title: Phase IB study of gene-mediated cytotoxic immunotherapy adjuvant to up-front surgery and intensive timing radiation for malignant glioma.
abstract: OBJECTIVE
  Despite aggressive therapies, median survival for malignant gliomas is less than 15 months. Patients with unmethylated O(6)-methylguanine-DNA methyltransferase (MGMT) fare worse, presumably because of temozolomide resistance. AdV-tk, an adenoviral vector containing the herpes simplex virus thymidine kinase gene, plus prodrug synergizes with surgery and chemoradiotherapy, kills tumor cells, has not shown MGMT dependency, and elicits an antitumor vaccine effect.
  
  
  METHODS
  Patients with newly diagnosed malignant glioma received AdV-tk at 3 × 10(10), 1 × 10(11), or 3 × 10(11) vector particles (vp) via tumor bed injection at time of surgery followed by 14 days of valacyclovir. Radiation was initiated within 9 days after AdV-tk injection to overlap with AdV-tk activity. Temozolomide was administered after completing valacyclovir treatment.
  
  
  RESULTS
  Accrual began December 2005 and was completed in 13 months. Thirteen patients were enrolled and 12 completed therapy, three at dose levels 1 and 2 and six at dose level 3. There were no dose-limiting or significant added toxicities. One patient withdrew before completing prodrug because of an unrelated surgical complication. Survival at 2 years was 33% and at 3 years was 25%. Patient-reported quality of life assessed with the Functional Assessment of Cancer Therapy-Brain (FACT-Br) was stable or improved after treatment. A significant CD3(+) T-cell infiltrate was found in four of four tumors analyzed after treatment. Three patients with MGMT unmethylated glioblastoma multiforme survived 6.5, 8.7, and 46.4 months.
  
  
  CONCLUSIONS
  AdV-tk plus valacyclovir can be safely delivered with surgery and accelerated radiation in newly diagnosed malignant gliomas. Temozolomide did not prevent immune responses. Although not powered for efficacy, the survival and MGMT independence trends are encouraging. A phase II trial is ongoing.
authors.affiliation: James Cancer Hospital/Ohio State University Medical Center, N-1017 Doan Hall, 410 W. 10th Ave, Columbus, OH 43210, USA. ea.chiocca@osumc.edu
authors.forename: E Antonio
authors.initials: EA
authors.lastname: Chiocca
authors.forename: Laura K
authors.initials: LK
authors.lastname: Aguilar
authors.forename: Susan D
authors.initials: SD
authors.lastname: Bell
authors.forename: Balveen
authors.initials: B
authors.lastname: Kaur
authors.forename: Jayson
authors.initials: J
authors.lastname: Hardcastle
authors.forename: Robert
authors.initials: R
authors.lastname: Cavaliere
authors.forename: John
authors.initials: J
authors.lastname: McGregor
authors.forename: Simon
authors.initials: S
authors.lastname: Lo
authors.forename: Abhik
authors.initials: A
authors.lastname: Ray-Chaudhuri
authors.forename: Arnab
authors.initials: A
authors.lastname: Chakravarti
authors.forename: John
authors.initials: J
authors.lastname: Grecula
authors.forename: Herbert
authors.initials: H
authors.lastname: Newton
authors.forename: Kimbra S
authors.initials: KS
authors.lastname: Harris
authors.forename: Robert G
authors.initials: RG
authors.lastname: Grossman
authors.forename: Todd W
authors.initials: TW
authors.lastname: Trask
authors.forename: David S
authors.initials: DS
authors.lastname: Baskin
authors.forename: Carissa
authors.initials: C
authors.lastname: Monterroso
authors.forename: Andrea G
authors.initials: AG
authors.lastname: Manzanera
authors.forename: Estuardo
authors.initials: E
authors.lastname: Aguilar-Cordova
authors.forename: Pamela Z
authors.initials: PZ
authors.lastname: New
mesh_terms: D000212:Acyclovir / Q000008:administration & dosage / Q000031:analogs & derivatives; D000256:Adenoviridae / Q000235:genetics*; D000276:Adjuvants, Immunologic; D000328:Adult; D000368:Aged; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage; D000998:Antiviral Agents / Q000008:administration & dosage; D001932:Brain Neoplasms / Q000401:mortality / Q000628:therapy*; D019496:Cancer Vaccines / Q000627:therapeutic use*; D003131:Combined Modality Therapy; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives; D015316:Genetic Therapy; D005822:Genetic Vectors; D005910:Glioma / Q000401:mortality / Q000628:therapy*; D018259:Herpesvirus 1, Human / Q000201:enzymology; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D008875:Middle Aged; D019853:O(6)-Methylguanine-DNA Methyltransferase; D000077204:Temozolomide; D013937:Thymidine Kinase / Q000235:genetics*; D016896:Treatment Outcome; D000077483:Valacyclovir; D014633:Valine / Q000008:administration & dosage / Q000031:analogs & derivatives
chemical_list: D000276:Adjuvants, Immunologic; D018906:Antineoplastic Agents, Alkylating; D000998:Antiviral Agents; D019496:Cancer Vaccines; D003606:Dacarbazine; D019853:O(6)-Methylguanine-DNA Methyltransferase; D013937:Thymidine Kinase; D014633:Valine; D000077483:Valacyclovir; D000212:Acyclovir; D000077204:Temozolomide