title: Blockade of mTOR signaling via rapamycin combined with immunotherapy augments antiglioma cytotoxic and memory T-cell functions.
abstract: The success of immunotherapeutic approaches targeting glioblastoma multiforme (GBM) demands a robust antiglioma T-cell cytotoxic and memory response. Recent evidence suggests that rapamycin regulates T-cell differentiation. Herein, we tested whether administration of rapamycin could enhance the efficacy of immunotherapy utilizing Fms-like tyrosine kinase 3 ligand (Ad-Flt3L) and thymidine kinase/ganciclovir (Ad-TK/GCV). Using the refractory rat RG2 glioma model, we demonstrate that administration of rapamycin with Ad-Flt3L + Ad-TK/GCV immunotherapy enhanced the cytotoxic activity of antitumor CD8(+) T cells. Rats treated with rapamycin + Ad-Flt3L + Ad-TK/GCV exhibited massive reduction in the tumor volume and extended survival. Rapamycin administration also prolonged the survival of Ad-Flt3L + Ad-TK/GCV-treated GL26 tumor-bearing mice, associated with an increase in the frequency of tumor-specific and IFNγ(+) CD8(+) T cells. More importantly, rapamycin administration, even for a short interval, elicited a potent long-lasting central memory CD8(+) T-cell response. The enhanced memory response translated to an increased frequency of tumor-specific CD8(+) T cells within the tumor and IFNγ release, providing the mice with long-term survival advantage in response to tumor rechallenge. Our data, therefore, point to rapamycin as an attractive adjuvant to be used in combination with immunotherapy in a phase I clinical trial for GBM.
authors.affiliation: Department of Neurosurgery, The University of Michigan School of Medicine, Ann Arbor, Michigan.
authors.forename: Yohei
authors.initials: Y
authors.lastname: Mineharu
authors.affiliation: Department of Neurosurgery, The University of Michigan School of Medicine, Ann Arbor, Michigan. Department of Cell and Developmental Biology, The University of Michigan School of Medicine, Ann Arbor, Michigan.
authors.forename: Neha
authors.initials: N
authors.lastname: Kamran
authors.affiliation: Department of Neurosurgery, The University of Michigan School of Medicine, Ann Arbor, Michigan. Department of Cell and Developmental Biology, The University of Michigan School of Medicine, Ann Arbor, Michigan.
authors.forename: Pedro R
authors.initials: PR
authors.lastname: Lowenstein
authors.affiliation: Department of Neurosurgery, The University of Michigan School of Medicine, Ann Arbor, Michigan. Department of Cell and Developmental Biology, The University of Michigan School of Medicine, Ann Arbor, Michigan. mariacas@umich.edu.
authors.forename: Maria G
authors.initials: MG
authors.lastname: Castro
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000941:Antigens / Q000276:immunology; D000954:Antigens, Surface / Q000378:metabolism; D045744:Cell Line, Tumor; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D015774:Ganciclovir / Q000494:pharmacology; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics; D005909:Glioblastoma / Q000276:immunology / Q000378:metabolism / Q000628:therapy; D005910:Glioma / Q000276:immunology* / Q000378:metabolism* / Q000401:mortality / Q000628:therapy; D007156:Immunologic Memory; D016130:Immunophenotyping; D007167:Immunotherapy; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects*; D020123:Sirolimus / Q000494:pharmacology*; D016176:T-Lymphocyte Subsets / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D013937:Thymidine Kinase / Q000235:genetics
chemical_list: D000941:Antigens; D000954:Antigens, Surface; D016207:Cytokines; D008565:Membrane Proteins; C084881:flt3 ligand protein; D013937:Thymidine Kinase; D058570:TOR Serine-Threonine Kinases; D015774:Ganciclovir; D020123:Sirolimus