LAUSR

Functionalized superparamagnetic iron oxide nanoparticles (SPIONs) have emerged as potential clinical tools for cancer theranostics. Membrane-bound 70 kDa heat shock protein (mHsp70) is ubiquitously expressed on the cell membrane of various tumor types but not on normal cells and therefore provides a tumor-specific target. The serine protease granzyme B (GrB) that is produced as an effector molecule by activated T and NK cells has been shown to specifically target mHsp70 on tumor cells. Following binding to Hsp70, GrB is rapidly internalized into tumor cells inducing the process of cellular apoptosis. Decoration of the nanoparticles surface with GrB increased the targeting properties of the nanocarriers as was shown by confocal and electron microscopies. In series of in vivo studies it was demonstrated that GrB functionalized SPIONs act simultaneously as a contrast enhancement agent when being intravenously administered for magnetic resonance imaging and induce specific tumor cell apoptosis (human U87 glioblastoma in NMRI nu/nu mice, rat C6 glioma in Wistar rats, B16 melanoma in C57/Bl6 mice). Continuous prolonged administration of GrB-SPIONs via programmable subcutaneously implanted mini-pump system iPrecio further enhanced the therapeutic benefit of magnetic conjugates. Moreover, significant therapeutic response was achieved in immunocompromised mice models (advanced U87 brain tumor, small lung cancer H1339 with brain metastasis) with a high tumor burden. Combinatorial regimens employing stereotactic radiotherapy and/or magnetic targeting with immune checkpoint inhibitors (anti-CTLA-4 monoclonal antibodies) are found to further enhance the therapeutic efficacy of GrB-SPIONs in different tumor mouse models. The study was funded by RFBR, project № 19-08-00024; DFG grant SFB824/3, Germany, TaGoNaX DFG project № 336532926, STA1520/1-1. Citation Format: Maxim Shevtsov, Susanne Kaesler, Stefan Stangl, Luidmila Yakovleva, Ruslana Tagaeva, Yaroslav Marchenko, Boris Nikolaev, William Khachatryan, Oleg Galibin, Emil Pitkin, Gabriele Multhoff. Granzyme B functionalized nanocarriers targeting membrane-bound Hsp70 for multimodal cancer therapies [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 2878.