title: Phase II multicenter study of gene-mediated cytotoxic immunotherapy as adjuvant to surgical resection for newly diagnosed malignant glioma.
abstract: Despite aggressive standard of care (SOC) treatment, survival of malignant gliomas remains very poor. This Phase II, prospective, matched controlled, multicenter trial was conducted to assess the safety and efficacy of aglatimagene besadenovec (AdV-tk) plus valacyclovir (gene-mediated cytotoxic immunotherapy [GMCI]) in combination with SOC for newly diagnosed malignant glioma patients.
  
  
  
  Treatment cohort patients received SOC + GMCI and were enrolled at 4 institutions from 2006 to 2010. The preplanned, matched-control cohort included all concurrent patients meeting protocol criteria and SOC at a fifth institution. AdV-tk was administered at surgery followed by SOC radiation and temozolomide. Subset analyses were preplanned, based on prognostic factors: pathological diagnosis (glioblastoma vs others) and extent of resection.
  
  
  
  Forty-eight patients completed SOC + GMCI, and 134 met control cohort criteria. Median overall survival (OS) was 17.1 months for GMCI + SOC versus 13.5 months for SOC alone (P = .0417). Survival at 1, 2, and 3 years was 67%, 35%, and 19% versus 57%, 22%, and 8%, respectively. The greatest benefit was observed in gross total resection patients: median OS of 25 versus 16.9 months (P = .0492); 1, 2, and 3-year survival of 90%, 53%, and 32% versus 64%, 28% and 6%, respectively. There were no dose-limiting toxicities; fever, fatigue, and headache were the most common GMCI-related symptoms.
  
  
  
  GMCI can be safely combined with SOC in newly diagnosed malignant gliomas. Survival outcomes were most notably improved in patients with minimal residual disease after gross total resection. These data should help guide future immunotherapy studies and strongly support further evaluation of GMCI for malignant gliomas.
  
  
  
  ClinicalTrials.gov NCT00589875.
authors: Brigham and Women's Hospital/Harvard Medical School, Massachusetts (L.A.W., E.A.C.); Advantagene, Inc., Auburndale, Massachusetts (A.G.M., L.K.A., E.A.-C.); Ohio State University, Columbus, Ohio (S.D.B., R.C., J.M.M., J.C.G., H.B.N.); University Hospitals Seidman Cancer Center/ Case Western Reserve University, Cleveland, Ohio (S.S.L.); City of Hope, Duarte, California (B.B., J.B.); Houston Methodist Hospital, Houston, Texas (B.S.T., T.W.T., D.S.B., P.Z.N.).
authors: Lee A
authors: LA
authors: Wheeler
authors: Brigham and Women's Hospital/Harvard Medical School, Massachusetts (L.A.W., E.A.C.); Advantagene, Inc., Auburndale, Massachusetts (A.G.M., L.K.A., E.A.-C.); Ohio State University, Columbus, Ohio (S.D.B., R.C., J.M.M., J.C.G., H.B.N.); University Hospitals Seidman Cancer Center/ Case Western Reserve University, Cleveland, Ohio (S.S.L.); City of Hope, Duarte, California (B.B., J.B.); Houston Methodist Hospital, Houston, Texas (B.S.T., T.W.T., D.S.B., P.Z.N.).
authors: Andrea G
authors: AG
authors: Manzanera
authors: Brigham and Women's Hospital/Harvard Medical School, Massachusetts (L.A.W., E.A.C.); Advantagene, Inc., Auburndale, Massachusetts (A.G.M., L.K.A., E.A.-C.); Ohio State University, Columbus, Ohio (S.D.B., R.C., J.M.M., J.C.G., H.B.N.); University Hospitals Seidman Cancer Center/ Case Western Reserve University, Cleveland, Ohio (S.S.L.); City of Hope, Duarte, California (B.B., J.B.); Houston Methodist Hospital, Houston, Texas (B.S.T., T.W.T., D.S.B., P.Z.N.).
authors: Susan D
authors: SD
authors: Bell
authors: Brigham and Women's Hospital/Harvard Medical School, Massachusetts (L.A.W., E.A.C.); Advantagene, Inc., Auburndale, Massachusetts (A.G.M., L.K.A., E.A.-C.); Ohio State University, Columbus, Ohio (S.D.B., R.C., J.M.M., J.C.G., H.B.N.); University Hospitals Seidman Cancer Center/ Case Western Reserve University, Cleveland, Ohio (S.S.L.); City of Hope, Duarte, California (B.B., J.B.); Houston Methodist Hospital, Houston, Texas (B.S.T., T.W.T., D.S.B., P.Z.N.).
authors: Robert
authors: R
authors: Cavaliere
authors: Brigham and Women's Hospital/Harvard Medical School, Massachusetts (L.A.W., E.A.C.); Advantagene, Inc., Auburndale, Massachusetts (A.G.M., L.K.A., E.A.-C.); Ohio State University, Columbus, Ohio (S.D.B., R.C., J.M.M., J.C.G., H.B.N.); University Hospitals Seidman Cancer Center/ Case Western Reserve University, Cleveland, Ohio (S.S.L.); City of Hope, Duarte, California (B.B., J.B.); Houston Methodist Hospital, Houston, Texas (B.S.T., T.W.T., D.S.B., P.Z.N.).
authors: John M
authors: JM
authors: McGregor
authors: Brigham and Women's Hospital/Harvard Medical School, Massachusetts (L.A.W., E.A.C.); Advantagene, Inc., Auburndale, Massachusetts (A.G.M., L.K.A., E.A.-C.); Ohio State University, Columbus, Ohio (S.D.B., R.C., J.M.M., J.C.G., H.B.N.); University Hospitals Seidman Cancer Center/ Case Western Reserve University, Cleveland, Ohio (S.S.L.); City of Hope, Duarte, California (B.B., J.B.); Houston Methodist Hospital, Houston, Texas (B.S.T., T.W.T., D.S.B., P.Z.N.).
authors: John C
authors: JC
authors: Grecula
authors: Brigham and Women's Hospital/Harvard Medical School, Massachusetts (L.A.W., E.A.C.); Advantagene, Inc., Auburndale, Massachusetts (A.G.M., L.K.A., E.A.-C.); Ohio State University, Columbus, Ohio (S.D.B., R.C., J.M.M., J.C.G., H.B.N.); University Hospitals Seidman Cancer Center/ Case Western Reserve University, Cleveland, Ohio (S.S.L.); City of Hope, Duarte, California (B.B., J.B.); Houston Methodist Hospital, Houston, Texas (B.S.T., T.W.T., D.S.B., P.Z.N.).
authors: Herbert B
authors: HB
authors: Newton
authors: Brigham and Women's Hospital/Harvard Medical School, Massachusetts (L.A.W., E.A.C.); Advantagene, Inc., Auburndale, Massachusetts (A.G.M., L.K.A., E.A.-C.); Ohio State University, Columbus, Ohio (S.D.B., R.C., J.M.M., J.C.G., H.B.N.); University Hospitals Seidman Cancer Center/ Case Western Reserve University, Cleveland, Ohio (S.S.L.); City of Hope, Duarte, California (B.B., J.B.); Houston Methodist Hospital, Houston, Texas (B.S.T., T.W.T., D.S.B., P.Z.N.).
authors: Simon S
authors: SS
authors: Lo
authors: Brigham and Women's Hospital/Harvard Medical School, Massachusetts (L.A.W., E.A.C.); Advantagene, Inc., Auburndale, Massachusetts (A.G.M., L.K.A., E.A.-C.); Ohio State University, Columbus, Ohio (S.D.B., R.C., J.M.M., J.C.G., H.B.N.); University Hospitals Seidman Cancer Center/ Case Western Reserve University, Cleveland, Ohio (S.S.L.); City of Hope, Duarte, California (B.B., J.B.); Houston Methodist Hospital, Houston, Texas (B.S.T., T.W.T., D.S.B., P.Z.N.).
authors: Behnam
authors: B
authors: Badie
authors: Brigham and Women's Hospital/Harvard Medical School, Massachusetts (L.A.W., E.A.C.); Advantagene, Inc., Auburndale, Massachusetts (A.G.M., L.K.A., E.A.-C.); Ohio State University, Columbus, Ohio (S.D.B., R.C., J.M.M., J.C.G., H.B.N.); University Hospitals Seidman Cancer Center/ Case Western Reserve University, Cleveland, Ohio (S.S.L.); City of Hope, Duarte, California (B.B., J.B.); Houston Methodist Hospital, Houston, Texas (B.S.T., T.W.T., D.S.B., P.Z.N.).
authors: Jana
authors: J
authors: Portnow
authors: Brigham and Women's Hospital/Harvard Medical School, Massachusetts (L.A.W., E.A.C.); Advantagene, Inc., Auburndale, Massachusetts (A.G.M., L.K.A., E.A.-C.); Ohio State University, Columbus, Ohio (S.D.B., R.C., J.M.M., J.C.G., H.B.N.); University Hospitals Seidman Cancer Center/ Case Western Reserve University, Cleveland, Ohio (S.S.L.); City of Hope, Duarte, California (B.B., J.B.); Houston Methodist Hospital, Houston, Texas (B.S.T., T.W.T., D.S.B., P.Z.N.).
authors: Bin S
authors: BS
authors: Teh
authors: Brigham and Women's Hospital/Harvard Medical School, Massachusetts (L.A.W., E.A.C.); Advantagene, Inc., Auburndale, Massachusetts (A.G.M., L.K.A., E.A.-C.); Ohio State University, Columbus, Ohio (S.D.B., R.C., J.M.M., J.C.G., H.B.N.); University Hospitals Seidman Cancer Center/ Case Western Reserve University, Cleveland, Ohio (S.S.L.); City of Hope, Duarte, California (B.B., J.B.); Houston Methodist Hospital, Houston, Texas (B.S.T., T.W.T., D.S.B., P.Z.N.).
authors: Todd W
authors: TW
authors: Trask
authors: Brigham and Women's Hospital/Harvard Medical School, Massachusetts (L.A.W., E.A.C.); Advantagene, Inc., Auburndale, Massachusetts (A.G.M., L.K.A., E.A.-C.); Ohio State University, Columbus, Ohio (S.D.B., R.C., J.M.M., J.C.G., H.B.N.); University Hospitals Seidman Cancer Center/ Case Western Reserve University, Cleveland, Ohio (S.S.L.); City of Hope, Duarte, California (B.B., J.B.); Houston Methodist Hospital, Houston, Texas (B.S.T., T.W.T., D.S.B., P.Z.N.).
authors: David S
authors: DS
authors: Baskin
authors: Brigham and Women's Hospital/Harvard Medical School, Massachusetts (L.A.W., E.A.C.); Advantagene, Inc., Auburndale, Massachusetts (A.G.M., L.K.A., E.A.-C.); Ohio State University, Columbus, Ohio (S.D.B., R.C., J.M.M., J.C.G., H.B.N.); University Hospitals Seidman Cancer Center/ Case Western Reserve University, Cleveland, Ohio (S.S.L.); City of Hope, Duarte, California (B.B., J.B.); Houston Methodist Hospital, Houston, Texas (B.S.T., T.W.T., D.S.B., P.Z.N.).
authors: Pamela Z
authors: PZ
authors: New
authors: Brigham and Women's Hospital/Harvard Medical School, Massachusetts (L.A.W., E.A.C.); Advantagene, Inc., Auburndale, Massachusetts (A.G.M., L.K.A., E.A.-C.); Ohio State University, Columbus, Ohio (S.D.B., R.C., J.M.M., J.C.G., H.B.N.); University Hospitals Seidman Cancer Center/ Case Western Reserve University, Cleveland, Ohio (S.S.L.); City of Hope, Duarte, California (B.B., J.B.); Houston Methodist Hospital, Houston, Texas (B.S.T., T.W.T., D.S.B., P.Z.N.).
authors: Laura K
authors: LK
authors: Aguilar
authors: Brigham and Women's Hospital/Harvard Medical School, Massachusetts (L.A.W., E.A.C.); Advantagene, Inc., Auburndale, Massachusetts (A.G.M., L.K.A., E.A.-C.); Ohio State University, Columbus, Ohio (S.D.B., R.C., J.M.M., J.C.G., H.B.N.); University Hospitals Seidman Cancer Center/ Case Western Reserve University, Cleveland, Ohio (S.S.L.); City of Hope, Duarte, California (B.B., J.B.); Houston Methodist Hospital, Houston, Texas (B.S.T., T.W.T., D.S.B., P.Z.N.).
authors: Estuardo
authors: E
authors: Aguilar-Cordova
authors: Brigham and Women's Hospital/Harvard Medical School, Massachusetts (L.A.W., E.A.C.); Advantagene, Inc., Auburndale, Massachusetts (A.G.M., L.K.A., E.A.-C.); Ohio State University, Columbus, Ohio (S.D.B., R.C., J.M.M., J.C.G., H.B.N.); University Hospitals Seidman Cancer Center/ Case Western Reserve University, Cleveland, Ohio (S.S.L.); City of Hope, Duarte, California (B.B., J.B.); Houston Methodist Hospital, Houston, Texas (B.S.T., T.W.T., D.S.B., P.Z.N.).
authors: E Antonio
authors: EA
authors: Chiocca
mesh_terms: D000212:Acyclovir / Q000009:adverse effects / Q000031:analogs & derivatives / Q000627:therapeutic use; D000256:Adenoviridae; D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000009:adverse effects / Q000627:therapeutic use; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000601:surgery; D017024:Chemotherapy, Adjuvant / Q000009:adverse effects / Q000379:methods; D015316:Genetic Therapy / Q000009:adverse effects* / Q000379:methods*; D005822:Genetic Vectors / Q000627:therapeutic use; D005910:Glioma / Q000188:drug therapy* / Q000601:surgery; D006801:Humans; D007167:Immunotherapy / Q000009:adverse effects* / Q000379:methods*; D008875:Middle Aged; D018139:Simplexvirus / Q000235:genetics; D016019:Survival Analysis; D013937:Thymidine Kinase / Q000235:genetics; D016896:Treatment Outcome; D000077483:Valacyclovir; D014633:Valine / Q000009:adverse effects / Q000031:analogs & derivatives / Q000627:therapeutic use
chemical_list: D000998:Antiviral Agents; D013937:Thymidine Kinase; D014633:Valine; D000077483:Valacyclovir; D000212:Acyclovir
keywords: gene therapy; glioblastoma; immuno-oncology; immunotherapy; malignant glioma