Antigen dose escalation study of a VEGF-based therapeutic cancer vaccine in non human primates.
Summary of "Antigen dose escalation study of a VEGF-based therapeutic cancer vaccine in non human primates."
CIGB-247 is a cancer therapeutic, based on recombinant modified human vascular endothelial growth factor (VEGF) as antigen, in combination with the oil free adjuvant VSSP (very small sized proteoliposomes of Neisseria meningitidis outer membrane). Our previous experimental studies in mice with CIGB-247 have shown that the vaccine has both anti-tumoral and anti-metastatic activity, and produces both antibodies that block VEGF-VEGF receptor interaction, and a specific T-cell cytotoxic response against tumor cells. CIGB-247, with an antigen dose of 100μg, has been characterized by an excellent safety profile in mice, rats, rabbits, and non human primates. In this article we extend the immunogenicity and safety studies of CIGB-247 in non human primates, scaling the antigen dose from 100μg to 200 and 400μg/vaccination. Our results indicate that such dose escalation did not affect animal behavior, clinical status, and blood parameters and biochemistry. Also, vaccination did not interfere with skin deep skin wound healing. Anti-VEGF IgG antibodies and specific T-cell mediated responses were documented at all three studied doses. Antigen dose apparently did not determine differences in maximum antibody titer during the 8 weekly immunization induction phase, or the subsequent increase in antibodies seen for monthly boosters delivered afterwards. Higher antigen doses had a positive influence in antibody titer maintenance, after cessation of immunizations. Boosters were important to achieve maximum antibody VEGF blocking activity, and specific T-cell responses in all individuals. Purified IgG from CIGB-247 immunized monkey sera was able to impair proliferation and formation of capillary-like structures in Matrigel, for HMEC cells in culture. Altogether, these results support the further clinical development of the CIGB-247 therapeutic cancer vaccine, and inform on the potential mechanisms involved in its effect.
Cancer Immunotherapy Laboratory, Department of Pharmaceuticals, Center for Genetic Engineering and Biotechnology, P.O. Box 6162, Playa Cubanacábn, Havana 10600, Cuba.
This article was published in the following journal.
- PubMed Source: http://www.ncbi.nlm.nih.gov/pubmed/22075086
- DOI: http://dx.doi.org/10.1016/j.vaccine.2011.10.082
Medical and Biotech [MESH] Definitions
The specific failure of a normally responsive individual to make an immune response to a known antigen. It results from previous contact with the antigen by an immunologically immature individual (fetus or neonate) or by an adult exposed to extreme high-dose or low-dose antigen, or by exposure to radiation, antimetabolites, antilymphocytic serum, etc.
Maximum Tolerated Dose
The highest dose of a biologically active agent given during a chronic study that will not reduce longevity from effects other than carcinogenicity. (from Lewis Dictionary of Toxicology, 1st ed)
Lethal Dose 50
The dose amount of poisonous or toxic substance or dose of ionizing radiation required to kill 50% of the tested population.
A cancer registry mandated under the National Cancer Act of 1971 to operate and maintain a population-based cancer reporting system, reporting periodically estimates of cancer incidence and mortality in the United States. The Surveillance, Epidemiology, and End Results (SEER) Program is a continuing project of the National Cancer Institute of the National Institutes of Health. Among its goals, in addition to assembling and reporting cancer statistics, are the monitoring of annual cancer incident trends and the promoting of studies designed to identify factors amenable to cancer control interventions. (From National Cancer Institute, NIH Publication No. 91-3074, October 1990)
Vascular Endothelial Growth Factor Receptor-1
A 180-kDa VEGF receptor found primarily in endothelial cells that is essential for vasculogenesis and vascular maintenance. It is also known as Flt-1 (fms-like tyrosine kinase receptor-1). A soluble, alternatively spliced isoform of the receptor may serve as a binding protein that regulates the availability of various ligands for VEGF receptor binding and signal transduction.
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