This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ali, S. Articles by Castro, M. G. Search for Related Content PubMed PubMed Citation Articles by Ali, S. Articles by Castro, M. G.

Combined Immunostimulation and Conditional Cytotoxic Gene Therapy Provide Long-term Survival in a Large Glioma Model

¹ Molecular Medicine and Gene Therapy Unit, University of Manchester, Manchester, United Kingdom; ² Gene Therapeutics Research Institute, Cedars-Sinai Medical Center, and Departments of Medicine and Molecular and Medical Pharmacology, ³ Medicine Hematology and Oncology, and ⁴ Surgery, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California; ⁵ Department of Medicine, School of Medicine, University of Navarra, Pamplona, Spain; ⁶ VUmc FdG, Amsterdam, the Netherlands; and ⁷ Institute of Brain Research, Department of Neuroimmunology, University of Vienna, Vienna, Austria

Requests for reprints: Maria G. Castro, Gene Therapeutics Research Institute, Cedars-Sinai Medical Center, Davis Building, Room R5090, 8700 Beverly Boulevard, Los Angeles, CA 90048. Phone: 310-423-7303; Fax: 310-423-7308; E-mail: castromg{at}cshs.org.

In spite of preclinical efficacy and recent randomized, controlled studies with adenoviral vectors expressing herpes simplex virus-1 thymidine kinase (HSV1-TK) showing statistically significant increases in survival, most clinical trials using single therapies have failed to provide major therapeutic breakthroughs. Because glioma is a disease with dismal prognosis and rapid progression, it is an attractive target for gene therapy. Preclinical models using microscopic brain tumor models (e.g., 0.3 mm³) may not reflect the pathophysiology and progression of large human tumors. To overcome some of these limitations, we developed a syngeneic large brain tumor model. In this model, administration of single therapeutic modalities, either conditional cytotoxicity or immunostimulation, fail. However, when various immunostimulatory therapies were delivered in combination with conditional cytotoxicity (HSV1-TK), only the combined delivery of fms-like tyrosine kinase ligand (Flt3L) and HSV1-TK significantly prolonged the survival of large tumor-bearing animals (80%; P 0.005). When either macrophages or CD4⁺ cells were depleted before administration of viral therapy, TK + Flt3L therapy failed to prolong survival. Meanwhile, depletion of CD8⁺ cells or natural killer cells did not affect TK + Flt3L efficacy. Spinal cord of animals surviving 6 months after TK + Flt3L were evaluated for the presence of autoimmune lesions. Whereas macrophages were present within the corticospinal tract and low levels of T-cell infiltration were detected, these effects are not indicative of an overt autoimmune disorder. We propose that combined Flt3L and HSV1-TK adenoviral-mediated gene therapy may provide an effective antiglioma treatment with increased efficacy in clinical trials of glioma.

This article has been cited by other articles:

				M. Candolfi, K. Yagiz, D. Foulad, G. E. Alzadeh, M. Tesarfreund, A.K.M. G. Muhammad, M. Puntel, K. M. Kroeger, C. Liu, S. Lee, et al. Release of HMGB1 in Response to Proapoptotic Glioma Killing Strategies: Efficacy and Neurotoxicity Clin. Cancer Res., July 1, 2009; 15(13): 4401 - 4414. [Abstract] [Full Text] [PDF]

				M. Puntel, R. J. Barrett, S. Mondkar, V. Saxena, K. M. Kroeger, A. K. M. Muhammad, C. Liu, N. Bondale, S. Sciascia, W. Xiong, et al. Herpes Simplex Virus Type 1 Thymidine Kinase Sequence Fused to the lacZ Gene Increases Levels of {beta}-Galactosidase Activity per Genome of High-Capacity but Not First-Generation Adenoviral Vectors In Vitro and In Vivo J. Virol., February 15, 2009; 83(4): 2004 - 2010. [Abstract] [Full Text] [PDF]

				G. D. King, A. K. M. G. Muhammad, W. Xiong, K. M. Kroeger, M. Puntel, D. Larocque, D. Palmer, P. Ng, P. R. Lowenstein, and M. G. Castro High-Capacity Adenovirus Vector-Mediated Anti-Glioma Gene Therapy in the Presence of Systemic Antiadenovirus Immunity J. Virol., May 1, 2008; 82(9): 4680 - 4684. [Abstract] [Full Text] [PDF]

				G. D. King, A.K.M. G. Muhammad, J. F. Curtin, C. Barcia, M. Puntel, C. Liu, S. B. Honig, M. Candolfi, S. Mondkar, P. R. Lowenstein, et al. Flt3L and TK gene therapy eradicate multifocal glioma in a syngeneic glioblastoma model Neuro-oncol, February 1, 2008; 10(1): 19 - 31. [Abstract] [Full Text] [PDF]

				M. Candolfi, G. E. Pluhar, K. Kroeger, M. Puntel, J. Curtin, C. Barcia, A.K.M. G. Muhammad, W. Xiong, C. Liu, S. Mondkar, et al. Optimization of adenoviral vector-mediated transgene expression in the canine brain in vivo, and in canine glioma cells in vitro Neuro-oncol, July 1, 2007; 9(3): 245 - 258. [Abstract] [Full Text] [PDF]

				J. F. Curtin, G. D. King, C. Barcia, C. Liu, F. X. Hubert, C. Guillonneau, R. Josien, I. Anegon, P. R. Lowenstein, and M. G. Castro Fms-Like Tyrosine Kinase 3 Ligand Recruits Plasmacytoid Dendritic Cells to the Brain J. Immunol., March 15, 2006; 176(6): 3566 - 3577. [Abstract] [Full Text] [PDF]