Therapeutic Vaccination Halts Disease Progression in BALB-neuT Mice: The Amplitude of Elicited Immune Response Is Predictive of Vaccine Efficacy

Abstract

The aim of this study was to evaluate the efficacy of genetic vaccination with rat ErbB2 antigen in a therapeutic setting for the BALB-neuT mouse model of mammary carcinoma and to establish immunological correlates with vaccine efficacy. To define an early therapeutic setting we performed imaging studies of mouse mammary glands with a high-frequency ultrasound system that allowed the diagnosis of tumor lesions before they become palpable, starting from week 13 after mouse births. An intensive immunization protocol of vaccination was implemented at this stage, consisting of four weekly DNA injections with electroporation followed by two injections of adenovirus carrying the codon usage-optimized cDNA encoding the extracellular-transmembrane domain of rat ErbB2. Immunological parameters were monitored in each individual mouse by analyzing peripheral blood leukocytes. The appearance of the first palpable tumor in vaccinated mice was delayed and there was a statistically significant time gap before additional masses developed, indicating disease stabilization. As a result of the immunization, antibodies and CD8(+) T cells to rat ErbB2 were detected and the amplitude of elicited responses correlated with the efficacy of vaccination. Moreover, the vaccination regimen specifically halted the rise in circulating myeloid suppressor cells (MSCs). All three parameters, that is, CD8(+) T cells, antibodies to rat ErbB2, and circulating MSCs, measured at the end of vaccination could be used as predictive biomarkers for future tumor development. This study emphasizes the potential of genetic vaccines for the therapeutic treatment of malignancies and suggests possible predictive biomarkers to be further validated in the clinic for the follow-up of vaccinated cancer patients.

Preventive Vaccination with Telomerase Controls Tumor Growth in Genetically Engineered and Carcinogen-Induced Mouse Models of Cancer

“…Intracellular staining (ICS) was performed as described (19). Cells were then fixed with formaldehyde 1% in PBS and analyzed on a FACS Canto II using DIVA software (Becton Dickinson).…”

Mesenchymal Stromal Cells Expressing ErbB-2/neu Elicit Protective Antibreast Tumor Immunity In vivo, Which Is Paradoxically Suppressed by IFN-γ and Tumor Necrosis Factor-α Priming

“…Neu-specific antibody responses were measured in sera of individual mice by a flow cytometry-based assay, as described (16 (19) epitopes from the rat neu antigen, respectively. Peptides were synthesized at the McGill Sheldon Biotechnology Center with purity above 98%.…”

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

“…We have previously shown that this combination is highly efficient in generating immune responses to a variety of immunogens. 19,28,29 Two weeks after the Ad injection, cell-mediated immune response was measured by IFNc ELISPOT using four pools (A, B, C, and D from the NH 2 terminus to the COOH terminus of the protein, respectively) of 15mer peptides, overlapping by 11 residues and encompassing the entire rhCEA protein or hCEA. Control wild-type mice (C57BL/6) were vaccinated using the same protocol.…”

“…The effector T-cells recognize a 9-amino acid gp100 epitope (gp100 [25][26][27][28][29][30][31][32][33] ), restricted by MHC class I H-2D b , which is different in three positions (amino acids [25][26][27] between the two species. Differences in these three NH 2 -terminal amino acids result in a 2-log increase in the ability of the hgp100 [25][26][27][28][29][30][31][32][33] to stabilize ''empty'' H-2D b molecules on cells and a 3-log increase in its ability to trigger IFN-c release by T-cells.…”

“…Differences in these three NH 2 -terminal amino acids result in a 2-log increase in the ability of the hgp100 [25][26][27][28][29][30][31][32][33] to stabilize ''empty'' H-2D b molecules on cells and a 3-log increase in its ability to trigger IFN-c release by T-cells. No other differences in the two proteins are responsible for this ''xeno-vaccination effect.''…”