Abstract
Cancer vaccines are less effective at old than at young age because of immunosenescence. Besides, in preliminary observations we showed that the immunization with HER-2/neu DNA plasmid in transgenic young mice (standard immunization, SI) delays but not abrogate spontaneous mammary tumours progressively appearing during aging. In this study we evaluated whether booster immunizations (BI) of HER-2/neu transgenic mice with HER-2/neu DNA plasmids every 6 (ECD6), 3 (ECD3), or 1.5 (ECD1.5) months after SI induce a protective immunity that could be maintained over life span. The long term BI significantly improved the effect of SI increasing the number of tumour free mice at 110 weeks of age from 13% (SI) to 58% (BI). Both the number and the volume of tumour masses were reduced in BI than in SI groups. The protective effect of BI was associated with increased antibody production with isotype switching to IgG2a, augmented CD4 T cells, and increased in vivo cytotoxicity of HER-2/neu specific cytotoxic T lymphocytes, mainly in ECD1.5 and ECD3 groups. The transfer of sera from ECD1.5 mice to untreated HER-2/neu mice highly protected against tumour development than sera from SI mice. We conclude that BI induce a protective immunity effective over life span.
Highlights
Studies conducted in various animal models have demonstrated that anticancer vaccination represents an efficacious approach to elicit a potent immune response and to induce immune memory against tumour antigens[1,2,3]
In preliminary experiments, we observed that the standard immunization procedure with DNA coding for HER-2/neu in young transgenic mice delays but not abrogate the appearance of mammary tumours, since tumour masses progressively appeared after 40 weeks of age and more than 80% of mice were bearing tumour masses after 90 weeks of age
Long-term booster immunizations (BI) significantly improved the outcome of standard vaccination without significant differences among the three different immunization schedules (p < 0.01, p < 0.004, and p < 0.001, for ECD6, ECD3, or ECD1.5, respectively vs. ECD)
Summary
Studies conducted in various animal models have demonstrated that anticancer vaccination represents an efficacious approach to elicit a potent immune response and to induce immune memory against tumour antigens[1,2,3]. A good model for studying cancer immunoprevention through DNA vaccination is that of HER-2/neu transgenic mice, an in vivo experimental model of mammary cancer that strongly emulates human disease[17] In these mice, HER2/neu DNA immunization in young age, completely prevents the spontaneous development of mammary tumours, which normally occurs in 100% of animals at 5–6 months of age[13]. In preliminary experiments, we observed that the standard immunization procedure with DNA coding for HER-2/neu in young transgenic mice delays but not abrogate the appearance of mammary tumours, since tumour masses progressively appeared after 40 weeks of age and more than 80% of mice were bearing tumour masses after 90 weeks of age These effects could be explained by changes arising with the immunosenescence that render the “old” immune system unable to respond efficiently to the antigenic stimuli, and/or to the short-term protection of immunization strategies, that, once activated in young age, lose their effectiveness during aging. It has been shown that the time elapsed since last vaccination has a significant effect on the antibody titres and can be essential for a protective response[19]
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