Specific active immunotherapy with the HEBERSaVax VEGF-based cancer vaccine: From bench to bedside.

ABSTRACT

HEBERSaVax is a cancer therapeutic vaccine candidate based on the combination of a recombinant antigen representative of human vascular endothelial growth factor (VEGF), and clinically tested adjuvants. The vaccine has been shown to inhibit tumor growth and metastases in mice, and to induce VEGF-blocking antibodies and specific T-cell responses in several animal species, all with an excellent safety profile. After preclinical studies, two sequential phase 1 clinical trials were conducted with HEBERSaVax to assess safety, tolerance, and immunogenicity in patients with advanced solid tumors, at different antigen doses, and combined with two distinct adjuvants. HEBERSaVax was found to be safe and tolerable, with mainly low-grade local adverse effects. Immunized patients produced specific anti-VEGF IgG antibodies that blocked VEGF-VEGF Receptor 2 (KDR) interaction in an in vitro competitive ELISA assay. Gamma-IFN ELISPOT tests done with patient samples were positive after in vitro stimulation of peripheral blood mononuclear cells (PBMC) with a mutated VEGF molecule. Patients surviving week 16 in the trials received voluntary off-trial monthly re-immunizations with HEBERSaVax, until death, intolerance, marked disease progression, or patient's withdrawal of consent. No additional onco-specific treatment was administered. After up to 6 years of vaccinations, the safety profile of HEBERSaVax remained excellent, with patients showing positive results in the specific immune response tests. Evidence of clinical benefit has also been documented in some individuals. The results of these studies suggest that long-term vaccination with HEBERSaVax is a feasible strategy, and highlight the importance of continuing the clinical development program of this novel cancer therapeutic vaccine candidate.