Neuroblastoma is the most common cancer afflicting children under twelve months of age with average age of diagnosis about 18 months. Approximately 50% of patients have high-risk neuroblastoma, with half of these children eventually succumbing to the disease despite intensive chemotherapy and autologous bone marrow transplantation. Because of this, there is an urgency to develop new and more effective therapies. One major breakthrough in neuroblastoma treatment has involved the development of the anti-GD2 chimeric antibody ch14.18 by Dr. Yu. Ongoing phase III clinical trials of ch14.18, targeted to children diagnosed with high-risk disease after they enter remission, have resulted in a significant improvement in cure rate from 46% to 66%. Despite this breakthrough, however, it is still clear that almost one-third of the children continue to fail therapy and succumb to the disease, and there are significant toxicities associated with ch14.18 therapy. Thus, there is a pressing need for the identification of new biological markers that can refine outcome prediction and decrease toxicities without loss of efficacy, which is the focus of this application. We hypothesize that outcome may be predicted from the genotypes of the F receptor or KIR mismatch, that failure in some children may be due to preexisting antibodies against the non-human glycans Neu5Gc and alpha-gal residues which are present on ch14.18, and that the toxicities observed with ch14.18 may also be due to antibodies against the glycan residue of ch14.18, and/or be due to IL-6 or NO. We will use DNA, plasma and serum taken from blood samples of patients enrolled in two ongoing clinical trials of ch14.18 implemented by the Children's Oncology Group (ANBL0032, chaired by Dr. Yu, and ANBL0931) to address the following specific aims: 1) Determine the genotypes of Fc RIIIA and Fc RIIA and their correlation with ADCC activity and clinical outcome in patients randomized to immunotherapy;2) Determine the association of genotypes for KIR and KIR ligands (HLA class I) with ADCC activity and clinical outcome in patients randomized to immunotherapy;3) Determine if the serum cytokine IL-6 or serum nitrous oxide is associated with common toxicities associated with ch14.18 infusion and treatment, including hypersensitivity reaction capillary leak syndrome, and neuropathic pain;and 4) Determine if the presence and/or levels of antibodies to the non-human glycans Neu5Gc and alpha-gal in plasma samples is associated with allergic response or outcome to ch14.18 therapy, and/or post-treatment ch14.18 serum levels. The proposed research should yield the much needed information regarding biomarkers that may predict efficacy and toxicities of this now proven effective immunotherapy of high risk neuroblastoma. More importantly, it may lead to an improvement in ch14.18 therapy by providing a pathway for the """"""""personalization"""""""" of treatment by identifying ways to ameliorate toxicities, increase therapeutic efficacy, and predict outcome, thereby increasing the likelihood the child being treated is a child most likely to benefit under the most optimal and compassionate conditions.
Dr. Yu recently reported a significant improvement in the cure rate of high risk neuroblastoma from 46% to 66%. The treatment, however, is associated with significant side effects including pain, blood pressure drop and allergic reaction, and it is unknown why one-third of the patients do not respond to the therapy. This proposal seeks to identify biomarkers that will lead to an improved prediction of patient outcome and explores possible causes for the side effects and failure to respond, which together can lead to therapeutic approaches to ameliorate these toxicities and an improvement in survival.
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