Adjuvant Antitumor Immunity Contributes to the Overall Antitumor Effect of Pegylated Liposomal Doxorubicin (Doxil®) in C26 Tumor-Bearing Immunocompetent Mice

Abstract

Doxorubicin (DXR) has been reported to have direct cytotoxicity against cancer cells and indirect immunotoxicity by modulation of host antitumor immunity. Hence, it may prevent cancer progression by a dual mechanism. Doxil®, a formulation of DXR encapsulated in polyethylene glycol modified (PEGylated) liposomes, is the most widely used of the clinically approved liposomal anticancer drugs. However, the effect of Doxil® on host antitumor immunity is not well understood. In this study, Doxil® efficiently suppressed tumor growth in immunocompetent mice bearing C26 murine colorectal carcinomas, but not in T cell-deficient nude mice, indicating a contribution of T cells to the overall antitumor effect of Doxil®. In immunocompetent mice, Doxil® increased major histocompatibility complex (MHC-1) levels in C26 tumors, which may be an indicator of increased immunogenicity of tumor cells, and potentially amplified tumor immunogenicity by decreasing immunosuppressive cells such as regulatory T cells, tumor-associated microphages and myeloid-derived suppressor cells that collectively suppress T cell-mediated antitumor responses. This suggests that encapsulation of DXR into PEGylated liposomes increased the therapeutic efficacy of DXR though effects on host antitumor immunogenicity in addition to direct cytotoxic effects on tumor cells. This report describes the role of host antitumor immunity in the overall therapeutic effects of Doxil®. Manipulating pharmacokinetics and biodistribution of chemotherapeutic agents with immunomodulatory properties may increase their therapeutic efficacies by amplifying host antitumor immunity in addition to direct cytotoxic effects on tumor cells.

Clinical and molecular signature of survival and resistance to olaparib plus pegylated liposomal doxorubicin in platinum-resistant ovarian cancer: a stratified analysis from the phase II clinical trial ROLANDO, GEICO-1601

“…The effect of pegylated liposomal doxorubicin on the immune system is of particular interest, as doxorubicin has been shown to have a direct cytotoxic effect on cells and a second indirect immunotoxic effect on the host-antitumor immunity. A recent pre-clinical study suggested that pegylated liposomal doxorubicin is more active in the presence of T cells, suggesting that this immune effect is also important for this drug 36. In this context the impact seen in our study of the neutrophil/lymphocyte ratio could be related to the exposure of the patients to pegylated liposomal doxorubicin.…”

Effect of Doxorubicin Release Rate From Polyethylene Glycol-Modified Liposome on Anti-tumor Activity in B16-BL6 Tumor-Bearing Mice

“…Each liposome was intravenously injected at a dose of 5 mg DOX/kg because the intravenous injection of free DOX solution at 5 mg/kg did not provide any therapeutic effects against several types of cancers including B16-BL6. [27][28][29][30] L-Mid provided a significant and remarkable anti-tumor effect, while other liposomes did only a partial anti-tumor effect. Tumor growth rates during the early (0-11 days) and late (12-21 days) periods indicate that all the three preparations significantly suppressed the tumor growth in the early period, but only L-Mid provided a significant decrease of tumor growth rate during the late half, compared with the saline-treated control (Table 1).…”