Construction of a novel anti-Her-2/neu multi-level vaccine combining Trastuzumab and Pertuzumab binding site mimotopes together with anti-PD1 immune checkpoint inhibitor
Construction of a novel anti-Her-2/neu multi-level vaccine combining Trastuzumab and Pertuzumab binding site mimotopes together with anti-PD1 immune checkpoint inhibitor Joshua Tobias1, K. Baier1, K. Ambroz1, C. C. Zielinski2, U. Wiedermann1 1Institute of Specific Prophylaxis and Tropical Medicine, Medical University of Vienna, Austria; 2Division of Oncology, General Hospital, Vienna, Austria
Extracellular subdomains of Her-2/neu, which is overexpressed in 20-25% of breast and gastric cancers, have been the focus for immunotherapy. Combination of the monoclonal antibodies (mAbs) Trastuzumab and Pertuzumab has been shown to synergistically result in a significant improvement in clinical outcomes of patients with Her-2/neu-positive metastatic breast cancer. However active immunotherapy, unlike application of mAbs, provides advantages like induction of humoral, cellular and memory responses leading to achievement of anti-tumor activity.
The first generation of our B cell multi-peptide anti-Her-2/neu vaccine, containing three single peptides conjugated to virosomes, was recently improved to the second generation by fusing the peptides into a hybrid peptide which after conjugation to CRM197 and with use of the adjuvant Montanide (P467-CRM-Montanide) led to induction of enhanced and long term humoral and Th1-biased cellular responses with antitumor activity. To broaden the number of biologically active epitopes in the vaccine, its third generation has recently been developed by including the binding site epitopes (mimotopes) of Trastuzumab and Pertuzumab which in combination with P467 have shown to induce polyclonal humoral responses and cellular responses.
Combinational therapy of cancer vaccines and immune checkpoint inhibitors has been lately suggested to synergistically enhance antitumor immune responses. When immunizing mice with P467-CRM-Montanide combined with anti-mouse PD-1 mAb vaccination, we have seen generally elevated cellular responses compared to unvaccinated mice. The anti-tumor effect of the third generation of our vaccine in combination with anti-mouse PD1 mAb is now being evaluated in transgenic mice spontaneously developing rat Her-2/neu.
Construction of the third generation of our anti-Her2/neu vaccine combined with an immune checkpoint inhibitor may result in an effective novel multi-level vaccine against Her-2/neu overexpressing cancer entities.
The study is granted by Imugene Limited, Australia, and Medical University of Vienna.
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