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Enhancement of Antitumor Activity of Polyethylene Glycol-coated Liposomal Doxorubicin with Soluble and Liposomal Interleukin 2¹

Sharet Institute of Oncology, Hadassah Hebrew University Medical Center [A. C., J. Z., A. G.], and Department of Biochemistry [S. E-C., Y. B.] and Lautenberg Center for General and Tumor Immunology [J. Z., E. K.], Hebrew University-Hadassah Medical School, Jerusalem, Israel 91.120

Polyethylene glycol-coated liposomal doxorubicin (Doxil) has a sustained release profile and a mild myelosuppressive effect that may enable a beneficial interaction with lymphocyte-activating cytokines, such as interleukin 2 (IL-2). Previous studies have shown that liposome entrapment of IL-2 potentiates its immunomodulatory effects and reduces the need for frequent dosing. We assessed the therapeutic effect of Doxil (8 mg/kg) followed by free or liposomal IL-2 (50,000 Cetus Units x3) in mice bearing M109 lung adenocarcinoma transplanted i.v. or i.p. Doxil was always administered i.v., whereas IL-2 was given i.v. in the i.v. M109 model and i.p. in the i.p. M109 model. The optimal combined treatment was significantly more effective than liposomal chemotherapy alone, producing tumor-free, long-term survivors in 100% (i.v. M109) and 94% (i.p. M109) of the mice, compared with 50% and 56%, respectively, for Doxil alone. The efficacy boost of IL-2 appeared to be formulation dependent, with free IL-2 and IL-2 in small unilamellar vesicles most active in the i.v. tumor model, and IL-2 in multilamellar vesicles most active in the i.p. tumor model. The combination of Doxil with free or liposomal IL-2 was devoid of any conspicuous toxicity. Cytokine treatment without chemotherapy was completely ineffective. Liposome-based chemoimmunotherapy is a synergistic and highly efficacious approach to eradicate metastatic and regionally spread tumors.

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