A Phase I Open-Label Clinical Trial Evaluating the Therapeutic Vaccine hVEGF26-104/RFASE in Patients with Advanced...

The novel therapeutic vaccine hVEGF_26-104 /RFASE was found to be safe and well tolerated in patients with cancer. hVEGF_26-104 /RFASE failed to induce seroconversion against native hVEGF₁₆₅ and, accordingly, neither a decrease in circulating vascular endothelial growth factor (VEGF) levels nor clinical benefit was observed. Remarkably, hVEGF_26-104 /RFASE induced VEGF₁₆₅ -neutralizing antibodies in a nonhuman primate model. The absence of seroconversion in human calls for caution in the interpretation of efficacy of human vaccines in nonhuman primates.

Targeting vascular endothelial growth factor-A (VEGF) is a well-established anticancer therapy. We designed a first-in-human clinical trial to investigate the safety and immunogenicity of the novel vaccine hVEGF_26-104 /RFASE.

Patients with advanced solid malignancies with no standard treatment options available were eligible for this phase I study with a 3+3 dose-escalation design. On days 0, 14, and 28, patients received intramuscular hVEGF_26-104 , a truncated synthetic three-dimensional (3D)-structured peptide mimic covering the amino acids 26-104 of the human VEGF₁₆₅ isoform, emulsified in the novel adjuvant Raffinose Fatty Acid Sulphate Ester (RFASE), a sulpholipopolysaccharide. Objectives were to determine safety, induction of VEGF-neutralizing antibodies, and the maximum tolerated dose. Blood was sampled to measure VEGF levels and antibody titers.

Eighteen of 27 enrolled patients received three immunizations in six different dose-levels up to 1,000 μg hVEGF_26-104 and 40 mg RFASE. No dose-limiting toxicity was observed. Although in four patients an antibody titer against hVEGF_26-104 was induced (highest titer: 2.77 ¹⁰ log), neither a reduction in VEGF levels nor neutralizing antibodies against native VEGF₁₆₅ were detected.

Despite having an attractive safety profile, hVEGF_26-104 /RFASE was not able to elicit seroconversions against native VEGF₁₆₅ and, consequently, did not decrease circulating VEGF levels. Deficient RFASE adjuvant activity, as well as dominant immunoreactivity toward neoepitopes, may have impeded hVEGF_26-104 /RFASE's efficacy in humans.