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For Children with High-Risk Neuroblastoma, Immunotherapy Extends Progression-Free Survival

Laino, Charlene

doi: 10.1097/01.COT.0000361637.27659.d4

ORLANDO, FL—An experimental monoclonal antibody significantly improved progression-free survival rates in children with high-risk neuroblastoma, researchers reported at the ASCO Annual Meeting.

In the Children's Oncology Group (COG) randomized ANBL0032 trial of 226 patients, 66% of those who received standard treatment plus immunotherapy with the monoclonal antibody ch14.18 were alive without any sign of cancer two years later, compared with only 46% of children who received the standard treatment alone.

“The immunotherapy resulted in an absolute 20% improvement in the progression-free survival rate, and should now be considered the new standard of care,” said Alice L. Yu, MD, PhD, Professor of Pediatric Hematology/Oncology at the University of California, San Diego.

The benefits of immunotherapy were so evident that the study was stopped prematurely.

Neuroblastoma is the most common cancer diagnosed in the first year of life and is responsible for 15% of cancer-related deaths in children, Dr. Yu noted. Most patients are diagnosed as toddlers, but the disease can present in infants and older teenagers as well.

Forty percent of patients present at diagnosis with high-risk neuroblastoma, which is treated with aggressive therapy, including chemotherapy, surgery, radiotherapy, and stem cell transplant. “However, high-risk neuroblastoma often returns and most patients do not survive,” Dr. Yu said.

High-risk patients include those with advanced stage disease, older age, and certain tumor characteristics, including MYCN gene amplification and DNA ploidy. According to the NCI, patients assigned to low-, intermediate-, and high-risk groups have an overall survival rate of more than 90%, 70% to 90%, and about 30%, respectively, three years after diagnosis.

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43% Relative Improvement in PFS

Seeking to find a new modality of treatment to prevent relapse in high-risk neuroblastoma patients, Dr. Yu and colleagues turned to the monoclonal antibody ch14.18, which targets the glycolipid GD2 on the surface of neuroblastoma cells, she explained.



The monoclonal antibody binds to GD2, provoking an immune attack. Granulocyte monocyte colony stimulating factor (GM-CSF) and interleukin-2 (IL2) are also administered, to stimulate immune cells to attack the cancer.

In the study, all 226 patients were given intensive chemotherapy, surgery, and stem cell transplant, followed by standard treatment with six cycles of 13-cis-retinoic acid. Half the patients were also given five cycles of ch14.18 along with the cytokines GM-CSF and IL2.

At a median of 2.1 years of follow-up, the progression-free survival rate was 43% higher in the monoclonal antibody arm, compared with the standard treatment arm, Dr. Yu reported.

Standard therapy was well tolerated. The aggressive immunotherapy had some significant Grade 3 side effects, including pain, vascular leak, and allergic reactions, but all were manageable, she said.

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Several ‘Firsts’

The trial represents “several firsts,” Dr. Yu said. “This is the first clinical trial to document that a combination of anticancer monoclonal antibodies with cytokines is an effective anti-cancer therapy. Also, so far, all FDA-approved therapeutic anti-cancer monoclonal antibodies and vaccines have been directed against protein antigens. This is the first time a monoclonal antibody targeting a glycolipid has been shown to be effective for immunotherapy of cancer.”

The researchers plan to continue the immunotherapy protocol at COG institutions to collect a comprehensive safety profile that, it is hoped, will be sufficient for FDA approval, she said.

The antibody was produced for the study by the National Cancer Institute, Dr. Yu said, adding that while several biotechnology companies have since expressed interest in developing the agent, NCI is committed to producing it in the meantime.

She noted that the antibody might also be useful against other tumors that express GD2, including melanoma, small-cell lung cancer, and soft tissue sarcoma.

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‘Viscious Tumor’

ASCO 2008–2009 President Richard L. Schilsky, MD, Professor of Medicine and Associate Dean for Clinical Research at the University of Chicago, called the results “a major advance for pediatric oncology.”

High-risk neuroblastoma is “a rare but vicious tumor,” he said.

Early results suggest the treatment will also improve overall survival times, although those data are not yet mature, Dr. Schilsky said in an interview.

Copyright © 2009 Wolters Kluwer Health, Inc. All rights reserved.
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