![]() ![]() Two of the first generation constructs have advanced to clinical trials. The original HER2 vaccines were designed to be free of oncogenic kinase activity. Our HER2 DNA vaccines have evolved through three generations of construction and testing. Both humoral and cellular HER2 immunity contribute to tumor growth inhibition, whether by direct killing through antibodies or T cells, or by Ab-dependent cell-mediated cytotoxicity, culminating in a comprehensive, multi-effector anti-tumor response. HER2 is an epidermal growth factor receptor that is over-expressed in a variety of cancers to stimulate tumor growth, and endogenous HER2 immunity is found in patients. Here, we tested a new strategy to overcome immune tolerance by exploiting common amino acid (AA) substitutions occurring during evolution. While this could be due to immune suppressive mechanisms such as immune checkpoints and regulatory T cells, the greatest challenge remains in the balance between self-tolerance and tumor immunity. Only limited success, however, has been achieved from cancer vaccines targeting unmodified TAA. Additionally, active vaccination targeting known TAA may create a favorable tumor microenvironment for neoantigen priming to enhance immune protection. Although some tumor infiltrating lymphocytes (TIL) recognize neoantigens, the majority of TIL clones recognized tumor-associated self-antigens (TAA). The fundamental principle of exploiting evolution-selected amino acid substitutions is novel, effective and applicable to vaccine development in general.Ĭlinical successes of checkpoint inhibitors have demonstrated that endogenous immunity can destroy tumors. The elevation of tumor immunity by ph(es)E2TM vaccination would create a favorable tumor microenvironment for neoantigen priming, further enhancing the protective immunity. ph(es)E2TM vaccination reduced tumor growth more effectively than wild-type HER2 or HER2 vaccines with more extensive modifications. ![]() ph(es)E2TM, but not pE2TM immune serum, recognized HER2 peptide p95 355LPESFDGDPASNTAP 369, suggesting a broadening of epitope recognition induced by the minimally modified HER2 vaccine. Compared to native human HER2, electrovaccination of HER2 transgenic mice with ph(es)E2TM induced a threefold increase in HER2-binding antibody (Ab) and elevated levels of IFNγ-producing T cells. h(es)E2TM recombinant protein is recognized by a panel of anti-HER2 mAbs, demonstrating the preservation of HER2 protein structure. These ph(es)E2TM substitutions score 0 to 1 in blocks substitutions matrix (BLOSUM), indicating minimal biochemical alterations. ph(es)E2TM was designed to contain five evolution- selected substitutions: M198V, Q398R, F425L, H473R and A622T that occur frequently in 12 primate HER2 sequences. Toward this goal, we compared the efficacy of the following HER2 DNA vaccine constructs: vaccines encoding wild-type HER2, hybrid HER2 vaccines consisting of human HER2 and rat Neu, HER2 vaccines with single residue substitutions and a novel human HER2 DNA vaccine, ph(es)E2TM. Enhancement of endogenous immunity to tumor-associated self-antigens and neoantigens is the goal of preventive vaccination.
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