Optimizing the tolerability of intravenous oncolytic viral immunotherapy administration: investigation of a low-high-high dose schedule of enadenotucirev (EnAd) administration

Background:EnAd is a tumor-selective oncolytic adenovirus with highly selective replication and cell killing in a broad range of carcinoma cell lines. Following intravenous dosing in clinical studies, uptake and replication of EnAd, associated with CD8+ cell infiltration, has been shown. It is currently in combination studies with nivolumab and paclitaxel. Intravenous delivery of EnAd stimulates an acute response characterised by an increase in cytokines in peripheral blood. As previously reported (ESMO IO 2017, abstr 203), the MTD of EnAd (3x1012 viral particles (vp) Days 1, 3 and 5, flat dosing schedule) has been determined primarily based on AEs occurring on first dose (C1D1), with the cytokine response, including interleukin-6 (IL-6), to subsequent doses of EnAd appearing attenuated when delivered within a few days of the first dose. Methods: The effect of the first EnAd dose on subsequent acute particle-mediated cytokine (IL-6) responses in mice was investigated following administration of systemic doses equivalent to between 5.5 x 1012 vp and 5.5 x 1013 vp in humans. Results: The magnitude of IL-6 response to a low first dose, which itself induces very low or undetectable levels of IL-6 cytokine, is sufficient to attenuate the response to subsequent high doses (10 times more vp). When administered as first dose these high doses induced a significant elevation in systemic IL-6. Conclusions: Tolerability of EnAd is primarily determined by C1D1, correlating with the cytokine response across the patient cohort. The data from this in vivo pharmacology study support the concept of delivering a lower dose of enadenotucirev on Day 1 and administering higher doses thereafter, with the aim to deliver a higher viral load to tumour tissue and potentially optimise the overall risk:benefit of EnAd administration. This type of dosing regimen (low-high-high) has been successfully implemented in clinical studies of other systemically administered oncolytic viruses (Clin Cancer Res 2006;12:2555-2562) and is under clinical investigation as part of the ongoing combination study with nivolumab. (EudraCT:2013-001276-38). Citation Format: Hilary McElwaine-Johnn, Sam Illingworth, Rochelle Lear, Richard Brown, Brian Champion. Optimizing the tolerability of intravenous oncolytic viral immunotherapy administration: investigation of a low-high-high dose schedule of enadenotucirev (EnAd) administration [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1469.