Using combination chemotherapy and targeted immunotherapy, substantial gains have been made in the curative treatment of patients with stage 4 neuroblastoma diagnosed at over one year of age. In the last period of support, the applicant exploited three basic principles: (1) dose-intensive induction to improve remission rate and primary tumor control, (2) targeted radioimmunotherapy to eliminate occult metastatic disease, and (3) adjuvant monoclonal antibody for minimal residual disease. These evolutions in treatment strategy have produced a clear improvement in progression-free survival from 0% (N4 protocol), to 25% (N5), to 40% (N6), and now to greater than 60% for the N7 protocol. While these improved cure rates support efficacy of these novel approaches, the applicant has also applied sensitive and specific methods to measure the response of minimal residual disease. Immunofluorescence (with anti-GD2) and RT-PCR (for GAGE) have confirmed efficacy of monoclonal antibody therapy for microscopic tumors. Further, the applicant showed that a host anti-mouse response in the form of anti-idiotype (Ab2) and anti-anti-idiotype (Ab3) was associated with improved survival. Patients with positive but low Ab2 titers appeared to derive the most benefit. This application hypothesizes that the anti-idiotype network is critical for maintaining long-term remissions in these patients. To test this hypothesis directly, the applicant has produced anti-idiotypic antibodies which stimulate both B-cell and T-cell mediated anti-GD2 immune responses in mice which could protect mice from GD2-bearing B16 melanomas. GD2-oligosaccharide specificity was novel and consistent with the applicant's previous findings that T-cells could recognize carbohydrate epitopes. The unusually low optimal dosage of Ab2 paralleled clinical observations. In this application the applicant proposes to test the anti-idiotype A1G4 in a phase I clinical trial, with the intention to incorporate this vaccine modality into future protocols for neuroblastoma. The proposed studies will assess both humoral and T-cell mediated immune responses in patients following vaccination with anti-idiotypic antibody. B-lymphoblastoid lines will be transduced with retrovirus to express GD2 for T-cell studies. Immunofluorescence (new antibody panel) and RT-PCR (GAGE, MAGE, BAGE and tyrosine hydroxylase) will be used to test if minimal residual disease in blood and marrow samples will respond to immunotherapy. Based upon this phase I study, the applicant believes that the immune response to anti-idiotype vaccine can be further improved when adjuvants or engineered antigen presenting dendritic cells are optimized. Because GD2 is found on a variety of human tumors, these results may have therapeutic implications for other refractory human cancers.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Experimental Therapeutics Subcommittee 1 (ET)
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Wu, Roy S
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Sloan-Kettering Institute for Cancer Research
New York
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Kushner, Brian H; Kramer, Kim; Modak, Shakeel et al. (2010) Differential impact of high-dose cyclophosphamide, topotecan, and vincristine in clinical subsets of patients with chemoresistant neuroblastoma. Cancer 116:3054-60
Modak, Shakeel; Cheung, Nai-Kong V (2010) Neuroblastoma: Therapeutic strategies for a clinical enigma. Cancer Treat Rev 36:307-17
Kushner, Brian H; Cheung, Nai-Kong V; Barker, Christopher A et al. (2009) Hyperfractionated low-dose (21 Gy) radiotherapy for cranial skeletal metastases in patients with high-risk neuroblastoma. Int J Radiat Oncol Biol Phys 75:1181-6
Hu, Jian; Cheung, Nai-Kong V (2009) Methionine depletion with recombinant methioninase: in vitro and in vivo efficacy against neuroblastoma and its synergism with chemotherapeutic drugs. Int J Cancer 124:1700-6
Kushner, Brian H; Kramer, Kim; Modak, Shakeel et al. (2009) Sensitivity of surveillance studies for detecting asymptomatic and unsuspected relapse of high-risk neuroblastoma. J Clin Oncol 27:1041-6
Modak, Shakeel; Kushner, Brian H; LaQuaglia, Michael P et al. (2009) Management and outcome of stage 3 neuroblastoma. Eur J Cancer 45:90-8
Kushner, Brian H; Cheung, Irene Y; Kramer, Kim et al. (2007) High-dose cyclophosphamide inhibition of humoral immune response to murine monoclonal antibody 3F8 in neuroblastoma patients: broad implications for immunotherapy. Pediatr Blood Cancer 48:430-4
Kushner, Brian H; Kramer, Kim; Modak, Shakeel et al. (2006) Irinotecan plus temozolomide for relapsed or refractory neuroblastoma. J Clin Oncol 24:5271-6
Kushner, Brian H; Kramer, Kim; LaQuaglia, Michael P et al. (2006) Liver involvement in neuroblastoma: the Memorial Sloan-Kettering Experience supports treatment reduction in young patients. Pediatr Blood Cancer 46:278-84
Kushner, B H; Kramer, K; Modak, S et al. (2006) Topotecan, thiotepa, and carboplatin for neuroblastoma: failure to prevent relapse in the central nervous system. Bone Marrow Transplant 37:271-6

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