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Evaluation of proapototic transgenes to use in combination with Flt3L in an immune‐stimulatory gene therapy approach for Glioblastoma multiforme (GBM)
Author(s) -
Candolfi Marianela,
King Gwendalyn D,
Muhammad AKM G,
Puntel Mariana,
Kroeger Kurt M,
Liu Chunyan,
Ahlsadeh Gabrielle E,
Lerner Jonathan,
Lee Sharon,
Foulad David,
Sato Katsuaki,
Lowenstein Pedro R,
Castro Maria G
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.1077.13
Subject(s) - fas ligand , cancer research , immune system , apoptosis , cd8 , immunology , medicine , immunotherapy , biology , programmed cell death , biochemistry
We 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 antigens to be up taken by APCs recruited by Ad‐Flt3L for GBM immunotherapy. Ad‐TK, Ad‐FasL and Ad‐TRAIL exerted GBM cell 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 side effects. Thus, we treated large intracranial GBM in rats with Ad‐TK+Ad‐Flt3L, which significantly improved survival and induced antitumor immunological memory. Ad‐TK+Ad‐Flt3L induced intratumoral recruitment of APCs with features of immature pDCs (CD3−, CD4+, CD45R+ cells that were CD86− and MHCII−). In summary, TK is a very safe and efficient pro‐apoptotic strategy to induce GBM regression when combined with Ad‐Flt3L. Our results warrant further development of this approach for human GBM Phase I trials. Support: NIH/NINDS R01 NS44556.01, R21‐NSO54143.01; UO1 NS052465.01; RO3 TW006273 ‐01 to M.G.C.; RO1 NS 054193.01; RO1 NS 42893.01; U54 NS045309 ‐01, and R21 NS047298 ‐01 to P.R.L; F32 NS058156.01 to M.C.