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Lysis of MYCN-amplified Neuroblastoma Cells by MYCN Peptide-specific Cytotoxic T Lymphocytes¹

Departments of Surgery and Pediatrics, Baylor College of Medicine, and Texas Children’s Cancer Center, Texas Children’s Hospital, Houston, Texas 77030-2399

The effectiveness of cell-mediated immunotherapy for cancer can be limited by loss-of-antigen mutations that occur during tumor growth. In neuroblastoma, amplification of the MYCN oncogene correlates with rapid tumor progression and a poor prognosis overall. We propose that the MYCN protein, the high-level expression of which is required for maintenance of the malignant phenotype, would be an ideal target for vaccine therapy. The MYCN-derived S9K peptide (amino acids 7–15; STMPGMICK), which contains an HLA-A1 binding motif, was used to generate CTLs from the peripheral blood lymphocytes of an HLA-A1⁺ healthy donor and an HLA-A1⁺ patient with MYCN-amplified neuroblastoma. These CTL lines specifically lysed HLA-matched, MYCN-amplified neuroblastoma tumor cells. They did not lyse either HLA-mismatched, MYCN-amplified, or matched/nonmatched, non-MYCN-amplified tumor cells. The CTL activity was inhibited by a monoclonal antibody to a class I HLA monomorphic determinant but not by one specific for HLA class II, consistent with a class I-restricted mechanism of cytotoxicity. Antibodies to CD8, but not those to CD4, also inhibited CTL activity, identifying CD8⁺ lymphocytes as the effector cell population. These results show that MYCN-derived peptides can serve as tumor-specific antigens and suggest a rational approach to cell-mediated immunotherapy for MYCN-amplified neuroblastoma.

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