Immunogenicity and safety of a DNA prime/adenovirus boost vaccine against rhesus CEA in nonhuman primates

Abstract

Scaling up experimental protocols from rodents to humans is often not a straightforward procedure, and this particularly applies to cancer vaccines, where vaccination technology must be especially effective to overcome a variety of immune suppressive mechanisms. DNA electroporation (DNA-EP) and adenoviral vectors (Ad) have shown high potency and therapeutic efficacy for different antigens in several pre-clinical models. To evaluate the ability of DNA-EP and Ad to break tolerance to a self-antigen in large animals, we have cloned the CEA homologue (rhCEA) from rhesus monkeys (Macaca mulatta) colon tissue samples. rhCEA is a 705 aa protein and shares 78.9% homology to human CEA protein. Immunogenicity of rhCEA expressing vectors was tested in mice and subsequently in rhesus monkeys. To further increase the immunogenic potency of these vectors, a synthetic codon optimized rhCEA cDNA (rhCEAopt) was constructed. Genetic vaccination of rhesus monkeys was effective in breaking immune tolerance to rhCEA in all immunized animals, maintaining over time the elicited immune response, and most importantly, neither autoimmunity nor other side-effects were observed upon treatment. Our data confirm the efficacy of genetic cancer vaccines in large animals such as nonhuman primates and show that development of modified expression cassettes that result in increased potency of plasmid DNA and adenovirus may have a significant impact on vaccine development against malignancies expressing tumor associated antigens in patients. ' 2007 Wiley-Liss, Inc.

MMP11: A Novel Target Antigen for Cancer Immunotherapy

“…To identify the best immunogen for vaccination, we tested three different forms of murine MMP11: wild type (MMP11 wt ), codon optimized (MMP11 opt ), and fused to the LTB (MMP11-LTB opt ). Codon optimization of cDNA has been shown to enhance expression and the induction of the immune response (27,34,35), whereas fusion to LTB increases antigen immunogenicity (24). To abrogate enzymatic activity, a point mutation was introduced in the latter two versions, changing glutamic acid to alanine at position 220 (11).…”

Treatment of Mammary Carcinomas in HER-2 Transgenic Mice through Combination of Genetic Vaccine and an Agonist of Toll-Like Receptor 9

“…4A), different from the one recognized by trastuzumab (36) but within the region bound by pertuzumab (37). 6 To extend the analysis to a large number of mice, we set up an ELISA assay for peptide r70, and mice that received DNA-EP vaccine or DNA-EP vaccine/IMO were compared. Most of the mice treated with the combination of DNA-EP vaccine/IMO seroconverted, whereas only a small fraction of mice treated with DNA-EP vaccine alone showed antibodies against this particular epitope (P = 0.01, t test; Fig.…”

Superior Immunologic and Therapeutic Efficacy of a Xenogeneic Genetic Cancer Vaccine Targeting Carcinoembryonic Human Antigen

“…Rhesus CEA (rhCEA) encodes a protein of 705 amino acids that is 78.9% homologous to hCEA. 19 We also showed that rhCEA, when delivered by DNA-EGT and Ad vectors, is capable of inducing immune responses both in nontolerant mice and, more importantly, in tolerant rhesus monkeys. In the present work we have assessed the potency of rhCEA as xenoantigen both in single-transgenic mice for hCEA (CEA.Tg) and in double-transgenic mice for hCEA and for the human MHC HLA-A*0201 human haplotype (HHD/ CEA).…”