Viral infection of implanted meningeal tumors induces antitumor memory T-cells to travel to the brain and eliminate established tumors

• Published in: Neuro-oncology (Charlottesville, Va.) Vol. 17; no. 4; pp. 536 - 544
• Main Authors: Gao, Yanhua, Whitaker-Dowling, Patricia, Barmada, Mamdouha A, Basse, Per H, Bergman, Ira
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 01-04-2015
• Subjects: Animals; Basic and Translational Investigations; Cell Line, Tumor; Humans; Immunotherapy, Adoptive; Kaplan-Meier Estimate; Meningeal Neoplasms - secondary; Meningeal Neoplasms - therapy; Meningeal Neoplasms - virology; Mice; Receptor, ErbB-2 - metabolism; T-Lymphocytes - physiology; Treatment Outcome; Vesicular stomatitis virus; Vesiculovirus; VSV; viral therapy; meningeal tumor; blood-meningeal barrier; memory T-cells
• ISSN: 1522-8517; 1523-5866
• DOI: 10.1093/neuonc/nou231

Leptomeningeal metastases occur in 2%-5% of patients with breast cancer and have an exceptionally poor prognosis. The blood-brain and blood-meningeal barriers severely inhibit successful chemotherapy. We have developed a straightforward method to induce antitumor memory T-cells using a Her2/neu targeted vesicular stomatitis virus. We sought to determine whether viral infection of meningeal tumor could attract antitumor memory T-cells to eradicate the tumors.
Meningeal implants in mice were studied using treatment trials and analyses of immune cells in the tumors.
This paper demonstrates that there is a blood-meningeal barrier to bringing therapeutic memory T-cells to meningeal tumors. The barrier can be overcome by viral infection of the tumor. Viral infection of the meningeal tumors followed by memory T-cell transfer resulted in 89% cure of meningeal tumor in 2 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. Finally, this paper shows that successful viral therapy of peritoneal tumors generates memory CD8 T-cells that prevent establishment of tumor in the meninges of these same animals.
These results support the hypothesis that a virally based immunization strategy can be used to both prevent and treat meningeal metastases. The meningeal barriers to cancer therapy may be much more permeable to treatment based on cells than treatment based on drugs or molecules.