Discussion
MPM, tumor, Administered, tumors
TUMOR, VIRUS, DISEASE, VACCINIA, MALIGNANT PLEURAL MESOTHELIOMA, TUMORS, METASTATIC BREAST CANCER
Our phase I study of intrapleural oncolytic viral therapy is based on strong rationale developed in preclinical models of malignant pleural mesothelioma (Our observations in treating patients with MPE-associated immunosuppressive microenvironment are similar to published studies of vaccinia viral therapy without immunosuppression at the administered site. Administered as systemic therapy in clinical trials, vaccinia viral therapy was associated with a trend toward improved progression-free survival and increased CD4+/Treg ratio in patients with metastatic breast cancer (Intrapleural oncolytic viral therapy has been investigated by use of multiple oncolytic viruses. In patients with MPM, intrapleural delivery of adenoviral gene-mediated cytotoxic therapy has been investigated. Adenoviral vectors have been used for gene transfer of cytokines [such as IFN-α (Following adenovirus-mediated TK/ganciclovir therapy, gene transfer was observed to be limited to superficial layers of the tumor (In addition to effector immune responses (an increase in CD45+, Th1+, CD8+, NK+, cytotoxic T cells, and dendritic cells), we also observed an increase in exhausted CD8+ T cells and macrophages indicating the suppressor immune response. However, it is not certain whether these alterations are limited to tumors with pre-existing immune suppressor responses that are augmented following vaccinia viral therapy. In addition, our clinical trial was limited by the inclusion of a small number of patients from a single institution, who had heterogeneous types and stages of disease. Not all specimens investigated were available from all patients, a limitation inherent in a phase I clinical trial. Nevertheless, our correlative analyses demonstrating immune activation support the potential utility of vaccinia virus as an intrapleural oncolytic treatment for patients with MPM.