Harnessing MEM-288: A Dual-Transgene Oncolytic Adenovirus for Targeted Cancer Therapy

MEM-288 is an innovative oncolytic adenovirus engineered for the treatment of solid and liquid tumors, either as a monotherapy or in combination with immune checkpoint inhibitors (ICIs). It features multiple enhancements for tumor-selective replication, including delta-24 (Δ24) E1, E1b 55kb, and E3 deletions. The virus is equipped with two immune-stimulating transgenes: MEM40, a stable cell surface-expressed chimeric CD40 ligand (CD40L) that activates dendritic cells (DCs), and IFNβ, which aids in the maturation and activation of DCs and T cells.

Designed to surpass the limitations of conventional oncolytic viruses (OVs), MEM-288 has demonstrated significantly heightened tumor selectivity, oncolytic potency, and the capacity to boost DC and T cell functionality. It has shown approximately 100-fold greater replication and oncolytic action in various human tumor cell lines compared to control adenoviruses. MEM-288 also displayed a substantial preference for tumor cells over normal cells, including a 1,000-fold higher viral replication rate in tumor cells.

In vivo studies in immunocompetent mouse models have confirmed MEM-288's promising anti-metastatic activity and its ability to control both injected and non-injected tumors in melanoma models. The virus showed superior inhibition of tumor growth compared to the combination of anti-CTLA4 and PD-1 antibodies. Furthermore, the combination of MEM-288 with these ICIs led to enhanced anti-tumor effects, complete tumor regressions, and 100% mouse survival at day 30, a significant improvement over individual treatments.

In the B16-OVA melanoma model, MEM-288 induced superior T cell clonal expansion compared to a control OV, highlighting the critical role of IFNβ in T cell activation when combined with MEM40. These findings indicate that MEM-288 is a potent, tumor-selective oncolytic virus with unique features that make it a strong candidate for combination therapy with ICIs, even in refractory settings. The virus is under consideration for clinical evaluation for lung cancer and other tumor types.