title: Safety profile, efficacy, and biodistribution of a bicistronic high-capacity adenovirus vector encoding a combined immunostimulation and cytotoxic gene therapy as a prelude to a phase I clinical trial for glioblastoma.
abstract: Adenoviral vectors (Ads) are promising gene delivery vehicles due to their high transduction efficiency; however, their clinical usefulness has been hampered by their immunogenicity and the presence of anti-Ad immunity in humans. We reported the efficacy of a gene therapy approach for glioma consisting of intratumoral injection of Ads encoding conditionally cytotoxic herpes simplex type 1 thymidine kinase (Ad-TK) and the immunostimulatory cytokine fms-like tyrosine kinase ligand 3 (Ad-Flt3L). Herein, we report the biodistribution, efficacy, and neurological and systemic effects of a bicistronic high-capacity Ad, i.e., HC-Ad-TK/TetOn-Flt3L. HC-Ads elicit sustained transgene expression, even in the presence of anti-Ad immunity, and can encode large therapeutic cassettes, including regulatory elements to enable turning gene expression "on" or "off" according to clinical need. The inclusion of two therapeutic transgenes within a single vector enables a reduction of the total vector load without adversely impacting efficacy. Because clinically the vectors will be delivered into the surgical cavity, normal regions of the brain parenchyma are likely to be transduced. Thus, we assessed any potential toxicities elicited by escalating doses of HC-Ad-TK/TetOn-Flt3L (1×10(8), 1×10(9), or 1×10(10) viral particles [vp]) delivered into the rat brain parenchyma. We assessed neuropathology, biodistribution, transgene expression, systemic toxicity, and behavioral impact at acute and chronic time points. The results indicate that doses up to 1×10(9) vp of HC-Ad-TK/TetOn-Flt3L can be safely delivered into the normal rat brain and underpin further developments for its implementation in a phase I clinical trial for glioma.
authors: Department of Neurosurgery, The University of Michigan School of Medicine, MSRB II, RM 4570C, 1150 West Medical Center Drive, Ann Arbor, MI 48109-5689, USA.
authors: Mariana
authors: M
authors: Puntel
authors: Ghulam Muhammad
authors: GM
authors: A K M
authors: Catherine
authors: C
authors: Farrokhi
authors: Nathan
authors: N
authors: Vanderveen
authors: Christopher
authors: C
authors: Paran
authors: Ashley
authors: A
authors: Appelhans
authors: Kurt M
authors: KM
authors: Kroeger
authors: Alireza
authors: A
authors: Salem
authors: Liliana
authors: L
authors: Lacayo
authors: Robert N
authors: RN
authors: Pechnick
authors: Kyle R
authors: KR
authors: Kelson
authors: Sukhpreet
authors: S
authors: Kaur
authors: Sean
authors: S
authors: Kennedy
authors: Donna
authors: D
authors: Palmer
authors: Philip
authors: P
authors: Ng
authors: Chunyan
authors: C
authors: Liu
authors: Johnny
authors: J
authors: Krasinkiewicz
authors: Pedro R
authors: PR
authors: Lowenstein
authors: Maria G
authors: MG
authors: Castro
mesh_terms: D000256:Adenoviridae / Q000378:metabolism; D000818:Animals; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D017321:Clinical Trials, Phase I as Topic / Q000379:methods*; D003603:Cytotoxins / Q000008:administration & dosage* / Q000009:adverse effects / Q000378:metabolism; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004359:Drug Therapy, Combination; D015316:Genetic Therapy / Q000009:adverse effects / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage* / Q000009:adverse effects / Q000378:metabolism; D005909:Glioblastoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007114:Immunization / Q000379:methods*; D008297:Male; D051381:Rats; D011917:Rats, Inbred Lew; D014018:Tissue Distribution / Q000187:drug effects / Q000502:physiology; D016896:Treatment Outcome
chemical_list: D003603:Cytotoxins
references: Oncologist. 2006 Feb;11(2):165-80
references: 16476837
references: PLoS Med. 2009 Jan 13;6(1):e10
references: 19143470
references: Int J Mol Med. 2010 Jan;25(1):3-10
references: 19956895
references: Blood. 2003 Oct 1;102(7):2403-11
references: 12805062
references: Clin Cancer Res. 2009 Jul 1;15(13):4401-14
references: 19570774
references: Proc Natl Acad Sci U S A. 2000 Jun 20;97(13):7482-7
references: 10840055
references: Circulation. 2001 Mar 6;103(9):1274-81
references: 11238273
references: Clin Cancer Res. 2010 Aug 1;16(15):4005-15
references: 20670951
references: J Virol. 2000 May;74(10):4816-23
references: 10775620
references: J Virol. 1999 Aug;73(8):6729-42
references: 10400771
references: Mol Cancer Ther. 2008 Mar;7(3):439-48
references: 18347132
references: J Clin Oncol. 2011 Sep 20;29(27):3611-9
references: 21844505
references: Neuro Oncol. 2008 Feb;10(1):19-31
references: 18079358
references: Clin Cancer Res. 2009 Oct 1;15(19):6113-27
references: 19789315
references: J Clin Oncol. 2009 Dec 1;27(34):5763-71
references: 19884534
references: J Gene Med. 2007 Oct;9(10):833-42
references: 17721874
references: Neoplasia. 2012 Aug;14(8):757-70
references: 22952428
references: Curr Protoc Neurosci. 2008 Oct;Chapter 4:Unit 4.23
references: 18972378
references: Regul Toxicol Pharmacol. 1990 Oct;12(2):107-16
references: 2259752
references: Neurosci Lett. 2012 Oct 11;527(2):71-7
references: 22906921
references: Mol Ther. 2008 Apr;16(4):682-90
references: 18283279
references: Hum Gene Ther. 2001 May 1;12(7):839-46
references: 11339900
references: Proc Natl Acad Sci U S A. 2010 Mar 9;107(10):4716-21
references: 20133734
references: Mol Ther. 2008 Feb;16(2):343-51
references: 18180781
references: Curr Gene Ther. 2009 Oct;9(5):356-67
references: 19860650
references: Acta Neuropathol. 2007 Aug;114(2):97-109
references: 17618441
references: Neoplasia. 2011 Oct;13(10):947-60
references: 22028620
references: Mol Ther. 2002 Jan;5(1):63-73
references: 11786047
references: J Virol. 2006 Jan;80(1):27-37
references: 16352528
references: Methods Mol Biol. 2008;433:33-53
references: 18679616
references: Proc Natl Acad Sci U S A. 1996 Nov 26;93(24):13565-70
references: 8942974
references: Nat Med. 2003 May;9(5):596-603
references: 12704384
references: Curr Gene Ther. 2006 Apr;6(2):215-26
references: 16611043
references: Int J Oncol. 2001 Nov;19(5):1041-7
references: 11605007
references: Gene. 2004 Mar 3;327(2):153-60
references: 14980712
references: Mol Ther. 2011 Oct;19(10):1793-801
references: 21505426
references: Am J Epidemiol. 1983 Apr;117(4):455-66
references: 6301263
references: Mol Ther. 2005 Aug;12(2):189-211
references: 15946903
references: Curr Protoc Neurosci. 2010 Jan;Chapter 4:Unit 4.24
references: 20066657
references: Curr Gene Ther. 2011 Jun;11(3):155-80
references: 21453286
references: Curr Top Med Chem. 2005;5(12):1151-70
references: 16248789
references: Proc Natl Acad Sci U S A. 2005 Sep 27;102(39):13789-94
references: 16162668
references: J Gene Med. 2007 Oct;9(10):862-74
references: 17685494
references: Circulation. 2003 Jun 3;107(21):2726-32
references: 12742997
references: Cancer Res. 2005 Aug 15;65(16):7194-204
references: 16103070
references: J Virol. 2004 Sep;78(18):10111-21
references: 15331744
references: Int J Radiat Oncol Biol Phys. 2004 Apr 1;58(5):1520-9
references: 15050332
references: J Immunol. 2006 Mar 15;176(6):3566-77
references: 16517725
references: N Engl J Med. 2008 Jul 31;359(5):492-507
references: 18669428
references: Mol Ther. 2004 Sep;10(3):492-9
references: 15336649
references: J Cell Biochem. 2011 Aug;112(8):1969-77
references: 21465529
references: Mol Ther. 2004 Dec;10(6):1071-84
references: 15564139
references: Neurotherapeutics. 2012 Oct;9(4):827-43
references: 22996231
references: Cancer Immunol Immunother. 2009 Feb;58(2):259-70
references: 18594817
references: Cold Spring Harb Protoc. 2011 Jul 01;2011(7):857-66
references: 21724821
references: Clin Diagn Lab Immunol. 2004 Mar;11(2):351-7
references: 15013987
references: Curr Gene Ther. 2009 Oct;9(5):409-21
references: 19860655
references: Hum Gene Ther. 2006 May;17(5):531-44
references: 16716110
references: Discov Med. 2010 Oct;10(53):293-304
references: 21034670
references: Clin Pharmacol Ther. 2010 Aug;88(2):204-13
references: 20164833
references: Proc Natl Acad Sci U S A. 1998 Jul 7;95(14):7866-71
references: 9653106
references: Vaccine. 2010 Apr 26;28(19):3371-8
references: 20197146
references: J Neurooncol. 2007 Nov;85(2):133-48
references: 17874037
references: Antimicrob Agents Chemother. 2012 Jan;56(1):70-4
references: 22024822
references: J Virol. 2010 Jun;84(12):6007-17
references: 20375153
references: J Virol. 2008 May;82(9):4680-4
references: 18287240
references: PLoS One. 2008 Apr 23;3(4):e1983
references: 18431473
references: Gene Ther. 2004 Oct;11 Suppl 1:S98-S108
references: 15454964
references: N Engl J Med. 2005 Mar 10;352(10):987-96
references: 15758009
references: Clin Cancer Res. 2010 Apr 15;16(8):2443-9
references: 20371685
references: Mol Ther. 2007 Dec;15(12):2154-63
references: 17895861
references: Ann Oncol. 2008 Sep;19 Suppl 7:vii209-16
references: 18790951
references: J Clin Invest. 2009 Jul;119(7):2100-112
references: 19603551
references: Cancer Cell. 2011 Jan 18;19(1):72-85
references: 21251614
references: Methods Mol Biol. 2008;434:239-66
references: 18470649