Glioblastoma multiforme (GBM) is the most common subtype of primary brain tumors in adults. GB is very aggressive, highly invasive, and infiltrates critical brain structures. Mean survival time from the time of diagnosis is 6-12 months, in spite of advances in chemotherapy, surgery and radiotherapy. Harnessing the host's immune system to develop novel treatments for GBM has been attempted. Systemic immunization against glioma has not yielded beneficial effects, since it is limited by progressive tumor mutation, and a brain micro-environment not conducive to sustaining immune responses. Priming immune responses from within the brain parenchyma itself is limited by the paucity of dendritic cells (DC) and an immune-suppressive environment. We have tested in a large syngeneic rodent intracranial glioma model a combined gene therapy approach using first generation recombinant adenovirus vectors expressing fms-like tyrosine kinase 3 ligand (FltSL) (to recruit DCs to the brain), and herpes simplex virus type 1 thymidine kinase (HSV1-TK) that through the phosphorylation of the prodrug GCV (GCV) induces tumor cell death, making potentially antigenic tumor epitopes available to the DCs recruited to the brain. This approach was successful in eradicating a large rodent macroscopic tumor, for which all other single gene therapies tested failed. However, in humans who may have been exposed to adenovirus earlier in life, the immune response can completely abolish expression from first generation adenovirus. Therefore, we have now shown that this can be overcome by the use of the novel high capacity adenoviral vectors (HC-Ad). For this U01 proposal, we will perform experiments to stringently assess the efficiency and potential neuropathological, systemic, or behavioral side effects of the treatment of brain tumors with HC-Ad expressing FltSL in combination with HC- Ad- HSV1-TK+GCV. Our long term aim is to move this gene therapy approach towards Phase I clinical trials. Following a stringent timeline with specific milestones, we propose to test our HC-Ad approach first in a large rodent glioma for safety and efficacy, secondly in endogenous spontaneous dog GBMs for efficacy, safety, systemic biodistribution, and unforeseen side effects, and, finally, test safety and biodistribution in the brain of a non-human primate model. Having met all previous milestones, we propose to file for FDA approval towards the end of this U01 proposal.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project--Cooperative Agreements (U01)
Project #
3U01NS052465-04S1
Application #
8136810
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Program Officer
Mcgavern, Linda
Project Start
2007-09-19
Project End
2011-06-30
Budget Start
2010-09-01
Budget End
2011-06-30
Support Year
4
Fiscal Year
2010
Total Cost
$71,831
Indirect Cost
Name
Cedars-Sinai Medical Center
Department
Type
DUNS #
075307785
City
Los Angeles
State
CA
Country
United States
Zip Code
90048
Koschmann, Carl; Calinescu, Anda-Alexandra; Nunez, Felipe J et al. (2016) ATRX loss promotes tumor growth and impairs nonhomologous end joining DNA repair in glioma. Sci Transl Med 8:328ra28
Kamran, Neha; Candolfi, Marianela; Baker, Gregory J et al. (2016) Gene Therapy for the Treatment of Neurological Disorders: Central Nervous System Neoplasms. Methods Mol Biol 1382:467-82
VanderVeen, Nathan; Raja, Nicholas; Yi, Elizabeth et al. (2016) Preclinical Efficacy and Safety Profile of Allometrically Scaled Doses of Doxycycline Used to Turn ""On"" Therapeutic Transgene Expression from High-Capacity Adenoviral Vectors in a Glioma Model. Hum Gene Ther Methods 27:98-111
Baker, Gregory J; Yadav, Viveka Nand; Motsch, Sebastien et al. (2014) Mechanisms of glioma formation: iterative perivascular glioma growth and invasion leads to tumor progression, VEGF-independent vascularization, and resistance to antiangiogenic therapy. Neoplasia 16:543-61
Castro, Maria G; Candolfi, Marianela; Wilson, Thomas J et al. (2014) Adenoviral vector-mediated gene therapy for gliomas: coming of age. Expert Opin Biol Ther 14:1241-57
Assi, Hikmat; Espinosa, Jaclyn; Suprise, Sarah et al. (2014) Assessing the role of STAT3 in DC differentiation and autologous DC immunotherapy in mouse models of GBM. PLoS One 9:e96318
Lowenstein, Pedro R; Castro, Maria G (2014) The value of EGFRvIII as the target for glioma vaccines. Am Soc Clin Oncol Educ Book :42-50
Assi, Hikmat H; Paran, Chris; VanderVeen, Nathan et al. (2014) Preclinical characterization of signal transducer and activator of transcription 3 small molecule inhibitors for primary and metastatic brain cancer therapy. J Pharmacol Exp Ther 349:458-69
Lowenstein, P R; Yadav, Viveka Nand; Chockley, Peter et al. (2014) There must be a way out of here: identifying a safe and efficient combination of promoter, transgene, and vector backbone for gene therapy of neurological disease. Mol Ther 22:246-247
Mineharu, Yohei; Kamran, Neha; Lowenstein, Pedro R et al. (2014) Blockade of mTOR signaling via rapamycin combined with immunotherapy augments antiglioma cytotoxic and memory T-cell functions. Mol Cancer Ther 13:3024-36

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