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pubmed-article:10411920pubmed:abstractTextInduction, maintenance, and amplification of tumor-protective immunity after cytokine gene therapy is essential for the clinical success of immunotherapeutic approaches. We investigated whether this could be achieved by single-chain IL-12 (scIL-12) gene therapy followed by tumor-targeted IL-2 using a fusion protein containing a tumor-specific recombinant anti-ganglioside GD(2) antibody and IL-2 (ch14.18-IL-2) in a poorly immunogenic murine neuroblastoma model. Herein, we demonstrate the absence of liver and bone marrow metastases after a lethal challenge with NXS2 wild-type cells only in mice (five of six animals) vaccinated with scIL-12-producing NXS2 cells and given a booster injection of low-dose ch14.18-IL-2 fusion protein. This tumor-protective immunity was effective 3 months after initial vaccination, in contrast to control animals treated with a nonspecific fusion protein or an equivalent mixture of antibody and IL-2. Only vaccinated mice receiving the tumor-specific ch14.18-IL-2 fusion protein revealed a reactivation of CD8(+) T cells and subsequent MHC class I-restricted tumor target cell lysis in vitro. The sequential increase in the usage of TCR chains Vbeta11 and -13 in mouse CD8(+) T cells after vaccination and amplification with ch14.18-IL-2 suggests that the initial polyclonal CD8(+) T cell response is effectively boosted by targeted IL-2. In conclusion, we demonstrate that a successful boost of a partially protective memory T cell immune response that is induced by scIL-12 gene therapy could be generated by tumor-specific targeting of IL-2 with a ch14.18-IL-2 fusion protein. This approach could increase success rates of clinical cancer vaccine trials.lld:pubmed
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pubmed-article:10411920pubmed:authorpubmed-author:Theofilopoulo...lld:pubmed
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pubmed-article:10411920pubmed:articleTitleTumor-targeted IL-2 amplifies T cell-mediated immune response induced by gene therapy with single-chain IL-12.lld:pubmed
pubmed-article:10411920pubmed:affiliationThe Scripps Research Institute, Department of Immunology, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.lld:pubmed
pubmed-article:10411920pubmed:publicationTypeJournal Articlelld:pubmed
pubmed-article:10411920pubmed:publicationTypeResearch Support, U.S. Gov't, P.H.S.lld:pubmed
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