title: Combined Flt3L/TK gene therapy induces immunological surveillance which mediates an immune response against a surrogate brain tumor neoantigen.
abstract: 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.
authors.affiliation: Gene Therapeutics Research Institute, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, USA.
authors.forename: Gwendalyn D
authors.initials: GD
authors.lastname: King
authors.forename: A K M Ghulam
authors.initials: AK
authors.lastname: Muhammad
authors.forename: Daniel
authors.initials: D
authors.lastname: Larocque
authors.forename: Kyle R
authors.initials: KR
authors.lastname: Kelson
authors.forename: Weidong
authors.initials: W
authors.lastname: Xiong
authors.forename: Chunyan
authors.initials: C
authors.lastname: Liu
authors.forename: Nicholas S R
authors.initials: NS
authors.lastname: Sanderson
authors.forename: Kurt M
authors.initials: KM
authors.lastname: Kroeger
authors.forename: Maria G
authors.initials: MG
authors.lastname: Castro
authors.forename: Pedro R
authors.initials: PR
authors.lastname: Lowenstein
mesh_terms: D000951:Antigens, Neoplasm / Q000276:immunology*; D001932:Brain Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D045744:Cell Line, Tumor; D015316:Genetic Therapy; D005909:Glioblastoma / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D006801:Humans; D007156:Immunologic Memory; D007371:Interferon-gamma / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology; D013937:Thymidine Kinase / Q000235:genetics*; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics*
chemical_list: D000951:Antigens, Neoplasm; D007371:Interferon-gamma; D013937:Thymidine Kinase; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3