1460 - Active immunization with immune checkpoint inhibitors-mimotope elicits strong anti-tumor effect against Her-2/neu-expressing tumors

Background

Application of monoclonal antibodies (mAbs) as immune checkpoint inhibitors (ICIs) has demonstrated remarkable activity in cancer immunotherapy. Active immunization with mimotopes (B cell epitopes) of ICIs rather than application of the corresponding mAbs for passive immunotherapy may, however, provide advantages such as induction of antibodies by the patient’s own immune system and overcoming the costly treatment of the mAbs.

Methods

An established platform involving bacterial surface-display of overlapping peptides spanning the extracellular domains of human/mouse PD1 (h/mPD1), as well as in vitro assays based on T cells expressing h/mPD1 and h/mPDL1, were applied to identify and characterize mimotopes of an anti-human PD1 mAb as well as an anti-mouse PD1 mAb (as a proof of principle).

Results

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 a syngeneic mouse model with human Her-2/neu-expressing tumors, a significant tumor growth reduction by passive immunization with specific rabbit IgG against the mPD1-derived mimotope, comparable to the corresponding mAb, was shown. More importantly, active immunization with the mPD1-mimotope resulted in a significant tumor growth reduction associated with a marked increase of PD1 expressing lymphocytes in the tumors. Furthermore, a 68% homology between hPD1 and mPD1 sufficiently facilitated a significant induction of tumor growth reduction in the mice also by IgG against hPD1-derived mimotopes.

Conclusions

Our results demonstrate in vivo anti-tumor effect following active immunization with PD1-derived mimotope in syngeneic mice with tumors expressing human Her-2/neu, implying the use of ICIs mimotopes for cancer immunotherapy. Evaluation of efficacy and safety of our second generation of anti-Her-2/neu vaccine (HerVAXX; Tobias et al, 2017, BMC Cancer) in combination with mimotopes of ICIs as adjuvants is now being carried out. Use of ICI mimotopes may, thus, pave the way for construction of monovalent as well as polyvalent vaccines in combination with tumor specific antigens against different malignancies.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Medical University of Vienna and Ursula Wiedermann.

Funding

The study was supported by the Medical University of Vienna and by a research grant from Imugene (Australia) to the Medical University of Vienna.

Disclosure

M. Preusser: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Gerson Lehrman Group; Honoraria (self), Advisory / Consultancy: CMC Contrast; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): GlaxoSmithKline; Honoraria (self), Advisory / Consultancy: Mundipharma; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Roche; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: AbbVie; Honoraria (self), Advisory / Consultancy: Lilly; Honoraria (self), Advisory / Consultancy: Medahead; Honoraria (self), Advisory / Consultancy: Daiichi Sankyo; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Merck Sharp & Dome; Research grant / Funding (institution): Böhringer-Ingelheim. C.C. Zielinski: Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Institution (CECOG): BMS; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Institution (CECOG): MSD; Honoraria (self), Advisory / Consultancy, Scientific Advisory Board member, Until June 2018: Imugene; Honoraria (self), Advisory / Consultancy: Ariad; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Institution (CECOG): Pfizer; Honoraria (self), Advisory / Consultancy: Merrimack; Honoraria (self), Advisory / Consultancy: Merck KGaA; Honoraria (self), Advisory / Consultancy: Fibrogen; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Institution (CECOG): AstraZeneca; Honoraria (self), Advisory / Consultancy: Tesaro; Honoraria (self), Advisory / Consultancy: Gilead; Honoraria (self), Advisory / Consultancy: Servier; Honoraria (self), Advisory / Consultancy: Shire; Honoraria (self), Advisory / Consultancy: Eli Lilly; Honoraria (self), Advisory / Consultancy: Athenex. P. Steinberger: Non-remunerated activity/ies, Reports personal fees from Bristol-Myers Squibb outside the submitted work: Bristol-Myers Squibb. U. Wiedermann: Officer / Board of Directors, CSO, until Sept 2018: Imugene; Research grant / Funding (institution): Phizer; Research grant / Funding (institution): GSK ; Research grant / Funding (institution): Themis. All other authors have declared no conflicts of interest.