Tumor Treatment with Complexes of Cationic Lipid and Noncoding Plasmid DNA Results in the Induction of Cytotoxic T Cells and Systemic Tumor Elimination
Authors: William M. Siders, Kristin Vergillis, Carrie Johnson, Ronald K. Scheule, Johanne M. Kaplan
Journal: Molecular Therapy (2002)

We have demonstrated recently that treatment of established peritoneal mesothelial tumors with complexes composed of cationic lipid and noncoding plasmid DNA (pNull) results in the inhibition of tumor growth accompanied by the induction of a tumor-specific cellular immune response. In this study, treatment of mice bearing intraperitoneal (i.p.) M3 melanoma tumors with i.p. injections of lipid/pNull complex was found to inhibit tumor growth and induce the development of a cytolytic response against several M3 melanoma-associated antigens. Depletion of CD8+ T cells, as opposed to natural killer (NK) or CD4+ T cells, essentially abrogated the therapeutic effect of lipid+pNull complex, thus supporting the involvement of cytotoxic CD8+ T cells in the antitumor response. The antitumor effect of lipid/pNull complex was maximal following delivery into a tumor-bearing compartment. For example, i.p. delivery of complex was more effective than intravenous (i.v.) or subcutaneous (s.c.) treatment of i.p. M3 tumors. In addition, i.v. injection of complex displayed therapeutic activity against lung metastases caused by i.v. injection of tumor cells, and intratumoral injection of complex into solid s.c. tumors caused regression in most animals. Importantly, the immune response induced by local treatment of tumors with complex also offered systemic protection against tumor cells at distal sites, as illustrated by the eradication of both peritoneal tumors and lung metastases in mice treated with complex delivered i.p. Treatment with lipid/pNull complex, therefore, represents an attractive immune-based treatment modality that could potentially be applied to many tumor types. We have demonstrated recently that treatment of established peritoneal mesothelial tumors with complexes composed of cationic lipid and noncoding plasmid DNA (pNull) results in the inhibition of tumor growth accompanied by the induction of a tumor-specific cellular immune response. In this study, treatment of mice bearing intraperitoneal (i.p.) M3 melanoma tumors with i.p. injections of lipid/pNull complex was found to inhibit tumor growth and induce the development of a cytolytic response against several M3 melanoma-associated antigens. Depletion of CD8+ T cells, as opposed to natural killer (NK) or CD4+ T cells, essentially abrogated the therapeutic effect of lipid+pNull complex, thus supporting the involvement of cytotoxic CD8+ T cells in the antitumor response. The antitumor effect of lipid/pNull complex was maximal following delivery into a tumor-bearing compartment. For example, i.p. delivery of complex was more effective than intravenous (i.v.) or subcutaneous (s.c.) treatment of i.p. M3 tumors. In addition, i.v. injection of complex displayed therapeutic activity against lung metastases caused by i.v. injection of tumor cells, and intratumoral injection of complex into solid s.c. tumors caused regression in most animals. Importantly, the immune response induced by local treatment of tumors with complex also offered systemic protection against tumor cells at distal sites, as illustrated by the eradication of both peritoneal tumors and lung metastases in mice treated with complex delivered i.p. Treatment with lipid/pNull complex, therefore, represents an attractive immune-based treatment modality that could potentially be applied to many tumor types.