期刊
MOLECULAR THERAPY
卷 19, 期 10, 页码 1793-1801出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/mt.2011.77
关键词
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资金
- National Institutes of Health/National Institute of Neurological Disorders & Stroke (NIH/NINDS) [1R21-NS054143, 1UO1 NS052465, 1RO1-NS057711, 1RO1-NS 054193, 1RO1-NS061107, F32NS0503034]
- The Linda Tallen & David Paul Kane Foundation
- The Drown Foundation
- Board of Governors at CSMC
- The Bram and Elaine Goldsmith and the Medallions Group Endowed Chairs in Gene Therapeutics
Glioblastoma multiforme (GBM) is a primary brain tumor with a median survival of 14.6 months postdiagnosis. The infiltrative nature of GBM prevents complete resection and residual brain tumor cells give rise to recurrent GBM, a hallmark of this disease. Recurrent GBMs are known to harbor numerous mutations/gene rearrangements when compared to the primary tumor, which leads to the potential expression of novel proteins that could serve as tumor neoantigens. We have developed a combined immune-based gene therapeutic approach for GBM using adenoviral (Ads) mediated gene delivery of Herpes Simplex Virus Type 1-thymidine kinase (TK) into the tumor mass to induce tumor cells' death combined with an adenovirus expressing fms-like tyrosine kinase 3 ligand (Flt3L) to recruit dendritic cells (DCs) into the tumor microenvironment. This leads to the induction of specific anti-brain tumor immunity and immunological memory. In a model of GBM recurrence, we demonstrate that Flt3L/TK mediated immunological memory is capable of recognizing brain tumor neoantigens absent from the original treated tumor. These data demonstrate that the Flt3L/TK gene therapeutic approach can induce systemic immunological memory capable of recognizing a brain tumor neoantigen in a model of recurrent GBM. Received 23 December 2010; accepted 23 March 2011; published online 19 April 2011. doi:10.1038/mt.2011.77
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