title: Temozolomide does not impair gene therapy-mediated antitumor immunity in syngeneic brain tumor models.
abstract: OBJECTIVE
  Glioblastoma multiforme is the most common primary brain cancer in adults. Chemotherapy with temozolomide (TMZ) significantly prolongs the survival of patients with glioblastoma multiforme. However, the three-year survival is still approximately 5%. Herein, we combined intratumoral administration of an adenoviral vector expressing Flt3L (Ad-Flt3L) with systemic temozolomide to assess its impact on therapeutic efficacy.
  
  
  METHODS
  Wild-type or immunodeficient mice bearing intracranial glioblastoma multiforme or metastatic melanoma were treated with an intratumoral injection of Ad-Flt3L alone or in combination with the conditionally cytotoxic enzyme thymidine kinase (Ad-TK), followed by systemic administration of ganciclovir and temozolomide. We monitored survival and measured the tumor-infiltrating immune cells.
  
  
  RESULTS
  Although treatment with temozolomide alone led to a small improvement in median survival, when used in combination with gene therapy-mediated immunotherapy, it significantly increased the survival of tumor-bearing mice. The antitumor effect was further enhanced by concomitant intratumoral administration of Ad-TK, leading to 50% to 70% long-term survival in all tumor models. Although temozolomide reduced the content of T cells in the tumor, this did not affect the therapeutic efficacy. The antitumor effect of Ad-Flt3L+Ad-TK+TMZ required an intact immune system because the treatment failed when administered to knock out mice that lacked lymphocytes or dendritic cells.
  
  
  CONCLUSIONS
  Our results challenge the notion that chemotherapy leads to a state of immune-suppression which impairs the ability of the immune system to mount an effective antitumor response. Our work indicates that temozolomide does not inhibit antitumor immunity and supports its clinical implementation in combination with immune-mediated therapies.
authors: Department of Neurosurgery, The University of Michigan, School of Medicine, 1150 West Medical Center Drive, MSRB II, Rm: 4570, Ann Arbor, MI 48109-0650.|Department of Cell and Developmental Biology, The University of Michigan, School of Medicine, Ann Arbor, MI.
authors: Marianela
authors: M
authors: Candolfi
authors: Department of Neurosurgery, The University of Michigan, School of Medicine, 1150 West Medical Center Drive, MSRB II, Rm: 4570, Ann Arbor, MI 48109-0650.|Department of Cell and Developmental Biology, The University of Michigan, School of Medicine, Ann Arbor, MI.
authors: Kader
authors: K
authors: Yagiz
authors: Department of Neurosurgery, The University of Michigan, School of Medicine, 1150 West Medical Center Drive, MSRB II, Rm: 4570, Ann Arbor, MI 48109-0650.|Department of Cell and Developmental Biology, The University of Michigan, School of Medicine, Ann Arbor, MI.
authors: Mia
authors: M
authors: Wibowo
authors: Department of Neurosurgery, The University of Michigan, School of Medicine, 1150 West Medical Center Drive, MSRB II, Rm: 4570, Ann Arbor, MI 48109-0650.|Department of Cell and Developmental Biology, The University of Michigan, School of Medicine, Ann Arbor, MI.
authors: Gabrielle E
authors: GE
authors: Ahlzadeh
authors: Department of Neurosurgery, The University of Michigan, School of Medicine, 1150 West Medical Center Drive, MSRB II, Rm: 4570, Ann Arbor, MI 48109-0650.|Department of Cell and Developmental Biology, The University of Michigan, School of Medicine, Ann Arbor, MI.
authors: Mariana
authors: M
authors: Puntel
authors: Viral Immunology and Vaccine Development Center, Cedars-Sinai Medical Center, Los Angeles, CA.
authors: Homayon
authors: H
authors: Ghiasi
authors: Department of Neurosurgery, The University of Michigan, School of Medicine, 1150 West Medical Center Drive, MSRB II, Rm: 4570, Ann Arbor, MI 48109-0650.|Department of Cell and Developmental Biology, The University of Michigan, School of Medicine, Ann Arbor, MI.
authors: Neha
authors: N
authors: Kamran
authors: Department of Neurosurgery, The University of Michigan, School of Medicine, 1150 West Medical Center Drive, MSRB II, Rm: 4570, Ann Arbor, MI 48109-0650.|Department of Cell and Developmental Biology, The University of Michigan, School of Medicine, Ann Arbor, MI.
authors: Christopher
authors: C
authors: Paran
authors: Department of Neurosurgery, The University of Michigan, School of Medicine, 1150 West Medical Center Drive, MSRB II, Rm: 4570, Ann Arbor, MI 48109-0650.|Department of Cell and Developmental Biology, The University of Michigan, School of Medicine, Ann Arbor, MI.
authors: Pedro R
authors: PR
authors: Lowenstein
authors: Department of Neurosurgery, The University of Michigan, School of Medicine, 1150 West Medical Center Drive, MSRB II, Rm: 4570, Ann Arbor, MI 48109-0650.|Department of Cell and Developmental Biology, The University of Michigan, School of Medicine, Ann Arbor, MI.
authors: Maria G
authors: MG
authors: Castro
mesh_terms: D000256:Adenoviridae; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000473:pathology*; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004195:Disease Models, Animal; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors; D005909:Glioblastoma / Q000473:pathology*; D007167:Immunotherapy / Q000379:methods*; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000077204:Temozolomide; D013937:Thymidine Kinase / Q000235:genetics / Q000276:immunology
chemical_list: D000970:Antineoplastic Agents; D008565:Membrane Proteins; C084881:flt3 ligand protein; D003606:Dacarbazine; D013937:Thymidine Kinase; D000077204:Temozolomide