Project Details for

Completed Research Projects

Title: Improving a mM-CSF Tumor Vaccine for Established Intracranial Gliomas
Synopsis: This animal study tested several therapies for the treatment of brain and spinal cord cancers.
Overall Summary: See project objective.
Overall Project Objective: The goal of this proposal is to improve a treatment that will destroy a well-established intracranial T9 glial tumor by immunizing the tumor bearing animals at a subcutaneous site with glial tumor cells expressing the membrane form of macrophage colony stimulating factor (mM-CSF). We will identify those combinations of therapies (x-irradiation or the use of either chemical or biological inhibitors of angiogenesis) that best work with this vaccination regimen. Our long-term goal is to develop the preclinical data to justify a clinical trial to treat patients with high-grade gliomas with mM-CSF expressing glial tumor cells.
Results to Date: In preliminary studies we have found that 50% of the rats implanted with a lethal dose of parental T9 in the brain will survive if we wait four days before we begin vaccinating the rats in the skin with mM-CSF expressing T9 glioma cells. The type of anti-glioma specific immunity that protects rats against the intracranial T9 glioma lies within a CD4+ T cell population. Vaccination with mM-CSF transduced T9 glioma does generate cross-protective immunity against other syngeneic rat gliomas like RT2 and F98. This unique ability to generate cross-protective immunity against the different gliomas has not been seen with other cytokine-based tumor vaccination strategies and offers the possibility of using human transfected semi-allogeneic tumor vaccines to be used clinically. Finally, we discovered that the T9 gliomas can proliferate better in response to basic fibroblast growth factor (FGF) for its in vitro growth and may be a possible target for specific FGF receptor kinase inhibitors in vivo.
Project: VA-97
Agency: Department Of Veterans Affairs
Location: VAMC Long Beach
P.I. Name: Martin R Jadus
Status: Complete
Study Start Date: April 01, 2003
Estimated Completion Date: June 30, 2007
Specific Aims: See project objective.
Methodology: Rats will be surgically implanted with a lethal dose of T9 glioma cells in the brain and we will wait 5-20 days before we begin a therapy. This model closely resembles the human tumor at the time of initial diagnosis. We will then determine which therapy works best with the mM-CSF transfected T9 glioma. Three approaches will be evaluated to determine the best therapeutic combination with our tumor vaccination protocol. The first approach will employ a local x-irradiation of the brain tumor with a dose of x-rays that will partially kill the tumor thereby reducing the tumor burden. We will then investigate whether the mM-CSF tumor vaccine will stimulate sufficient immunity to kill the residual tumor. The second method involves the use of chemical anti-angiogenic drugs to inhibit the progression of either the glioma and/or the endothelial cells that are responsible for tumor vascularization. Specific anti-angiogenesis drugs, that inhibit several growth factor receptor kinases, like epidermal growth factor, fibroblast growth factor, platelet-derived growth factor and vascular endothelial growth factor, will be evaluated with the tumor vaccination protocol. The third approach will evaluate whether naturally-derived biologically derived anti-angiogenic compounds such as endostatin or the kringle 5 domain of plasminogen can be used to better treat the intracranial glioma with the mM-CSF tumor vaccine. A lethal glioma rat model previously developed by the investigators will be employed for this work. A stable mM-CSF transfected T9 glioma cell line has been established. This transduced tumor cell has been shown to be effective in generating cell mediated immunity against the T9 glioma and it will be used in this work. The success of our combined therapy will be judged on animal survival, tumor volume, apoptotic index and the tumor proliferation index.
Publications:
No Publications at this time...