Specific active immunotherapy with a VEGF vaccine in patients with advanced solid tumors. results of the CENTAURO antigen dose escalation phase I clinical trial

Abstract

CIGB-247 is a novel cancer therapeutic vaccine that uses a human VEGF variant molecule as antigen, in combination with a bacterial adjuvant. In mice, CIGB-247 has anti-tumor and anti-metastatic effects. The vaccine induces anti-VEGF blocking antibodies and a cellular response targeting tumor cells producing VEGF, and has proven to be safe in mice, rats, rabbits and non-human primates. Herein we report the results of a Phase I clinical trial (code name CENTAURO) where safety, tolerance, and immunogenicity of CIGB-247 were studied in 30 patients with advanced solid tumors, at three antigen dose levels. Individuals were subcutaneously immunized for 8 consecutive weeks with 50, 100 or 400 μg of antigen, and re-immunized on week twelve. On week sixteen, evaluations of safety, tolerance, clinical status, and immunogenicity (seroconversion for anti-VEGF IgG, serum VEGF/KDR-Fc blocking ability, and gamma-IFN ELISPOT with blood cells stimulated in vitro with mutated VEGF) were done. Surviving patients were eligible for off-trial additional 4-week re-immunizations with 400 μg of antigen. Immunogenicity and clinical status were again studied on weeks 25 and 49. Vaccination was shown to be safe at the three dose levels, with only grade 1-2 adverse events. CIGB-247 was immunogenic and higher numbers of individuals positive to the three immune response tests were seen with increasing antigen dose. Off-protocol long-term vaccination produced no additional adverse events or negative changes in immunogenicity. Eleven patients are still alive, with overall survivals ranging from 20 to 24 months. Twelve of the thirty patients exhibited objective clinical benefits, and two individuals have complete responses. Most patients with higher survivals are positive in the three immune response tests. In summary, this is the first clinical testing report of a cancer therapeutic vaccine based on a human VEGF related molecule as antigen. The CIGB-247 vaccine is safe, immunogenic, and merits further clinical development.

Registration number and name of trial registry: RPCEC00000102. Cuban Public Clinical Trial Registry (WHO accepted Primary Registry). Available from: http://registroclinico.sld.cu/.

Keywords: Active immunotherapy; Angiogenesis; Cancer; Clinical trial; VEGF; Vaccine.