Changing Delivery Method Reduces Pain of Neuroblastoma Treatment

Prof. Dr. Holger Lode Clinical Immunology, Pediatrics University of Greifswald, Interview with:
Prof. Dr. Holger Lode

Clinical Immunology, Pediatrics
University of Greifswald, Greifswald

Medical Research: What is the background for this study?

Response: Neuroblastoma is a cancer in childhood with one of the highest death rates.  Standard treatment is already very intensive. It includes chemotherapy, surgery, radiation, high dose chemotherapy followed by autologous stem cell transplantation. However, the progress made in improving survival rates is still poor.

The use of an immune-modulatory treatment with a neuroblastoma specific monoclonal antibody ch14.18 (100 mg/m2 /cycle) in combination with cytokines and 13cis retinoic acid (13 cis RA) has shown benefit for patients with this disease [1].  This antibody targets ganglioside GD2 abundantly expressed on neuroblastoma with limited to no expression on healthy tissue. Low expression of GD2 on pain fibers is associated with an on-target side effect of the treatment, which is the induction of neuropathic pain. Approval of ch14.18 (dinutuximab) for the treatment of children with neuroblastoma has been provided by FDA.

In Europe, ch14.18 was not available for a long time. There were several reasons why the antibody in the US could not be given to children in Europe. Therefore a new development of this side of the Atlantic was initiated following the remanufacturing of the antibody in CHO cells [2] (dinutuximab beta) and was made available within clinical trials of the SIOPEN group. The SIOPEN group is a network of leading European pediatric oncology centers to improve outcome for children with neuroblastoma (, similar to the COG (children`s oncology group in the USA;

Following the recloning procedure, ch14.18/CHO was first evaluated for safety in a Phase I study [3], which confirmed the tolerability and showed activity at a dosing regimen of 20 mg/m2 given by 8 hour infusions on 5 consecutive days. Dinutuximab beta is further developed by Apeiron Biologics.

The current way to apply 100 mg /m2 / cycle is by 4 short term infusions of 25 mg/m2/day each over 8 hrs on 4 consecutive days. The entire treatment consists of 5 cycles. The drawback is that STI is associated with a high amount of intravenous morphine required to make this treatment tolerable for patients. Also the rate of inflammatory side effects observed is substantial.

Clinical observation indicates that if patients treated by STI suffer from pain despite analgesic treatments, a decrease in speed of antibody infusion improves this on target toxicity. Therefore, we hypothesized that significant prolongation of the time of antibody infusion will improve tolerability of that treatment, but at the same time maintains clinical activity and efficacy in high risk neuroblastoma patients.

Medical Research: What are the main findings?

Response: We tested a treatment regimen consisting of ch14.18/CHO at 100 mg /m2 / cycle given as 10 day continuous long term infusion (LTI) combined with IL2 and 13cis RA and systematically evaluated pain toxicity, objective clinical response and survival of treated patients.,

The key finding is that by changing the method of antibody delivery, we observe an impressive reduction of on- (pain) and off- (inflammation) target side effects, maintaining effective drug levels over the entire treatment period as demonstrated in a variety of bioassays showing the immune modulatory effect over a period of 6 months.

Medical Research: What should clinicians and patients take away from your report?

Response: The major implication is that changing the method of delivery of ch14.18/CHO antibody will dramatically improve tolerability of the treatment. We also learned from PK parameters and the analysis of immune modulatory effects of LTI that we maintain active antibody levels over a time period of 6 months. This should provide a substantial improvement for children treated with ch14.18/CHO.

Medical Research: What recommendations do you have for future research as a result of this study?

Response: The data provide an important base line. Future research may involve a randomized controlled clinical trial comparing STI and LTI.


CRI-CIMT-EATI-AACR – The Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival

September 16 – 19, 2015  abstract discussing:

LTI  Immunotherapy Delivery Lowers Pain in Children With High-risk Neuroblastoma

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Prof. Dr. Holger Lode (2015). Changing Delivery Method Reduces Pain of Neuroblastoma Treatment 

Last Updated on September 16, 2015 by Marie Benz MD FAAD