Ribbon-like structures result when amphotericin B interacts with lipid in an aqueous environment. At high ratios of amphotericin to lipid these structures, which are lipid-stabilized amphotericin aggregates, become prevalent resulting in a dramatic attenuation of amphotericin-mediated mammalian cell, but not fungal cell, toxicity. Studies utilizing freeze-etch electron microscopy, differential scanning calorimetry, "P NMR, x-ray diffraction, and optical spectroscopy revealed that this toxicity attenuation is related to the macromolecular structure of the complexes in a definable fashion. It is likely that amphotericin in this specific form will have a much improved therapeutic utility.Amphotericin B, a polyene antibiotic, is the drug ofchoice for a variety of systemic fungal infections that were almost always fatal prior to its introduction (1). The cytotoxic mechanism of this compound has been the subject of intensive investigation over many years and is thought to reside in its ability to form membrane ion channels particularly in the presence of sterols (2). That these channels and associated lethal permeability changes occur at somewhat lower membrane concentrations in the presence of ergosterol (the predominant sterol in fungal cell membranes) rather than cholesterol (the predominant sterol in mammalian cell membranes) most likely forms the basis of the selective toxicity of this drug (3). Still, in its present dosage form, which is a deoxycholate micelle, its clinical utility is profoundly limited by host cell toxicity particularly in those cases (such as in patients with acquired immunodeficiency syndrome) where high-dose therapy is indicated.Much attention has focused on liposome suspensions containing 5-10 mol % amphotericin B because these systems have been shown to produce a significant attenuation of toxicity with little compromise to efficacy (4-7). In fact one such formulation in which amphotericin comprises 5 mol % of a 1,2-dimyristoyl-sn-glycero(3)phosphocholine/1,2-dimyristoyl-sn-glycero(3)phospho (1) PtdGro at a molar ratio of 7:3 was deposited from chloroform as a thin film on the bottom ofa 500-ml round-bottomed flask by rotoevaporation. This film was solubilized in 100 ml of amphotericin B in methanol (0.1 mg/ml) and again rotoevaporated to a thin film. When dry, the film was suspended in isotonic phosphatebuffered saline (PBS) and subjected to bath sonication for 0.5 hr or until particles exhibiting Brownian motion were observed by phase-contrast microscopy.Sucrose Density Centrifugation. Typically, 200 gl of material was layered onto a continuous sucrose gradient in 150 mM NaCI/20 mM Hepes, pH 7.4. The gradient was centrifuged for 22 hr at 22TC in a SW 60 rotor (Beckman) at 230,000 x g. After centrifugation the gradient was fractionated into 150-,ul aliquots and assayed for amphotericin B (from absorbance at 412 nm in dimethylformamide) and phospholipid (from phosphate assay after digestion).In Vivo Toxicity. LD50 values were determined by the method of Reed and Muench (12). Female...
Purpose: The idiotype (Id) of the immunoglobulin on a given B-cell malignancy is a clonal marker that can serve as a tumor-specific antigen. We developed a novel vaccine formulation by incorporating Id protein with liposomal lymphokine that was more potent than a prototype, carrierconjugated Id protein vaccine in preclinical studies. In the present study, we evaluated the safety and immunogenicity of this vaccine in follicular lymphoma patients.Experimental Design: Ten patients with advanced-stage follicular lymphoma were treated with five doses of this second generation vaccine after chemotherapy-induced clinical remission. All patients were evaluated for cellular and humoral immune responses.Results: Autologous tumor and Id-specific type I cytokine responses were induced by vaccination in 10 and 9 patients, respectively. Antitumor immune responses were mediated by both CD4 ؉ and CD8 ؉ T cells, were human lymphocyte antigen class I and II associated, and persisted 18 months beyond the completion of vaccination. Specific anti-Id antibody responses were detected in four patients. After a median follow-up of 50 months, 6 of the 10 patients remain in continuous first complete remission.Conclusions: This first clinical report of a liposomal cancer vaccine demonstrates that liposomal delivery is safe, induces sustained tumor-specific CD4؉ and CD8 ؉ T-cell responses in lymphoma patients, and may serve as a model for vaccine development against other human cancers and infectious pathogens.
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