%) compared to those patients who received all other treatments (standard induction, consolidation, ASCT, and isotretinoin) but not the anti GD2 immunotherapy (2 years event-free survival 46 ± 5% and overall survival 75 ± 5%). This study was the first and only randomized trial in neuroblastoma showing significant improvement in overall survival.
Two anti-GD2 antibody families have been tested clinically in neuroblastoma, 3F8, and 14.18. Chimeric (ch) 14.18 was derived from the variable region of the murine monoclonal antibody (MoAb) 14.18 showing antibody-dependent cell cytotoxicity (ADCC) and complement-mediated cytotoxicity (CMC) of neuroblastoma. Murine 3F8 (m3F8) is a murine IgG3 murine monoclonal antibody specific for GD2 that also induces cell death and mediates efficient antibody-dependent cell cytotoxicity and complement-mediated cytotoxicity against neuroblastoma in vitro.
m3F8 was the first anti-GD2 administered to a neuroblastoma patient in 1987 and was developed and used exclusively at Memorial Sloan Kettering Cancer Center (MSKCC) in New York (USA) where they demonstrated that m3F8 + GM-CSF + cis-retinoic acid was mainly effective against chemotherapy-resistant bone marrow minimal residual disease (MRD). Humanization (hu) of m3F8 was undertaken by the MSKCC team in 2010 with the financial support of parents and families, and the whole idea to circumvent human anti-mouse antibody response, to enhance antibody-dependent cell cytotoxicity, and to reduce dosing and pain. In vitro comparison with m3F8 and dinutuximab in binding, cytotoxicity, and cross-reactivity assays showed that hu3F8 had an improved pharmacokinetic profile. Similar to m3F8, hu3F8 inhibited tumor cell growth in vitro, while cross-reactivity with other gangliosides was comparable to that of m3F8. Importantly, the antitumor effect against neuroblastoma xenografts was better with hu3F8 than m3F8.
In summary, humanizing m3F8 produced the next generation of anti-GD2 antibodies with substantially more potent antibody-dependent cell cytotoxicity in vitro and antitumor activity in vivo. Phase 1 (at MSKCC) and 2 (MSKCC and SJD Barcelona Children’s Hospital) clinical trials of hu3F8 (Naxitamab) have shown the effectiveness of hu3F8 + GM-CSF against chemotherapy-resistant bone/bone marrow disease, which prompted a fast record Food and Drug Administration (FDA) approval of hu3F8 (naxitamab; Danyelza) in November 2020. The first human infusion of naxitamab produced by Ymabs Therapeutics in combination with GM-CSF was performed on June 12, 2017, at SJD Barcelona Children’s Hospital.
SJD Pediatric Cancer Center Barcelona is one of the largest in Europe in terms of activity (350 new cases per year) equipped with the latest technology (intraoperative magnetic resonance imaging - MRI).
The SJD Barcelona Children's Hospital neuroblastoma team, led by Dr. Jaume Mora, Scientific Director of the SJD Pediatric Cancer Center Barcelona, offers the best survival outcome worldwide in this disease. Several recent publications (Cancers, Frontiers in Pharmacology y Pediatric Blood & Cancer) demonstrate how the new strategy of naxitamab based immunotherapy, in combination with short and intensive chemotherapy, comprehensive surgery, and radiotherapy, provides survival outcomes never paralleled before. As reported, patients in first complete remission present a 3-year event-free survival of 74.3% and overall survival of 91.6%. More importantly, without the use of high-dose chemotherapy and transplant with the spare of cost and potential long-term toxicities implied. Families highly appreciate this low-toxicity strategy.
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