GENE THERAPY STRATEGIES FOR CENTRAL NERVOUS SYSTEM GERM CELL TUMORS: FROM BENCH TO BEDSIDE

CASTRO; KING; CURTIN; CANDOLFI; LIU; KROEGER; PUNTEL; XIONG; LOWENSTEIN

Los Angeles, California

Simposio; symposium on Central Nervous Systm and Germ cell tumors; 2005

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GENE THERAPY STRATEGIES FOR CENTRAL NERVOUS SYSTEM GERM CELL TUMORS: FROM BENCH TO BEDSIDE Maria G. Castro, Gwendalyn D. King, James F. Curtin, Marianela Candolfi, Chunyan Liu, Kurt Kroeger, Mariana Puntel, Weidong Xiong, and Pedro R. Lowenstein; Gene Therapeutics Research Institute, Cedars Sinai Medical Center, Departments of Medicine and Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California, USA Intracranial germ cell tumors (CNSGCTs) constitute a group of neoplastic lesions which include teratoma, malignant germinoma, embryonal carcinoma, yolk sac tumors, and choriocarcinoma. The current treatment for CNSGCTs includes a combination of tumor resection, irradiation of the tumor cavity to prevent tumor spread, and craniospinal irradiation to control spread of the tumor to the leptomeninges. Chemotherapy is also used to prevent leptomeningeal and systemic tumor dissemination. Combination therapy, using cisplatin-based chemotherapy with radiation therapy, yielded promising results, achieving survival rates of 30% to 60%. Patients with progressive disease could benefit from resection of the primary tumor. In these patients, a more aggressive treatment regime would be justified, including high doses of chemotherapy with stem cell treatment. Since some patients do not develop metastatic disease, this highlights the importance of local tumor control using a combination of surgery, chemotherapy, and radiotherapy. In spite of the advances in patient’s survival and improved treatment modalities, taking into account the side effects of both chemotherapy and radiotherapy, and also to improve outcomes in patients with disseminated disease, it is critical to develop new treatment strategies, such as stem or gene therapies. Gene therapy utilizes gene transfer vectors, such as viruses or plasmid DNA, to transfer therapeutic genes to target tissues or tumors. One of the most powerful viral vectors for gene transfer into the CNS is recombinant adenoviruses (RAds), which are currently being used in clinical trials for treating GBMs with very promising results (Trask et al., Mol. Ther. 1:195, 2000). RAds have also been used successfully in preclinical models of intracranial brain tumors (Dewey et al., Nat. Med. 5:1256, 1999; Ali et al., Mol. Ther. 10:1071 Ali et al., Mol. Ther. 10:2004). New generation RAds, deleted of all viral genes, can sustain long-term and stable therapeutic gene expression, even in the presence of a systemic antiadenovirus immune response as could be encountered in human patients (Thomas et al., PNAS 97:7482, 2000). We have recently shown that using a combination of suicide/conditional cytotoxic (HSV1-TK plus ganciclovir) gene therapy together with the expression of the cytokine, soluble human fms-like tyrosine kinase (Flt3L), which generates a very powerful systemic immune response against the tumor, we can achieve cure in 80% of animals bearing large intracranial tumors. Importantly, the combined gene therapy elicited immunological memory, protecting the animals from a new tumor challenge. We propose that combining HSV1-TK with Flt3L adenoviral gene therapy may provide an effective adjuvant treatment modality for CNSGCTs in patients that present with disseminated disease. This work was funded by NIH/NINDS 1RO1 NS44556.01, 1RO3 TW006273.01, 1RO1 NS42893.01, U54 NS045309.01, and 1R21 NS047298.01, the Linda Tallen and Paul Kane Foundation, and the BOG at CSMC.