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Systemic Flt3L and intratumoral HSV1‐TK treatment eradicates intracranial GBM in a syngeneic model
Author(s) -
Muhammad A.K.M Ghulam,
King Gwendalyn D.,
Candolfi Marianela,
Curtin James,
Liu Chunyan,
Kroeger Kurt,
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.1077.10
Subject(s) - medicine , cd8 , immune system , cytotoxic t cell , oncolytic virus , immunotherapy , neurotoxicity , cancer research , immunology , toxicity , biology , in vitro , biochemistry
Adenoviral vector (Ad) expressing FMS‐like tyrosine kinase 3 ligand (Flt3L) was delivered systemically to make less invasive our recently developed combined gene therapy for GBM. Six days after intra‐striatal stereotactic implantation of 4,500 CNS‐1 cells in Lewis rats, intravenous pre‐dosing with an empty Ad (Ad0) was performed and within 4~6 hours, AdFlt3L was delivered via the tail vein followed by intra‐tumoral herpes simplex type 1 thymidine kinase (AdTK) delivery. Controls (treated with Ad0 systemically and AdTK intra‐tumor) succumbed by day 22, whereas, 80% of the treated group survived long term (p<0.05). The survivors were rechallenged with GBM in the contralateral striatum and 70% survived long‐term without additional treatment. Brains of long‐term survivors displayed no residual tumor or local neurotoxicity; CD68+ macrophages, few CD8+ T cells, and MHC II immune positive cells were detected; no liver toxicity was encountered. Positive delayed type hypersensitivity reaction in the treatment group indicated the presence of memory T cells. In conclusion, gene therapy combining immune stimulation using systemic AdFlt3L and intra‐tumor cytotoxic/oncolytic treatment (AdTK) elicits tumor regression and immunological memory inhibiting tumor recurrence.