Viral Immunotherapy to Eradicate Subclinical Brain Metastases.

摘要

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 Her2/neu 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, D2F2/E2. 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.