Abstract A256: Epigenetic priming with novel hypomethylating agent SGI-110 improved antitumor activity of CTLA-4 blockade in a syngenic mouse model.

Abstract

Abstract Background. The second generation DNA hypomethylating agent SGI-110, a dinucleotide of decitabine (DAC) and deoxyguanosine formulated as a small volume SQ injection allowing extended DAC exposure compared to DAC i.v., has shown promising anti-cancer clinical activity. Our recent pre-clinical in vitro and in vivo data provides evidence that SGI-110 bears immunomodulating activities which improve the recognition of neoplastic cells by cytotoxic T lymphocytes. In addition, the hypomethylating activity of SGI-110 on cancer testis antigens (CTA)-specific promoters and the resulting induction/up-regulation of CTA expression have been extensively characterized in PBMCs from MDS or AML patients enrolled in a randomized Phase 1-2 First in Human PK/PD-guided, dose-escalation study. These well-defined immunomodulatory properties of SGI-110 prompt its potential use for the development of new immunotherapeutic approaches. Accordingly, in this study, we explored whether SGI-110 might improve the clinical efficacy of an anti-CTLA-4 monoclonal antibody (mAb). Materials and Methods. Balb/c mice (6/group) were injected SQ in the flank region with murine mammary carcinoma cells TS/A (2×105). Mice bearing palpable tumor grafts (diameter ≥ 0.2 cm) were treated with 3mg/kg of reconstituted SGI-110 (daily x 5) from day 1, alone or in combination with 100µg/hamster anti-murine CTLA-4 mAb concomitant with (days 2, 5 and 8) or subsequent to (days 8, 11 and 14) SGI-110. Control mice were injected with diluent for reconstitution. The effectiveness and tolerability of treatment was evaluated by tumor volume and body weight measurements, respectively. Results. The best antitumor effect was achieved in mice treated with SGI-110 followed by anti-CTLA-4 mAb; in detail, a tumor mass significantly (p<0.05) smaller than that of control mice was observed, indicating, at day 26, a tumor growth inhibition of 84.4%. Moreover, a significant, but lower, reduction in tumor mass occurred in SGI-110-treated mice as compared to control mice, with a tumor growth inhibition of 62.9% at days 26. No difference was observed in tumor growth inhibition in mice treated with SGI-110 combined with concomitant anti-CTLA-4 mAb treatment as compared to mice treated with SGI-110 alone. Noteworthy, no loss in body weight was observed in all mice investigated, demonstrating a good tolerability of therapeutic regimens tested. Conclusion. Altogether, these data provide evidence for a scientific rationale to develop novel and more effective epigenetic-immunotherapeutic strategies for cancer patients. Accordingly, an exploratory phase I clinical trial to evaluate safety and immunobiologic activities of epigenetic priming with SGI-110 followed by CTLA-4 blockade is being planned. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A256. Citation Format: Alessia Covre, Carolina Fazio, Hugues Nicolay, Giulia Parisi, Pietro Taverna, Mohammad Azab, Sandra Coral, Michele Maio. Epigenetic priming with novel hypomethylating agent SGI-110 improved antitumor activity of CTLA-4 blockade in a syngenic mouse model. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A256.