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

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.

Specific humoral and cellular immune responses in cancer patients undergoing chronic immunization with a VEGF-based therapeutic vaccine.

CIGB-247 is a cancer therapeutic vaccine, based on recombinant modified human vascular endothelial growth factor (VEGF) as antigen, in combination with the adjuvant VSSP, a bacterially-derived adjuvant. The vaccine have demonstrated efficacy in several murine malignancy models. These studies supported the rationale for a phase I clinical trial where safety, tolerance, and immunogenicity of CIGB-247 was studied in patients with advanced solid tumors at three antigen dose level. Surviving individuals of this clinical trial were eligible to receive off-trial voluntary re-immunizations. The present work is focus in the immunological follow up of these patients after approximately three years of immunizations, without additional oncological treatments. Long term vaccination was feasible and safe. Our results indicated that after sustained vaccination most of the patients conserved their seroconversion status. The specific anti-VEGF IgG titer diminished, but in all the cases keeps values up from the pre-vaccination levels. Continued vaccination was also important to produce a gradual shift in the anti-VEGF IgG response from IgG1 to Ig4. Outstanding, our results indicated that long-term off-trial vaccination could be associated with the maintaining of one reserve of antibodies able to interfere with the VEGF/Receptor interaction and the production of IFNγ secretion in CD8+ cells. The results derived from the study of this series of patients suggest that long term therapeutic vaccination is a feasible strategy, and highlight the importance of continuing the clinical development program of this novel cancer therapeutic vaccine candidate. We also highlight the future clinical applications of CIGB-247 in cancer and explain knowledge gaps that future studies may address. Registration number and name of trial registry: RPCEC00000102. Cuban Public Clinical Trial Registry (WHO accepted Primary Registry). Available from: http://registroclinico.sld.cu/.

Indirect and competitive enzyme-linked immunosorbent assays for monitoring the humoral response against human VEGF.

CIGB-247, a VEGF-based vaccine, was studied in a clinical trial. This advance demands the refinement of the methodologies for assessment of vaccine immune responses. This study aimed to improve the performance of ELISAs for detecting IgG antibodies against human VEGF and the blocking activity of the serum to inhibit the VEGF/VEGFR2 interaction. The best experimental conditions were established through the evaluation of several blocking buffers, immobilization surfaces, and plate suppliers using human sera as test samples. As a result, two controlled ELISAs were used in testing of elicited immune response against VEGF in patients immunized with CIGB-247.