Immune Characterization Of Metastatic Colorectal Cancer Patients Post Reovirus Administration

Abstract KRAS mutations are prevalent in 40-45% of patients with colorectal cancer (CRC) and targeting this gene has remained elusive. Reovirus is an endogenous double-stranded RNA virus with specificity for KRAS -mutated CRC. Using peripheral blood mononuclear cells (PBMC) and serum samples from patients with metastatic CRC (mCRC) post reovirus treatment in combination with FOLFIRI and bevacizumab (a phase 1 clinical study), we demonstrate that administration of reovirus results in immunomodulatory changes across genomic, protein and cellular levels. These changes include alterations in expression of several genes including KRAS, VEGFA and CXCR2; sustained reductions in exosomal and cellular levels of miR-29a-3p (a microRNA upregulated in CRC and associated with decreased expression of the tumor suppressor WWOX gene); increases in serum anti-tumorigenic cytokines GM-CSF, IL-15 and IL-12p40 and IL-12p70; reductions in serum pro-tumorigenic cytokines VEGF, RANTES and IL-8; increases in the population of dendritic cells, CD4+ and CD8+ T-cells; increased expression of granzyme B a marker CD8+T activation. These data lend valuable insight into the potential of reovirus as an adjuvant when administered with established chemotherapy regimens in patients with KRAS-mutated mCRC. The findings warrant further study of reovirus in other cancers.SIGNIFICANCE: Reovirus has profound immunomodulatory properties that span the genomic, protein and immune cell distribution levels. This is the first study with reovirus in cancer patients that demonstrates these multi-layered effects, demonstrating how reovirus can function as an immune stimulant (augmenting the efficacy of immuno-chemo-therapeutic drugs), and an oncolytic agent.