| Popis: |
Background: Immune checkpoint blockade (ICB) antibodies have demonstrated that effective induction of T cell responses can elicit tumor regression of different metastatic cancers, although these responses are restricted to certain individuals with specific types of cancer. To enhance these responses, there has been renewed emphasis in developing different types of cancer-specific vaccines to stimulate and direct T cell and B cell immunity to important oncologic targets, such as the oncogene human epidermal growth factor receptor 2 (HER2), which is expressed in ~20% of breast cancers (BC). In our previous work we used a DNA plasmid vaccine targeting HER2, which utilized a lysosome-associated membrane protein 1 (LAMP) domain to traffic HER2 antigen to endolysosomal compartments. We demonstrated that this approach was more effective at eliciting antigen specific CD4+ and CD8+ T cell responses, and provided a significant but limited survival benefit in an endogenous mouse model of HER2+ BC compared to a HER2-wild type vaccine. Methods: In our current study, we explored the use of this modified antigen construct using different vaccine modalities, including DNA plasmid, adenoviral (Ad), modified vaccinia ankara (MVA), and self-replicating RNA vaccines to identify effective vaccine platforms to elicit HER2-specific immunity and anti-tumor immunity. Additionally, we have tested the combination of these modalities in homologous and heterologous vaccine boosting regimens to determine an optimal strategy to elicit anti-tumor immunity in vivo. Results: In our studies, plasmid and MVA vectors elicited suboptimal immune priming responses, in comparison to Ad and self-replicating RNA vectors that elicit significant HER2-specific T and B cell responses upon vaccination. While timing of boosting is critical, our results reflect that certain platforms (e.g., plasmid DNA vectors) are capable of homologous boosting capacity, while others (e.g., Ad vectors) elicit more robust T and B cell responses to capsid epitopes, limiting homologous boosting capacity for HER2-specific immunity. Significantly, using an endogenous model of metastatic HER2+ BC, we have found that heterologous vaccination with different HER2-LAMP targeted vectors can elicit significantly augmented HER2-specific T and B cell responses that translated into more effective anti-tumor immunity. This immunity proved capable of eliciting tumor regression in ~80% of vaccinated mice, compared to 0% using homologous HER2-WT plasmid vaccination, 30% using homologous HER2-LAMP plasmid vaccination, or 50% with HER2-WT heterologous vaccination. Conclusions: These data demonstrate the potential of utilizing heterologous vaccine platforms encoding LAMP-based endolysosomal trafficking vaccines to elicit HER2-specific immunity and effect anti-tumor responses. Citation Format: Robert D. Marek, Alan Chen, Renhuan Xu, Junping Wei, Tao Wang, Xiao Yang, Gangjun Lei, Teri Heiland, Zachary C. Hartman. Vaccination using different platforms encoding HER2-LAMP with heterologous boosting enhances adaptive HER2-specific immunity to enable potent anti-tumor responses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3564. |
