Combining low-dose cyclophosphamide with GM-CSF-secreting prostate cancer immunotherapy enhances antitumor immune effects

Abstract

Prostate GVAX((R)) is an allogeneic cell-based prostate cancer vaccine engineered to secrete GM-CSF. The release of GM-CSF by this immunotherapy serves to recruit dendritic cells, which then present tumor antigens to T cells, thus initiating antitumor immune responses. However, preclinical data show that, when used alone, cell-based immunotherapy is generally unable to break specific T-cell tolerance in tumor-bearing hosts. The study by Wada and colleagues employed an autochthonous prostate cancer mouse model to demonstrate that low-dose cyclophosphamide given prior to a cell-based GM-CSF-secreting vaccine (T-GVAX) abrogated immune tolerance, augmented prostatic CD8(+) T-cell infiltration, mediated depletion of regulatory T cells (Tregs), and increased expression of dendritic cell maturation markers. In addition, this combination decreased the wet weight of mouse prostate glands, lowered histological tumor scores, and increased the density of apoptotic bodies. These findings add to existing data from other preclinical models showing enhancement of antitumor immunity when cyclophosphamide is administered in sequence with GM-CSF-secreting immunotherapy for the treatment of breast and pancreatic cancers. These studies provide a rationale for designing clinical trials that combine low-dose cyclophosphamide with GM-CSF-secreting cell-based immunotherapy in patients with prostate and other cancers.