Abstract 4578: Development of MEM-288, a dual-transgene armed and conditionally replication-enhanced oncolytic adenovirus with potent systemic antitumor immunity

Abstract

Abstract MEM-288 is a conditionally replication-enhanced and dual-transgene armed oncolytic adenovirus designed for the treatment of both solid and liquid tumor indications as either a standalone product or in combination with immune checkpoint inhibitors (ICI). Multiple modifications to the adenovirus backbone have been incorporated to confer tumor-selective replication that includes delta-24 (Δ24) E1, E1b 55kb and E3 viral genome deletions. Furthermore, MEM-288 is armed with two potent immune agonist transgenes: MEM40, a novel chimeric CD40 ligand (CD40L) designed for stable cell surface expression of CD40L that functions as a potent activator of CD40 expressing dendritic cells (DCs), and the DC and T cell maturation and activating cytokine IFNβ. MEM-288 is rationally designed to overcome limitations of other OV by conferring enhanced tumor selectivity, oncolytic activity, and ability to directly enhance dendritic cell (DC) and T cell functionality. MEM-288 exhibited ~100-fold greater replication and oncolytic activity in a broad range of human solid tumors and blood tumor types, including a variety of human lung tumor cell lines, in comparison with control Δ24, ΔE1b 55kb and ΔE3 backbone adenoviruses. MEM-288 also exhibited ~1,000-fold greater viral replication in tumor cells compared to normal cell types, including immature dendritic cells and cancer associated human lung fibroblasts cells. These positive in vitro results were expanded upon in multiple in vivo immunocompetent mouse tumor models. Intratumoral administration of MEM-288 in the syngeneic mouse lung metastatic model 344SQ demonstrated potent anti-metastatic activity of MEM-288 compared to control OVs. MEM-288 also generated a highly efficacious response against both intratumoral injected and distant non-injected contralateral tumors in the B16-F10 melanoma model, including significantly greater inhibition of tumor growth with MEM-288 compared to the combination of anti-CTLA4 + PD-1. In addition, the combination of MEM-288 with anti-CTLA4 + PD-1 significantly enhanced anti-tumor activity with tumor regressions and 100% mouse survival at day 30 compared to 56% and 0% survival with individual treatments of either MEM-288 or anti-CTLA4 + PD-1, respectively. MEM-288 generated significantly better T cell tumor antigen clonal expansion following intratumoral administration in the B16-OVA melanoma model compared to a matched control OV that only expresses MEM40, suggesting IFNβ is a critical mediator of the T cell clonal expansion in combination with MEM40. These positive preclinical data suggest MEM-288 is a potent tumor-selective oncolytic virus with desirable mechanistic features that can be ideally combined with ICI, even in the ICI refractory setting. These studies warrant clinical evaluation for lung cancer and other tumor types that are currently under development. Citation Format: Hong Zheng, Wenjie Dai, Scott Antonia, Mark J. Cantwell, Amer A. Beg. Development of MEM-288, a dual-transgene armed and conditionally replication-enhanced oncolytic adenovirus with potent systemic antitumor immunity [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 4578.