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503483 
Journal Article 
Antiglioma Immunological Memory in Response to Conditional Cytotoxic/Immune-Stimulatory Gene Therapy: Humoral and Cellular Immunity Lead to Tumor Regression 
Muhammad, A; Candolfi, M; King, GD; Yagiz, K; Foulad, D; Mineharu, Y; Kroeger, KM; Treuer, KA; Nichols, WS; Sanderson, NS; Yang, JP; Khayznikov, M; Van Rooijen, N; Lowenstein, PR; Castro, MG 
2009 
1 
Clinical Cancer Research
ISSN: 1078-0432
EISSN: 1557-3265 
15 
19 
6113-6127 
English 
Purpose: Glioblastoma multiforme is a deadly primary brain cancer. Because the tumor kills due to recurrences, we tested the hypothesis that a new treatment would lead to immunological memory in a rat model of recurrent glioblastoma multiforme. Experimental Design: We developed a combined treatment using an adenovirus (Ad) expressing fms-like tyrosine kinase-3 ligand (Flt3L), which induces the infiltration of immune cells into the tumor microenvironment, and an Ad expressing herpes simplex virus-1-thymidine kinase (TK), which kills proliferating tumor cells in the presence of ganciclovir. Results: This treatment induced immunological memory that led to rejection of a second glioblastoma multiforme implanted in the contralateral hemisphere and of an extracranial glioblastoma multiforme implanted intradermally. Rechallenged long-term survivors exhibited anti-glioblastoma multiforme-specific T cells and displayed specific delayed-type hypersensitivity. Using depleting antibodies, we showed that rejection of the second tumor was dependent on CD8(+) T cells. Circulating anti-glioma antibodies were observed when glioblastoma multiforme cells were implanted intradermally in naive rats or in long-term survivors. However, rats bearing intracranial glioblastoma multiforme only exhibited circulating antitumoral antibodies upon treatment with Ad-Flt3L + Ad-TK. This combined treatment induced tumor regression and release of the chromatin-binding protein high mobility group box 1 in two further intracranial glioblastoma multiforme models, that is, Fisher rats bearing intracranial 9L and F98 glioblastoma multiforme cells. Conclusions: Treatment with Ad-Flt3L + Ad-TK triggered systemic anti-glioblastoma multiforme cellular and humoral immune responses, and anti-glioblastoma multiforme immunological memory. Release of the chromatin-binding protein high mobility group box 1 could be used as a noninvasive biomarker of therapeutic efficacy for glioblastoma multiforme. The robust treatment efficacy lends further support to its implementation in a phase I clinical trial. (Clin Cancer Res 2009;15(19):6113-27) 
malignant brain-tumors; type-1 thymidine kinase; glioblastoma-multiforme; extraneural metastases; recurrent; glioblastoma; extracellular hmgb1; mouse glioblastoma; glioma model; immunotherapy; survival