Active Immunization With Pd1-Derived Mimotope-Combination Immunotherapy Against Her-2/Neu-Expressing Tumors

Application of monoclonal antibodies (mAbs) as immune checkpoint inhibitors (ICIs) has demonstrated a tremendous effect in cancer immunotherapy. However, high costs for and frequent applications of mono- or combination-therapies or possible development of resistance justify modifications of this approach. In this line, active immunization with mimotopes (B cell peptides) of ICIs, activating the patients9 own immune system, rather than application of the corresponding therapeutic mAbs, may provide advantages over the costly treatment of the mAbs. Overlapping peptides spanning the extracellular domains of human PD1 (hPD1) were used to identify hPD1-derived mimotope, using the therapeutic mAb Nivolumab as a proof of concept. Additionally, for in vivo evaluation in a tumor mouse model, a mouse PD1 (mPD1)-derived mimotope was identified using an anti-mPD1 mAb with mPD1/mPDL-1 blocking capacity. The identified mimotopes were characterized by in vitro assays, including a reporter cell-based assay, and their anti-tumor effect was evaluated in a syngeneic mouse model involving grafting with human Her-2/neu-expressing tumors. The PD1-mimotopes were shown to specifically inhibit the binding of the corresponding mAbs, and also the mAbs capacity in blocking the respective PD1-PDL1 interactions. Applying the syngeneic tumor mouse model, a significant tumor growth reduction following active immunization with the mPD1-mimotope was shown. Importantly, combined vaccination with the mimotope and a multiple B-cell epitope Her-2/neu vaccine potentiated the anti-tumor effect in the syngeneic mice. Tumor growth reduction in the mice immunized with the mimotope was associated with a significant increase of the apoptotic (CC3) and significant reduction of proliferation (Ki67) markers, as evaluated by immunohistochemistry (IHC) staining. However, the tumor growth reduction following active immunization with the cancer vaccine (alone or in combination with the checkpoint mimotope) showed a different IHC picture, namely highly increased levels of CC3 without reduction of proliferation (Ki67 levels) in the tumor cells. In depth studies on the underlying mechanisms of tumor growth reduction are currently ongoing. Our results suggest active immunization with B cell mimotopes of ICIs as either monovalent vaccine or a combination therapy with tumor specific vaccines to enhance the anti-tumor efficacy. Such strategies may potentially lead to multipurpose treatment regimens adapted to the type, stage and progression phase of the various tumors. Citation Format: Joshua Tobias, Claire Battin, Annika De Sousa Linhares, Michael Lebens, Karin Baier, Katharina Ambroz, Mirjana Drinic, Sandra Hogler, Aleksandra Inic-Kanada, Erika Garner-Spitzer, Matthias Preusser, Lukas Kenner, Michael Kundi, Christoph C. Zielinski, Peter Steinberger, Ursula Wiedermann. Active immunization with PD1-derived mimotope-Combination immunotherapy against Her-2/neu-expressing tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3151.