Evaluation of proapototic transgenes to use in combination with Flt3L in an immune-stimulatory gene therapy approach for Glioblastoma multiforme (GBM)

CANDOLFI; KING; MUHAMMAD; PUNTEL; KROEGER; LIU; ALZADEH; LERNER; LEE; FOULAD; SATO; LOWENSTEIN; CASTRO

San Diego, California, USA

Congreso; American Association of Immunology; 2008

Evaluation of proapototic transgenes to use in combinationwith Flt3L in an immune-stimulatory gene therapy approachfor Glioblastoma multiforme (GBM)Marianela Candolfi1, Gwendalyn D King1, AKM G Muhammad1,Mariana Puntel1, Kurt M Kroeger1, Chunyan Liu1, Gabrielle EAhlsadeh1, Jonathan Lerner1, Sharon Lee1, David Foulad1,Katsuaki Sato2, Pedro R Lowenstein1, Maria G Castro1. 1GeneTherapy Reseacrh Institute, UCLA-Cedars Sinai Medical Center,Los Angeles, CA, 2RIKEN Yokohama Institute, Kanagawa, JapanWe showed that Flt3L recruits and activates APCs within GBM.We tested adenoviral vectors expressing pro-apoptotic transgenes[HSV1-thymidine kinase (Ad-TK), TNF-á (Ad-TNF-á), FasL (Ad-FasL) or TRAIL (Ad-TRAIL)], that would release tumor antigensto be up taken by APCs recruited by Ad-Flt3L for GBMimmunotherapy. Ad-TK, Ad-FasL and Ad-TRAIL exerted GBMcell death in vitro, but only Ad-TK and, at a lesser extent Ad-FasL,improved survival of GBM-bearing rats. Also, Ad-TRAIL and Ad-FasL were very neurotoxic, while Ad-TK did not induce any sideeffects. Thus, we treated large intracranial GBM in rats with Ad-TK+Ad-Flt3L, which significantly improved survival and inducedantitumor immunological memory. Ad-TK+Ad-Flt3L inducedintratumoral recruitment of APCs with features of immature pDCs(CD3-, CD4+, CD45R+ cells that were CD86- and MHCII-). Insummary, TK is a very safe and efficient pro-apoptotic strategy toinduce GBM regression when combined with Ad-Flt3L. Ourresults warrant further development of this approach for humanGBM Phase I trials.Support: NIH/NINDS R01 NS44556.01, R21-NSO54143.01; UO1NS052465.01; RO3 TW006273-01 to M.G.C.; RO1 NS054193.01; RO1 NS 42893.01; U54 NS045309-01, and R21NS047298-01 to P.R.L; F32 NS058156.01 to M.C.