Analysis of the immunologic response generated by Ad.IFN-beta during successful intraperitoneal tumor gene therapy.

One promising therapeutic approach to intracavitary tumors, such as malignant mesothelioma and ovarian cancer, is immuno-gene therapy. In a previous study, intraperitoneal (i.p.) instillation of an adenoviral vector encoding the mouse interferon-beta gene (Ad.muIFN-beta) was shown to eradicate established mesothelioma tumors in the peritoneal cavity of immune competent, but not immunodeficient mice. The goal of this study was to understand more completely the kinetics and mechanisms of this immune-mediated response. Two days after a single intraperitoneal (i.p.) injection of Ad.muIFN-beta into BALB/c mice with established tumors, the response in the peritoneum was characterized by an influx of activated natural killer (NK) cells, polymorphonuclear (PMN) cells, and macrophages with minimal infiltration into the tumor nodules. However, depletion of PMN or NK cells after Ad.IFN-beta treatment had only minimal effects. At later time points (up to 10 days after Ad.IFN-beta i.p.), a large influx of CD4(+) and activated CD8(+) T cells was present in the peritoneal fluid and within the tumor nodules. The CD8(+) T cells had cytolytic activity, and adoptive transfer of peritoneal exudate cells (obtained by peritoneal lavage) resulted in effective tumor cell killing. Antitumor effects of Ad.IFN-beta may be different in different tumor types or in different anatomic locations. However, these results demonstrate that tumor-specific CD4(+) and CD8(+) T cells are the key effector cells for tumor eradication in this model.