ENHANCED IMMUNOGENICITY OF NEUROBLASTOMA CELLS BY GENETIC ENGINEERING

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Neuroblastoma is the most common extracranial solid tumor in children. Despite the ability to achieve minimal residual disease (MRD) with myeloablative therapy and autologous bone marrow transplantation (ABMT), over 50% of high risk patients develop recurrent fatal disease. We wish to determine whether active specific immunotherapy with neuroblastoma cells engineered to evoke an immune response can play a role in eradication of MRD and improve prognosis for high risk patients. We shall introduce cytokine genes, specifically interferon-gamma (IFN-gamma) and GM-CSF genes, into autologous and HLA single locus matched allogeneic neuroblastoma cells, assay levels of cytokine expression, and determine phenotypic changes. A panel of cytokine transduced tumor cells that stably express common HLA A or B antigens will be derived. The ability of neuroblastoma cells to process and present specific peptide antigens derived from HTLV-1 tax and MAGE-1 as targets for cytolytic T-cells (CTL) will be assayed. The ability of cytokine expressing autologous and MHC class I matched allogeneic neuroblastoma cells to elicit CTL will be assessed following administration of genetically engineered tumor cells to patients. Preliminary results using retroviral IFN-gamma producing vectors are sufficiently encouraging to warrant a phase 1/lb clinical trial. Future clinical trials employing GM-CSF transduced neuroblastoma cells are envisioned. Neuroblastoma offers a unique setting in which to test immunotherapeutic gene transfer strategies due to availability of cell lines, the predictable relapse rate despite achievement of MRD status, and the strong correlation of cell line outgrowth with poor survival.