Abstract 2194: New oxazaphosphorine prodrugs for immunotherapy and nanomedicine against cancer

Abstract

Abstract Oxazaphosphorines (Oxaza) are widely used in the treatment of numerous cancers, activity against various tumor types, from soft tissue sarcomas to genito-urinary cancers for ifosfamide (IFO), from lymphoma to breast cancer for cyclophosphamide (CPA) and are still the corner stone of several polychemotherapy protocols. Limiting their toxicity and increasing their efficacy and safety through a better specificity could be of major interest. By consequence, we have designed new pre-activated oxazaphosphorines (X-Oxaza, Skarbek et al J Med Chem. 2015 Jan 22;58(2):705-17) to improve antitumoral response with reduced toxicity or side effects, as metabolization is not needed to liberate the active metabolite. We also aimed to design new drug delivery systems (DDS) based on these X-Oxaza to take advantage of passive and active targeting in order to improve the response selectivity. Indeed, nanocarriers formulations take advantage of the so-called enhanced permeability and retention effect (EPR effect) and increase the circulation time in the bloodstream. Active targeting is planed by grafting targeting ligands on the surface of DDS such as monoclonal antibody-mAbs and amino acids… The different steps leading to the design of the X-Oxaza has been developed within our laboratory and the proof of concept has been validated by their in vitro evaluation on a panel of tumor cell lines (Skarbek et al J Med Chem. 2015 Jan 22;58(2):705-17; Paci et al Bioorg Med Chem Lett. 2001 May 21;11(10):1347-9). These pre-activated Oxaza have been formulated as DDS either using the physicochemical properties of the terpene derivatives, which can self-assembly into nano-assemblies (NAs), or by encapsulating the short-chain X-Oxaza into Lipid nanocapsules (LNCs). Both DDS were tested on rhabdomyosarcoma and Ewing sarcoma cell lines and showed an increased activity compared to the free form. Regarding the immunological field, CPA was shown to enhance the immune defenses particularly promoting differentiation of CD4+ cell toward Th1. The isomeric form of CPA, IFO, leads us to believe that IFO could have an influence on the immune system. Indeed, we have studied the immunomodulatory activity of IFO and the results show that IFO participates in the modulation of the secretion of cytokines from immune cells with a dose / effect relationship. In the meantime, we investigate the influence of IFO and these X-Oxaza on the immune system using immunocompetent and immunodepressed mouse models. With the link of immune checkpoint antibodies, this strategy will benefit of the immunomodulatory effects of X-Oxaza combined to the antiproliferative properties of these antibodies. These new functionalized DDS may provide a useful strategy to give specificity to active drugs used for many years in clinical practice. Both DDS could be grafted with mAbs which could lead to a new family of DDS aiming to combine antiproliferative and immunomodulatory properties for a dual antitumoral action Citation Format: Charles Skarbek, Henri Gonde, Mélanie Desbois, Julia Delahousse, Nathalie Chaput-Gras, Jean-Pierre Benoit, Emilie Roger, Angelo Paci. New oxazaphosphorine prodrugs for immunotherapy and nanomedicine against cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2194.