93: Trans-oral Delivery of Oncolytic Vaccinia Virus expressing Membrane-Bound IL2 for Esophageal Cancer Treatment.

This study explores the potential of an oncolytic vaccinia virus (VV), expressing membrane-bound interleukin 2 (IL2), for the immune treatment of esophageal adenocarcinoma (EAC). EAC  often presents late, limiting treatment options. Viral immunotherapy, using VV to express immunotherapeutic genes, is a promising approach. The addition of IL2 to the virus enhances the immune response within the tumor microenvironment.  One critical yet unexplored barrier is how best to deliver the virus to the tumor. In this study, we explore the trans-oral intake of this modified VV, in a de novo esophageal adenocarcinoma model in Sprague-Dawley rats.


Methods:

Rats underwent surgical procedures inducing reflux and then observed for 35 weeks, resulting in distal esophageal tumors. They received two treatments with the 1E9 vaccinia virus containing membrane-bound IL2 administered via oral gavage (OG) or tail vein (TV), +/- the PD-1 inhibitor AUNP-12 (n=5/group). MRI imaging was performed on weeks 2 and 8, and animals were euthanized after 13 weeks for tumor analysis of weight, immunohistochemistry, and polymerase chain reaction.


Results:

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Treatment outcomes varied. Median tumor weights: TV alone (253 mg, IQR 154), OG alone (109 mg, IQR 1581), PD-1 inhibitor alone (512 mg, IQR 816), TV + PD1 inhibitor (51 mg, IQR 99), OG + PD1 inhibitor (124.9 mg, IQR 613.35), No treatment (417.1 mg, IQR 1253). Median percent total change in tumor volume by MRI: No treatment (+32%), TV alone (-11%), OG alone (+29%), PD-1 inhibitor alone (+49%), TV + PD1 inhibitor (-110%), OG + PD1 inhibitor (-217%). Kruskal-Wallis test showed significant tumor volume reduction for OG + PD1 (p=0.0315) and TV + PD1 (p=0.0012) vs. PD1 alone, and OG + PD1 (p=0.0164) and TV + PD1 (p=0.0005) vs. no treatment. Immunofluorescence revealed increased CD3/CD8 infiltration 2-4 days post-vaccinia virus treatment compared to no treatment



Conclusions:

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In conclusion, our investigation into the trans-oral delivery of oncolytic vaccinia virus expressing membrane-bound IL2 for EAC treatment presents compelling evidence of its therapeutic potential. Notably, OG and TV administrations, with the PD-1 inhibitor, demonstrated distinct effects on median tumor weights and percent total change in tumor volume by MRI. Future work addressing immunomodulatory mechanisms, viral replication dynamics and immune memory and long-term immune responses will bolster the scientific rationale for this therapeutic approach.