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Journal of Neuro-Oncology = Publisher: Springer=20 Netherlands ISSN: 0167-594X=20 (Paper) 1573-7373 (Online) DOI: 10.1007/s11060-005-9058-0=20 Issue: =20 Volume 78, Number 1
Date: =20 May 2006 Pages: 71=20 - 80

Technical = hurdles in a=20 pilot clinical trial of combined B7-2 and GM-CSF = immunogene=20 therapy for glioblastomas and melanomas

Ian F. Parney^{1, =
6}, = Lung-Ji Chang²,=20 Maxine A. Farr-Jones³,=20 Chunhai Hao⁴, = Michael Smylie⁵=20 and Kenneth C. Petruk³

(1) Department of = Clinical=20 Neurosciences, Southern Alberta Cancer Research=20 Institute, and Hotchkiss Brain Institute, = University of=20 Calgary, Calgary, Alberta,=20 Canada

(2) Department of = Molecular=20 Genetics and Microbiology, Powell Gene Therapy = Center,=20 and McKnight Brain Institute, University of = Florida,=20 Gainesville, FL, = USA

(3) Division of = Neurosurgery,=20 Department of Surgery, University of Alberta, = Edmonton,=20 Canada

(4) Department of = Pathology,=20 Emory University, Atlanta, GA,=20 USA

(5) Department of = Oncology,=20 University of Alberta, Edmonton,=20 Canada

(6) Division of = Neurosurgery,=20 Department of Clinical Neurosciences, Foothills = Medical=20 Centre, 1403 =E2=80=93 29th Street NW, T2N = 2T9 Calgary,=20 Alberta, Canada

Received:=20 = 9 February 2005  Accepted:=20 = 12 October 2005  Published=20 online: 21 April 2006

Summary

Objective  Malignant = glioblastomas and melanomas continue to have a dismal=20 prognosis despite advances in conventional therapy. = This has=20 led to investigations of novel treatment strategies = including=20 immunogene therapy. We report a pilot clinical trial = of=20 combined B7-2 and GM-CSF immunogene therapy for = gliomas and=20 melanomas and discuss technical hurdles=20 encountered.

Methods  Patients = with=20 recurrent malignant gliomas or medically refractory = melanomas=20 were vaccinated with irradiated autologous tumor cells = transduced with B7-2 and GM-CSF genes using a = retroviral=20 vector. Patients were monitored for toxicity,=20 inflammatory/immune reactions, and clinical=20 status.

Results  Vaccine = preparation=20 was attempted from 116 malignant glioma and 32 = melanoma=20 specimens. Adequate vaccines could only be prepared = for five=20 glioblastoma and three melanoma patients. Six patients = (three=20 recurrent glioblastomas and three melanomas) were = actually=20 vaccinated. Minor toxicities included flu-like = symptoms (3/6),=20 injection site erythema (4/6), and asymptomatic = elevations in=20 liver enzymes (3/6). Most patients showed evidence of = an=20 inflammatory response but specific anti-tumor immunity = was not=20 demonstrated. All six patients have died, although = three=20 patients with minimal residual disease at treatment = had=20 prolonged recurrence-free intervals after=20 vaccination.

Conclusions  Combined B7-2 and=20 GM-CSF immunogene therapy for glioblastomas and = melanomas=20 using autologous tumor cells has many technical = pitfalls=20 hindering large scale application and evaluation. As a = result,=20 this pilot study was too limited to draw meaningful=20 conclusions regarding safety or anti-tumor immunity. = While=20 immunotherapy has been promising in pre-clinical = studies,=20 alternate strategies will be required to bring these = benefits=20 to patients.

Keywords  costimulation -&nb= sp;cytokine - gene=20 = therapy - glioblastoma - immunotherapy - me= lanoma

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3D"Contact Ian F. Parney
Email:=20 ian.parney@calgaryhealt= hregion.ca

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BORDER-LEFT-WIDTH: 1px; FONT-SIZE: 13px; BORDER-LEFT-COLOR: #000000; = BACKGROUND: #d3cfcf; BORDER-BOTTOM-WIDTH: 1px; BORDER-BOTTOM-COLOR: = #000000; PADDING-BOTTOM: 1px; COLOR: #ffffff; BORDER-TOP-COLOR: #000000; = PADDING-TOP: 1px; FONT-FAMILY: Arial, Helvetica, sans-serif; HEIGHT: = 22px; TEXT-ALIGN: left; BORDER-RIGHT-WIDTH: 1px; TEXT-DECORATION: none; = BORDER-RIGHT-COLOR: #000000 } .ButtonDialogHover { BACKGROUND: #4573a5 } .ButtonAnchor { BORDER-RIGHT: #000000 1px solid; BORDER-TOP: #000000 1px solid; = PADDING-LEFT: 6px; FONT-WEIGHT: normal; FONT-SIZE: 11px; BACKGROUND: = #959595; PADDING-BOTTOM: 3px; BORDER-LEFT: #000000 1px solid; COLOR: = #ffffff; PADDING-TOP: 2px; BORDER-BOTTOM: #000000 1px solid; = FONT-FAMILY: Trebuchet MS, Verdana, Tahoma, Arial, Helvetica, = sans-serif; HEIGHT: 22px; TEXT-ALIGN: left; TEXT-DECORATION: none } .ButtonAnchor:hover { BACKGROUND: #4573a5; COLOR: #ffffff; HEIGHT: 22px; TEXT-DECORATION: = none } .ButtonAnchor:visited { COLOR: #ffffff; HEIGHT: 22px; TEXT-DECORATION: none } .ContainerBodyText { FONT-WEIGHT: normal; FONT-SIZE: 12px } DIV.ContainerBodyText { FONT-WEIGHT: normal; FONT-SIZE: 12px } .ContainerBodyBoldText { FONT-WEIGHT: bold; FONT-SIZE: 12px; COLOR: #000000 } .ContainerBodyMarginText { FONT-WEIGHT: normal; FONT-SIZE: 12px; MARGIN-LEFT: 20px } A { FONT: 8.5pt Arial, Helvetica, sans-serif; COLOR: #003399; = TEXT-DECORATION: none } A:hover { COLOR: #ff6600; TEXT-DECORATION: underline } A:link { =09 } A:visited { COLOR: #6699cc } A.Bold { FONT: bold 12px Arial, Helvetica, sans-serif; COLOR: #003399; = TEXT-DECORATION: none } A.ContainerBodyText { FONT: bold 12px Arial, Helvetica, sans-serif; COLOR: #003399; = TEXT-DECORATION: none } A:hover { COLOR: #ff6600; TEXT-DECORATION: underline } A.ListItem { FONT: bold 12px Arial, Helvetica, sans-serif; COLOR: #003399; = TEXT-DECORATION: none } A.ListItem:hover { TEXT-DECORATION: underline } A.LeftMenuHeader { PADDING-LEFT: 4px; FONT-WEIGHT: bold; FONT-SIZE: 13px; WIDTH: 116px; = COLOR: #003399; FONT-FAMILY: Arial, Helvetica, sans-serif; = TEXT-DECORATION: none } A.LeftMenuHeader:hover { COLOR: #ff6600; TEXT-DECORATION: none } A.LeftMenu { PADDING-LEFT: 12px; FONT-WEIGHT: normal; FONT-SIZE: 13px; WIDTH: 116px; = COLOR: #003399; FONT-FAMILY: Arial, Helvetica, sans-serif; = TEXT-DECORATION: none } A.LeftMenu:hover { COLOR: #ff6600; TEXT-DECORATION: none } A.Menu { FONT: bold 12px Arial, Helvetica, sans-serif; COLOR: #003399; = TEXT-DECORATION: none } A.Menu:hover { COLOR: #ff6600; TEXT-DECORATION: underline } A.Popup { FONT-WEIGHT: bold; WIDTH: 110px; TEXT-DECORATION: none } A.Flat { COLOR: #333333 } A.Treeview { FONT: 12px Arial, Helvetica, sans-serif; TEXT-DECORATION: none } A.Footer { FONT: 12px Arial, Helvetica, sans-serif } DIV.Block { FONT: 12px Arial, Helvetica, sans-serif; MARGIN-LEFT: 10px; COLOR: = #404040; MARGIN-RIGHT: 10px } DIV.Menu { BORDER-RIGHT: #84836b 1px solid; PADDING-RIGHT: 5px; BORDER-TOP: = #84836b 1px solid; PADDING-LEFT: 5px; VISIBILITY: hidden; = PADDING-BOTTOM: 5px; BORDER-LEFT: #84836b 1px solid; WIDTH: 120px; = PADDING-TOP: 5px; BORDER-BOTTOM: #84836b 1px solid; POSITION: absolute; = BACKGROUND-COLOR: #404040 } UL.BlockColumn { MARGIN-LEFT: 10px; WIDTH: 500px; MARGIN-RIGHT: 10px } P { FONT: 12px Arial, Helvetica, sans-serif; COLOR: #404040 } P.Block { MARGIN-LEFT: 10px; MARGIN-RIGHT: 10px } P.BlockColumn { MARGIN-LEFT: 10px; WIDTH: 500px; MARGIN-RIGHT: 10px } P.Margin { MARGIN-LEFT: 20px } TABLE.Block { FONT: 12px Arial, Helvetica, sans-serif; MARGIN-LEFT: 10px; COLOR: = #404040; MARGIN-RIGHT: 10px } TD { FONT: 12px Arial, Helvetica, sans-serif; COLOR: #404040; = TEXT-DECORATION: none } TD.ContainerLine { BACKGROUND-COLOR: #000000 } TD.ContainerHeader { BORDER-RIGHT: #000000 1px solid; PADDING-RIGHT: 4px; BORDER-TOP: = #000000 1px solid; PADDING-LEFT: 4px; FONT-WEIGHT: bold; FONT-SIZE: = 12px; BORDER-LEFT: #000000 1px solid; COLOR: #000000; BORDER-BOTTOM: = #000000 1px solid; BACKGROUND-COLOR: #ffffff } TD.ContainerBody { BORDER-RIGHT: #000000 1px solid; PADDING-RIGHT: 4px; BORDER-TOP: = #000000 0px solid; PADDING-LEFT: 4px; FONT-WEIGHT: normal; FONT-SIZE: = 13px; BORDER-LEFT: #000000 1px solid; COLOR: #000000; BORDER-BOTTOM: = #000000 1px solid; BACKGROUND-COLOR: #ffffff } TD.ContainerBodySubText { FONT-WEIGHT: normal; FONT-SIZE: 12px } TD.DialogHead { FONT-WEIGHT: bold; BACKGROUND-COLOR: #ffffff } TD.DialogBody { FONT-WEIGHT: normal; BACKGROUND-COLOR: #ffffff } TD.MessageFeedback { COLOR: #008000; FONT-STYLE: italic } TD.ErrorFeedback { COLOR: #af5f5f; FONT-STYLE: italic } TD.Footer { FONT: 12px Arial, Helvetica, sans-serif } TD.SectionHead { FONT-WEIGHT: bold; COLOR: #000000 } B { FONT: bold 12px Arial, Helvetica, sans-serif; COLOR: #000000; = TEXT-DECORATION: none } B.SectionHead { FONT: bold 12px Arial, Helvetica, sans-serif; COLOR: #000000 } B.Menu { FONT-WEIGHT: bold; COLOR: #84836b } B.MenuDisabled { FONT-WEIGHT: bold; COLOR: #c0c0c0 } B.Footer { FONT: bold 12px Arial, Helvetica, sans-serif } .MenuButton { BORDER-TOP-WIDTH: 1px; FONT-WEIGHT: bold; BORDER-LEFT-WIDTH: 1px; = FONT-SIZE: 13px; BORDER-LEFT-COLOR: #7f9db9; BACKGROUND: #ffffff; = BORDER-BOTTOM-WIDTH: 1px; BORDER-BOTTOM-COLOR: #7f9db9; WIDTH: 70px; = COLOR: #84836b; BORDER-TOP-COLOR: #7f9db9; FONT-FAMILY: Arial, = Helvetica, sans-serif; HEIGHT: 21px; BORDER-RIGHT-WIDTH: 1px; = TEXT-DECORATION: none; BORDER-RIGHT-COLOR: #7f9db9 } .MenuTextbox { BORDER-TOP-WIDTH: 1px; FONT-WEIGHT: bold; BORDER-LEFT-WIDTH: 1px; = FONT-SIZE: 13px; BORDER-LEFT-COLOR: #7f9db9; BORDER-BOTTOM-WIDTH: 1px; = BORDER-BOTTOM-COLOR: #7f9db9; WIDTH: 150px; COLOR: #84836b; = BORDER-TOP-COLOR: #7f9db9; FONT-FAMILY: Arial, Helvetica, sans-serif; = HEIGHT: 21px; BORDER-RIGHT-WIDTH: 1px; TEXT-DECORATION: none; = BORDER-RIGHT-COLOR: #7f9db9 } .MenuDropdownListbox { BORDER-TOP-WIDTH: 1px; FONT-WEIGHT: bold; BORDER-LEFT-WIDTH: 1px; = FONT-SIZE: 13px; BORDER-LEFT-COLOR: #7f9db9; BORDER-BOTTOM-WIDTH: 1px; = BORDER-BOTTOM-COLOR: #7f9db9; WIDTH: 80px; COLOR: #84836b; = BORDER-TOP-COLOR: #7f9db9; FONT-FAMILY: Arial, Helvetica, sans-serif; = HEIGHT: 21px; BORDER-RIGHT-WIDTH: 1px; TEXT-DECORATION: none; = BORDER-RIGHT-COLOR: #7f9db9 } .headlinkarrow { FONT-SIZE: 9px; COLOR: #333333; LINE-HEIGHT: 11px } .bodycontentnavliste { FONT-SIZE: 11px; COLOR: #333333; LINE-HEIGHT: 13px } .bodycontentnavlistebold { FONT-WEIGHT: bold; FONT-SIZE: 12px; COLOR: #333333; LINE-HEIGHT: 13px } .bodyfooter { FONT-SIZE: 11px; COLOR: #333333; LINE-HEIGHT: 12px } .bodyfootnotetext { FONT-SIZE: 9px; COLOR: #333333; LINE-HEIGHT: 11px } .bodyformerrortext { FONT-SIZE: 12px; COLOR: #ff0033; LINE-HEIGHT: 14px } .bodyheadlinebold { FONT-WEIGHT: bold; FONT-SIZE: 12px; COLOR: #333333; LINE-HEIGHT: 14px } .bodyheadlineextrabold { FONT-SIZE: 25px; COLOR: #333333; LINE-HEIGHT: 27px } .bodyheadlinetop { FONT-SIZE: 12px; COLOR: #333333; LINE-HEIGHT: 16px } .bodyimageborder { MARGIN: 2px 10px 8px 0px } .bodymorelink { FONT-SIZE: 11px; COLOR: #333333; LINE-HEIGHT: 11px } .bodysubnav { FONT-SIZE: 11px; COLOR: #333333; LINE-HEIGHT: 11px } .bodytext { FONT-SIZE: 12px; COLOR: #333333; LINE-HEIGHT: 14px } .breadcrumb { FONT-SIZE: 11px; COLOR: #333333; LINE-HEIGHT: 11px } .select1 { WIDTH: 256px } .select2 { WIDTH: 255px } .select3 { FONT: 12px Arial, Helvetica, sans-serif; WIDTH: 110px } .select4 { WIDTH: 152px } .select5 { WIDTH: 310px } .select6 { WIDTH: 68px } .select7 { WIDTH: 142px } .select8 { WIDTH: 48px } .select9 { WIDTH: 100px } .select10 { WIDTH: 191px } .select11 { WIDTH: 78px } .select12 { WIDTH: 160px } .select13 { WIDTH: 71px } .select14 { WIDTH: 139px } .select15 { WIDTH: 235px } .select16 { WIDTH: 250px } .input1 { WIDTH: 139px } .input2 { WIDTH: 142px } .input3 { WIDTH: 310px } .input4 { WIDTH: 76px } .input5 { WIDTH: 233px } .input6 { WIDTH: 67px } .input7 { WIDTH: 109px } .input8 { WIDTH: 33px } .input9 { WIDTH: 479px } .input10 { WIDTH: 87px } .input11 { WIDTH: 235px } .input12 { WIDTH: 94px } .input13 { WIDTH: 130px } .input14 { WIDTH: 152px } .input15 { WIDTH: 122px } .input16 { WIDTH: 45px } .input17 { WIDTH: 180px } .textarea1 { FONT-SIZE: 12px; WIDTH: 479px; LINE-HEIGHT: 14px; FONT-FAMILY: arial, = verdana, helvetica; HEIGHT: 140px } .textarea2 { FONT-SIZE: 12px; WIDTH: 479px; LINE-HEIGHT: 14px; FONT-FAMILY: arial, = verdana, helvetica; HEIGHT: 65px } .textarea3 { FONT-SIZE: 12px; WIDTH: 479px; LINE-HEIGHT: 14px; FONT-FAMILY: arial, = verdana, helvetica; HEIGHT: 395px } BODY { MARGIN: 0px; margin-width: 0px } P { FONT-FAMILY: Arial,verdana,Helvetica,sans-serif } H1 { FONT-FAMILY: Arial,verdana,Helvetica,sans-serif } H2 { FONT-FAMILY: Arial,verdana,Helvetica,sans-serif } H3 { FONT-FAMILY: Arial,verdana,Helvetica,sans-serif } H4 { FONT-FAMILY: Arial,verdana,Helvetica,sans-serif } UL { FONT-FAMILY: Arial,verdana,Helvetica,sans-serif } OL { FONT-FAMILY: Arial,verdana,Helvetica,sans-serif } LI { FONT-FAMILY: Arial,verdana,Helvetica,sans-serif } TD { FONT-FAMILY: Arial,verdana,Helvetica,sans-serif } TH { FONT-FAMILY: Arial,verdana,Helvetica,sans-serif } ADDRESS { FONT-FAMILY: Arial,verdana,Helvetica,sans-serif } BLOCKQUOTE { FONT-FAMILY: Arial,verdana,Helvetica,sans-serif } NOBR { FONT-FAMILY: Arial,verdana,Helvetica,sans-serif } B { FONT-FAMILY: Arial,verdana,Helvetica,sans-serif } I { FONT-FAMILY: Arial,verdana,Helvetica,sans-serif } SPAN { FONT-FAMILY: Arial,verdana,Helvetica,sans-serif } INPUT { FONT-FAMILY: Arial,verdana,Helvetica,sans-serif } #toplist { LEFT: 93px; VISIBILITY: visible; WIDTH: 504px; POSITION: absolute; TOP: = 84px; HEIGHT: 84px } #topmenu { LEFT: 378px; VISIBILITY: visible; WIDTH: 378px; POSITION: absolute; = TOP: 1px; HEIGHT: 80px } #headline { LEFT: 14px; VISIBILITY: visible; WIDTH: 688px; POSITION: absolute; TOP: = 9px; HEIGHT: 84px } #forumbuttons { LEFT: 616px; VISIBILITY: visible; WIDTH: 140px; POSITION: absolute; = TOP: 249px; HEIGHT: 30px } #homesub { LEFT: 84px; VISIBILITY: visible; WIDTH: 689px; POSITION: absolute; TOP: = 84px; HEIGHT: 84px } #mainnavibar { Z-INDEX: 10; LEFT: 84px; VISIBILITY: visible; WIDTH: 688px; POSITION: = absolute; TOP: 98px; HEIGHT: 21px } #mainnav1 { Z-INDEX: 20; LEFT: 84px; VISIBILITY: visible; WIDTH: 50px; POSITION: = absolute; TOP: 98px; HEIGHT: 21px } #mainnav2 { Z-INDEX: 20; LEFT: 133px; VISIBILITY: visible; WIDTH: 57px; POSITION: = absolute; TOP: 98px; HEIGHT: 21px } #mainnav3 { Z-INDEX: 20; LEFT: 189px; VISIBILITY: visible; WIDTH: 73px; POSITION: = absolute; TOP: 98px; HEIGHT: 21px } #mainnav4 { Z-INDEX: 20; LEFT: 261px; VISIBILITY: visible; WIDTH: 51px; POSITION: = absolute; TOP: 98px; HEIGHT: 21px } #mainnav5 { Z-INDEX: 20; LEFT: 311px; VISIBILITY: visible; WIDTH: 97px; POSITION: = absolute; TOP: 98px; HEIGHT: 21px } #mainnav6 { Z-INDEX: 20; LEFT: 407px; VISIBILITY: visible; WIDTH: 57px; POSITION: = absolute; TOP: 98px; HEIGHT: 21px } #breadcrumb { LEFT: 0px; VISIBILITY: visible; WIDTH: 772px; POSITION: absolute; TOP: = 119px; HEIGHT: 21px } A.bodycolor1 { COLOR: #003399; TEXT-DECORATION: none } A.bodycolor1:active { COLOR: #ff6600; TEXT-DECORATION: none } A.bodycolor1:hover { COLOR: #ff6600; TEXT-DECORATION: underline } A.bodycolor1:visited { COLOR: #003399; TEXT-DECORATION: none } A.bodycolor1high { COLOR: #ff6600; TEXT-DECORATION: underline } A.bodycolor3 { COLOR: #003399; TEXT-DECORATION: none } A.bodycolor3:active { COLOR: #003399; TEXT-DECORATION: none } A.bodycolor3:hover { COLOR: #ff6600; TEXT-DECORATION: underline } A.bodycolor3high { COLOR: #ff6600; TEXT-DECORATION: underline } ------=_NextPart_000_0021_01C68351.D2E795E0--