Viral Immunotherapy to Eradicate Subclinical Brain Metastases
Final rept. 1 Sep 2011-28 Feb 2014
PITTSBURGH UNIV PA
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To develop an immunologically based strategy for the treatment of breast cancer metastases to the brain BM. Scope To establish an animal model of BM and to demonstrate that anti-tumor memory T-cells can be activated to enter and destroy BM by the following methods 1. Viral infection of BM by a recombinant replicating vesicular stomatitis virus VSV targeted to the Her2neu receptor and causing oncolysis and cytokine expression and 2. Adoptive transfer of cytotoxic, cytokine-producing natural killer NK cells capable of accumulating in smaller metastases of the brain. Major Findings A meningeal model was produced using the mammary cancer cell line, D2F2E2. A parenchyma model was difficult to produce with this cell line. We showed that there is a blood-brain-barrier to bringing therapeutic memory T-cells to meningeal tumors. The barrier could be overcome by viral infection of the tumor. Viral infection of the meningeal tumors followed by memory T-cells transfer resulted in 89 cure of meningeal tumor in two different mouse strains. Viral infection produced increased infiltration and proliferation of transferred memory T-cells in the meningeal tumors. Following viral infection, the leukocyte infiltration in meninges and tumor shifted from predominantly macrophages to predominantly T-cells. Successful viral therapy of peritoneal tumors generates memory CD8 T-cells that prevent establishment of tumor in the brain meninges of these same animals. A-NK cells traffic to brain tumors but less well than seen in pulmonary and hepatic tumors. Conclusions These results support the hypothesis that a virally-based immunization strategy can be used to both prevent and treat brain metastases.
- Medicine and Medical Research