Minimal Residual Disease
Many patients with high-risk neuroblastoma, despite being in clinical remission after completing induction chemotherapy, are often left with minimal residual disease (MRD), i.e., the presence of microscopic levels of tumor cells not detectable by conventional clinicopathological methods. Unfortunately, the presence of MRD is likely to contribute to an eventual relapse and death. Immunotherapy, including anti-GD2 monoclonal antibodies and anti-GD2 vaccine directed against MRD, has been demonstrated to markedly improve outcomes. It stands to reason that the ability to measure MRD is critical. It helps gauge the success of these targeting strategies, especially in the key metastatic compartments of bone marrow and peripheral blood, as well as in the emerging relapse sites, including the brain, leptomeninges, and soft tissues, such as the lymph nodes, liver, and lung. Using transcriptome analysis, we have developed and validated a panel of four molecular markers. This marker panel was found to be highly predictive of eventual relapse and survival in about 400 people with metastatic neuroblastoma in a series of retrospective marrow analysis. This tool is extremely important because MRD status helps determine treatment efficacy, and for some people, it means avoiding the devastating late effects from prolonged therapy.
Pharmacokinetics of Monoclonal Antibodies
Pharmacokinetics (PK) of novel biologics provide rationale for appropriate dosing. In the phase I trial of hu3F8 used in combination with GM-CSF, we analyzed a comprehensive collection of serial blood samples to study the PK and immunogenicity of hu3F8. There were several key observations from the PK analyses of hu3F8. First, drug exposure, as measured by the area under the curve, decreased with body weight, suggesting that smaller children might have been underdosed despite using a mg/kg prescription. Some people were found to mount their own anti-GD2 antibody response after hu3F8 treatment (the vaccination effect), and this response correlated with survival outcomes. These observations have profound implications for the dosing of antibodies and antibody conjugates, as well as the future directions of the immunotherapy program at MSK.
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Irene Cheung discloses the following relationships and financial interests:
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