Cationic lipid : bacterial DNA complexes elicit adaptive cellular immunityin murine intraperitoneal tumor models

Previous studies with a mycobacterial heat shock protein (hsp-65) have demo nstrated some efficacy using cationic liposome-mediated gene transfer in mu rine i.p. sarcoma models. To further analyze the efficacy of hsp-65 immunot herapy in clinically relevant models of localized cancer, immunocompetent m ice bearing i.p. murine mesothelioma were treated with four i.p. doses of a cationic lipid complexed with plasmid DNA (pDNA) containing hsp65, LacZ, o r a null plasmid. We observed >90% long-term survival (median survival, 150 days versus similar to 25 days, treated versus saline control, respectivel y) in a syngeneic, i.p. murine mesothelioma model (AC29), Long-term survivo rs were observed in all groups treated with lipid complexed with any pDNA, Lipid alone or DNA alone provided no demonstrable survival advantage. In a more aggressive i.p. model of mesothelioma (AB12), we observed >40% long-te rm survival in groups treated with lipid:pDNA complexes, again irrespective of the transgene, To ask whether these antitumor effects had led to an ada ptive immune response against the tumor cell, we rechallenged long-term sur vivors in both murine models s.c. with the parental tumor cell line. Specif ic, long-lasting systemic immunity against the tumor was readily demonstrat ed in both models (AB12 and AC29), Consistent with these results, splenocyt es from long-term survivors specifically lysed the parental tumor cell line s. Depleting the CD8(+) T cells from the splenocyte pool eliminated this ly tic activity. Lipid:pDNA treatment of athymic, SCID, and SCID/Beige mice be aring a murine i.p. mesothelioma (AC29) resulted in only a slight survival advantage, but there were no long-term survivors. Treatment of immunocompet ent mice depleted of specific immune effector cells demonstrated roles for CD8(+) and natural killer cells. Although the exact mechanism(s) responsibl e for these antitumor effects is unclear, the results are consistent with r oles for both innate and adaptive immune responses. An initial tumor cell k illing stimulated by cationic lipid:pDNA complexes appears to be translated into long-term, systemic immunity against the tumor cell. These results ar e the first to demonstrate that adaptive immunity against a tumor cell can be induced by the administration of lipid:pDNA complexes. Multiple administ rations of cationic lipid complexed with pDNA lacking an expressed transgen e could provide a promising generalized immune-mediated modality for treati ng cancer.