Recombinant Aspergillus fumigatus antigens Asp f 3 and Asp f 9 in liposomal vaccine protect mice against invasive pulmonary aspergillosis.

Invasive pulmonary aspergillosis caused by the ubiquitous mold Aspergillus fumigatus is a major threat to immunocompromised patients, causing unacceptably high mortality despite standard of care treatment, and costing an estimated $1.2 billion annually. Treatment for this disease has been complicated by the emergence of azole resistant strains of A. fumigatus, rendering first-line antifungal therapy ineffective. The difficulties in treating infected patients using currently available drugs make immunotherapeutic vaccination an attractive option. Here, we demonstrate the efficacy of VesiVax® adjuvant liposomes, consisting of a combination of two individual liposome preparations, to which two recombinant A. fumigatus surface antigens, Asp f 3 and Asp f 9 (VesiVax® Af3/9), have been chemically conjugated. Using a murine model, we demonstrate that VesiVax® Af3/9 is protective against infection by azole resistant strains of A. fumigatus in both steroid-suppressed and neutropenic mice as quantified by improved survival and reduced fungal burden in the lungs. This protection correlates with upregulation of IL-4 produced by splenocytes, and the presence of Asp f 3 and Asp f 9 specific IgG2a antibodies in the serum of mice given VesiVax® Af3/9. Furthermore, mice given VesiVax® Af3/9 with a subsequent course of liposomal amphotericin B (AmBisome®) had improved survival over those given either treatment alone, indicating a benefit to VesiVax® Af3/9 vaccination even in the case of infections that require follow-up antifungal treatment. These data demonstrate that prophylactic vaccination with VesiVax® Af3/9 is a promising method of protection against invasive pulmonary aspergillosis even as the changing face of the disease renders current therapies ineffective.

Phase I dose escalation clinical trial of phenylbutyrate sodium administered twice daily to patients with advanced solid tumors.

BACKGROUND: Phenylbutyrate (PBA), and its metabolite phenylacetate (PAA), induce growth inhibition and cellular differentiation in multiple tumor models. However, despite their potential anti-cancer properties, several pharmacodynamic aspects remain unknown. METHODS: We conducted a dose escalating trial to evaluate twice-daily intravenous PBA infusions for two consecutive weeks (Monday through Friday) every month at five dose levels (60-360 mg/kg/day). Twenty-one patients with the following malignancies were treated: colon carcinoma 4, non-small cell lung carcinoma 4; anaplastic astrocytoma 3, glioblastoma multiforme 3, bladder carcinoma 2, sarcoma 2, and ovarian carcinoma, rectal hemangiopericytoma, and pancreatic carcinoma 1 each. RESULTS: Conversion of PBA to PAA and phenylacetylglutamine (PAG) was documented without catabolic saturation. Plasma content of PBA > or =1 mM was documented for only 3 h following each dose at the top two dosages. The therapy was well tolerated overall. Common adverse effects included grade 1 nausea/vomiting, fatigue, and lightheadedness. Dose limiting toxicities were short-term memory loss, sedation, confusion, nausea, and vomiting. Two patients with anaplastic astrocytoma and a patient with glioblastoma remained stable without tumor progression for 5, 7, and 4 months respectively. CONCLUSIONS: Administration of PBA in a twice-daily infusion schedule is safe. The maximum tolerated dose is 300 mg/kg/day. Study designs with more convenient treatment schedules and specific molecular correlates may help to further delineate the mechanism of action of this compound. Future studies evaluating PBA's ability to induce histone acetylation and cell differentiation alone or in combination with other anti-neoplastics are recommended.