Anti-GD2 for the treatment of neuroblastoma.

15 January 2013

Progress report of project anti-GD2 mAb.

Proposers: Peter Kapitein, following his visit in August 2010 to Richard O’Reilly, head of Pediatric Oncology at Memorial Sloan-Kettering Hospital (MSK) in New York; and the parents of a patient with neuroblastoma; entry no. 247 October 2010.

This monoclonal antibody (mAb) improves survival in children with stage 4 neuroblastoma, which has a very poor prognosis. Neuroblastoma is a very rare type of cancer in children. In the Netherlands there are an average of 25 new cases each year, most of which can be cured. Until recently, patients with high-risk neuroblastoma were treated with a combination of high-dose chemotherapy and stem cell transplants, but this only works in a minority of patients. The recent addition to this treatment of the anti-GD2 monoclonal antibody ch14.18, in combination with cytokines, increases survival significantly (reference 3). It was the first major sign of progress after dozens of years of research.

The drug is not available in the Netherlands or elsewhere in Europe. Dutch patients can only be treated in Philadelphia (USA), and only if they satisfy the admission requirements for the protocol there. Treatment lasts for 6 months and since most children are very young they must be accompanied by other members of their family. The total costs of treatment amount to between 400,000 and 500,000 dollars. Not only were there problems obtaining reimbursement from the health insurance companies, there are also the additional costs for accompanying family members.

Project proposers pointed out to Cinderella that something needed to be done about the limited access to this new life-saving drug and that treatment in a patient’s own country was far and away preferable to treatment abroad. Furthermore, the costs are exorbitant and until the mAb becomes available in the Netherlands, clinical research into its use is not feasible.
Anti-GD2 has shown to be a promising form of treatment not only for neuroblastomas but also for melanomas, some types of incurable lung tumours, some types of brain tumours, as well as various other less common types of cancer. Because the antibody binds specifically to cancer cells, it is also a promising means of effective radio-immunotherapy. The first clinical studies with various anti-GD2 antibodies date back to the 1980s, and although several groups in the USA and in Germany have done clinical research, its development has come to a standstill. All this means that anti-GD2 qualifies for stepchild drug status by a wide margin.

What Cinderella has done
There was a lot known about anti-GD2 within Cinderella. Two of the board members became familiar with the antibody during their work at Crucell and co-founder Dr H.M. Vriesendorp has published research in animals using this antibody.

In October 2010, Cinderella asked United Therapeutics, the American company in Maryland that produces chimeric mAb ch14.18 for the patients in Philadelphia, to send Cinderella a sample of this cell line so that we could start not-for-profit manufacture of mAb for Dutch children. The company was not prepared to do this. Further investigations revealed that ch14.18 is produced in the Biological Resources Branch of the Frederick National Laboratory for Cancer Research, a division of the National Cancer Institute (NCI) in Bethesda, USA. When asked, the official responsible, Dr Karen Muszynski, informed us that they do not produce enough mAb to supply it to anyone other than the patients participating in the Philadelphia treatment programme. We were also told that the NCI has granted a licence to United Therapeutics and that NCI can therefore not make the cell line and corresponding manufacturing details available to us.

Cinderella’s chairman then appealed to the director of the National Cancer Institute, Dr Harold Varmus, referring to the fact that the NCI is a public institution and that the free exchange of information and materials between Europe and the US in their joint fight against cancer have been in place for more than 50 years.

Even he appeared to be powerless to neutralize the conflict of interest with United Therapeutics: “I will look into the issue you raise about antibody producing cells, but it is virtually certain that the work being done by the NCI is carried out in conjunction with an industrial partner under restrictions that limit availability. I will see what is happening, but I don’t offer much hope of reversing the situation.” – Dr Harold Varmus, 11 January 2011.

In the meantime, discussions were underway with the paediatricians Cheung and O’Reilly at the Memorial Sloan-Ketting (MSK) Cancer Center, who had also improved treatment results using another anti-GD2 mAb called 3F8 (reference 6). 3F8 has been patented and humanized by MSK and is produced in-house for MSK patients, but the production capacity is insufficient to provide antibody for any other patients. The researchers at MSK are prepared to make the cell line available to Cinderella for the production of antibody, on the condition that it be used for innovative clinical research, for example into its therapeutic effect in stage 3 neuroblastoma. The general aim is to improve the results of treatment, as well as reducing toxicity and improving quality of life. Such research could be organized in collaboration between MSK and interested parties in the Netherlands and other countries.

In January 2011, this possibility was reported to Dr Max van Noesel, pediatric oncologist and neuroblastoma expert at Erasmus Medical Center (MC) in Rotterdam, whom we had contacted before about the stepchild drug anti-GD2. We asked him to find out whether the Neuroblastoma Working Party (NWP) of the Dutch child oncology foundation (SKION) might be interested in the 3F8 proposal, in which case Cinderella was prepared to quickly draw up a production plan together with the parties involved. Professor Caron, pediatric oncologist and neuroblastoma expert at the AMC in Amsterdam, was also informed.

At the same time, Rowald Steijn, chairman of Villa Joep (a neuroblastoma fund), was informed about MSK’s offer by Cinderella’s chairman. Further communications with Villa Joep were through Jos Huijbrechts, the member of the board responsible for research financed by the fund. Villa Joep is in favour of developing a new source of anti-GD2.

Because of a lack of response from NWP/SKION, Cinderella approached them again in November 2011 and this resulted in a meeting with the pediatric oncologists Prof. Pieters, Dr van Noesel and Dr Zwaan at Erasmus MC. They agreed that it was about time to get the anti-GD2 treatment available in the Netherlands. Not only is the present arangement extremely demanding on the patients and their families, the insurance companies were also pressing for changes. The oncologists told us that the NWP is currently collaborating with SIOPEN*, a European network of neuroblastoma specialists, to prepare a clinical trial for anti-GD2 treatment in which Dutch patients may participate.

SIOPEN is finalizing a study protocol with mAb ch14.18 to be provided by Apeiron Biologics, a spin-off company of the Austrian Institute of Technology in Vienna.
APN311 is a monoclonal chimeric antibody produced in CHO cells targeting the GD2 antigen on neuroblastoma cells. It is undergoing a randomized Phase III in Europe in patients with high-risk neuroblastoma and minimal residual disease. More than half of the patients have already been recruited by Apeiron’s partners, the Children’s Cancer Research Institute CCRI and SIOPEN. Apeiron is in contact with the European Regulatory Authority EMA to discuss how to make this therapy available to all patients as quickly as possible. – Quote from Apeiron’s website.

In 2010, SKION’s neuroblastoma committee declared the protocol used by the Children’s Oncology Group in the USA (reference 3) to be part of the standard treatment. The committee also intends for this protocol to constitute one of the arms of the future European study, in which ch14.18 will be given together with GM-CSF (a cytokine that stimulates immune cells). SKION is not interested in the 3F8 antibody since it has not been shown to be as effective as ch14.18 for so-called ‘triple therapy’. It is not yet known when ch14.18 will become available for treatment in the Netherlands.

In October 2012 things became unsettled once more when Peter Kapitein reported that the insurance company Menzis was objecting to the reimbursement of a patient who was about to be treated in the US. When asked about this, Professor Caron told us that reimbursement by healthcare insurers for the ‘Philadelphia route’ had now been arranged satisfactorily. He is currently negotiating with Apeiron to arrange to have ch14.18 available in the Netherlands in the first half of 2013. Also, United Therapeutics’ expects to obtain orphan drug designation in Europe for the triple immunotherapy protocol, including their product ch14.18.

* SIOPEN (Society of Paediatric Oncology European Neuroblastoma Network) consists of 17 European countries plus Israel.


– Our experiences with United Therapeutics and the NCI in the US have shown that the prices charged for this product are sky-high, despite a government-supported collaboration between the public and private sector in the development of this new drug. Now that this type of cooperation is receiving strong support here in the Netherlands, it is in the public interest to take appropiate measures to prevent such excesses, ensuring that successful products will be affordable.

– We did not expect the Dutch pediatric oncologists to have little interest in the proposal by Cinderella of using a different anti-GD2 antibody as an alternative. The oncologists feel that there is insufficient evidence that 3F8 is equally effective as ch14.18. This is why the NWP favours participation in a European initiative that uses the ch14.18 mAb. Understandably, Villa Joep has followed the recommendations of the physicians.

– Despite current efforts by the pharmaceutical industry, Cinderella is of the opinion that it is worthwhile to pursue the non-commercial not-for-profit production of these types of drugs. This will facilitate research into the expansion of their applications, such as the treatment of other tumours, and enable better control over the costs.

Additional information

1. Preclinical analysis of radiolabeled anti-GD1 immunoglobulin G
F. J. Vriesendorp et al. Cancer 1997 Dec 15;80 Supplement P 2642-2649

2. A review of the intravenous administration of radiolabeled immunoglobulin G to cancer patients. High or low protein dose?
Vriesendorp HM, Vriesendorp FJ. Cancer Biother Radiopharm. 2003Feb;18(1):35-46. Review

3. Anti-GD2 Antibody with GM-CSF, Interleukin-2, and Isotretinoin for Neuroblastoma
Alice L. Yu, et al. for the Children’s Oncology Group. N Engl J Med September 30, 2010 363;14.

4. Activation of Peripheral-Blood Granulocytes Is Strongly Correlated With Patient Outcome After Immunotherapy With Anti-GD2 Monoclonal Antibody and Granulocyte-Macrophage Colony-Stimulating Factor
Irene Y. Cheung, Katharine Hsu, and Nai-Kong V. Cheung. J Clin OncolFebruary 1, 2012, vol. 30, no. 4, 426-432

5. Neuroblastoma: Therapeutic strategies for a clinical enigma
Shakeel Modak, Nai-Kong V. Cheung. Cancer Treatment Reviews 2010; 36; 307–317

6. Murine Anti-GD2 Monoclonal Antibody 3F8 Combined Granulocyte-Macrophage Colony-Stimulating Factor and 13-Cis-Retinoic Acid in High-Risk Patients with Stage 4 Neuroblastoma in First Remission
Nai-Kong V. Cheung, Irene Y. Cheung, Brian H. Kushner, et al. J Clin OncolSeptember 10, 2012.30 (26): 3264-3270

7. Anti-GD2 antibody therapy for GD2 expressing tumors.
F.Navid et al. Curr Cancer Drug Targets2010 March 1; 10(2): 200-209.

8. Villa Joep

9. SKION (website in Dutch)

10. SIOPEN International Society of Paediatric Oncology European Neuroblastoma Research Network 

From the United Therapeutics website:
In July 2010, United Therapeutics entered into a Cooperative Research and Development Agreement (CRADA) with the National Cancer Institute (NCI) to collaborate on the late-stage development and commercialization of chimeric (ch)14.18 for the treatment of neuroblastoma. Pivotal Phase 3 clinical study results for Study ANBL0032 sponsored by NCI and conducted by the Children’s Oncology Group (COG) were published in the New England Journal of Medicine (September 2010). The results described that immunotherapy with ch14.18 granulocyte-macrophage colony stimulating factor (GM-CSF) and interleukin-2 (IL-2) significantly improved patient outcome compared with standard therapy in patients with high risk neuroblastoma. Specifically, the 2-year estimate for event-free survival was 66±5% in the immunotherapy group and 46±5% in the standard therapy group (p=0.01). The immunotherapy group was also significantly better than the standard therapy group in the estimated rate of overall survival (86±4% vs. 75±5% at 2 years, p=0.02 without adjustment for interim analyses). United Therapeutics plans to manufacture ch14.18 in its Silver Spring, Maryland manufacturing facility and complete the necessary development work for filing a BLA [Biologic Licence Application].

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