Enhanced anti-melanoma efficacy through a combination of the armed oncolytic adenovirus ZD55-IL-24 and immune checkpoint blockade in B16-bearing immunocompetent mouse model

Abstract

Although the recent treatment in melanoma through the use of anti-PD-1 immunotherapy is successful, the efficacy of this approach remains to be improved. Here, we explore the feasibility of combination strategy with the armed oncolytic adenovirus ZD55-IL-24 and PD-1 blockade. We find that combination therapy with localized ZD55-IL-24 and systemic PD-1 blockade leads to synergistic inhibition of both local and distant established tumors in B16-bearing immunocompetent mouse model. Our further mechanism investigation reveals that synergistic therapeutic effect is associated with marked promotion of tumor immune infiltration and recognition in both local and distant tumors as well as spleens. PD-1 blockade has no obvious effect on promotion of tumor immune infiltration and recognition. Localized therapy with ZD55-IL-24, however, can help PD-1 blockade to overcome the limitation of relatively low tumor immune infiltration and recognition. This study provides a rationale for investigation of such combination therapy in the clinic.

Enhanced Cancer Therapy Using an Engineered Designer Cytokine Alone and in Combination With an Immune Checkpoint Inhibitor

“…As predicted, M7S significantly improved the outcome in comparison with parental MDA-7. One notable attribute of MDA-7 that contributes to its broad-spectrum anticancer properties is its ability to synergize with other therapies, including radiation ( 54 ), chemotherapy ( 55 , 56 ) and antibody-based therapies ( 31 ). Our current study provides the first report that MDA-7 and to a greater extent M7S therapy is enhanced in the context of an aggressive melanoma when combined with a checkpoint inhibitor (α-PD-L1) ( Figure 8 ).…”

“…We demonstrated previously that intratumorally delivery of MDA-7 (by means of a replication-incompetent Ad.5 -mda-7) stimulated systemic antigen-specific CD8 + T cell responses in breast cancer ( 14 ), supporting an immunological contribution of MDA-7 in mediating breast cancer killing. A recent study describes potential synergy between anti-PD-1 and an armed replicating adenovirus expressing wild type mda-7 in B16 mouse melanoma cells in vivo in syngeneic mice ( 31 ). In the present study, we demonstrate enhanced therapeutic potential in vitro and in vivo of M7S vs. parental MDA-7 against multiple human tumors (melanoma, prostate and breast) and murine B16 melanoma tumors when delivered by a replication incompetent adenovirus (Ad.5- M7S ) and the antitumor effect is further enhanced when combined with α-PD-L1 in the aggressive B16 melanoma model.…”

Improving cancer immunotherapy by rationally combining oncolytic virus with modulators targeting key signaling pathways

“…IL-10, originally considered to be a Th2 cytokine, but later shown to be a Th1 cytokine in certain environments, has been incorporated into OVs and demonstrated improved antitumor immunity and enhanced efficacy [ 68 , 69 ]. IL-24, a member of the IL-10 family, has also been shown to be potent antitumor factor when expressed from an OV [ 70 , 71 ]. We and others have engineered oncolytic vaccinia viruses (VVs) expressing recombinant IL-2, IL-12, IL-15, IL-21, IL-23, and IL-36γ for improved efficacy and safety in multiple tumor models [ 64 , 72 – 77 ].…”

Oncolytic viruses combined with immune checkpoint therapy for colorectal cancer is a promising treatment option

“…However, as ZD55-IL-24 must currently be administered intratumorally, it is only indicated for treating those few tumors with visible lesions such as melanoma and is challenging to use for the vast majority of tumors in clinical practice. Nonetheless, this study provides a viable experimental basis for the combination therapy of "armed" OVs (75).…”