Cancer Therapy: Preclinical Antiglioma Immunological Memory in Response to Conditional Cytotoxic/Immune-Stimulatory Gene Therapy: Humoral and Cellular Immunity Lead to Tumor Regression

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: Wedeveloped a combined treatment using an adenovirus (Ad) expressing fms-like tyrosine kinase-3 ligand (Flt3L), which induces the infiltrationof immune cells into the tumormicroenvironment, andanAdexpressingherpes 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 glioblastomamultiforme implanted intradermally. Rechallenged long-term survivors exhibited anti-glioblastoma multiforme–specific T cells and displayed specific delayedtype 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 naïve rats or in long-term survivors. However, rats bearing intracranial glioblastomamultiforme 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) Gliomas represent the most common primary brain tumors, and ∼50% of these are the most aggressive type, that is, glioblastoma multiforme. The available multimodality clinical treatment for glioblastoma multiforme, that is, surgery, radiotherapy, and chemotherapy, results in an improved median survival from 6 to 18 months (1, 2). This has led to the development of various novel adjuvant treatments such as gene therapy and immunotherapy. Although numerous clinical Authors' Affiliations: Gene Therapeutics Research Institute; Department of Pathology, Cedars-Sinai Medical Center; Department of Molecular and Medical Pharmacology; Department of Medicine; Brain Research Institute, Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California; and Department of Molecular Cell Biology, Vrije Universiteit, Amsterdam, The Netherlands Received4/29/09; revised6/16/09; accepted6/18/09; publishedOnlineFirst 9/29/09. Grant support: NIH/National Institute of Neurologic Disorders and Stroke (NINDS) grants 1R21-NS054143, 1UO1 NS052465, and 1RO1-NS057711, and Medallions Group Endowed Chairs in Gene Therapeutics (M.G. Castro); NIH/NINDS grants 1 RO1 NS 054193, RO1 NS061107, and 1R21 NS047298, and Bram and Elaine Goldsmith (P.R. Lowenstein); the Linda Tallen and David Paul Kane Foundation Annual Fellowship; the Board of Governors at Cedars Sinai Medical Center; NIH/NINDS 1F32NS050303 (G.D. King); and NIH/NINDS 1F32 NS058156 (M. Candolfi). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). Requests for reprints: Maria G. Castro, Gene Therapeutics Research Institute, Cedars-Sinai Medical Center/University of California at Los Angeles, Room 5090, Davis Building Research Pavilion, 8700 Beverly Boulevard, Los Angeles, CA 90048. Phone: 310-423-7303; Fax: 310-4237308; E-mail: [email protected]. F 2009 American Association for Cancer Research. doi:10.1158/1078-0432.CCR-09-1087 6113 Clin Cancer Res 2009;15(19) October 1, 2009 www.aacrjournals.org Research. on June 6, 2017. © 2009 American Association for Cancer clincancerres.aacrjournals.org Downloaded from Published OnlineFirst September 29, 2009; DOI: 10.1158/1078-0432.CCR-09-1087