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.

Application of stem cells and exosomes in the treatment of intracerebral hemorrhage: an update

“…After 7 days of model establishment, ATRA-treated ESCs were infused into the healthy hemispheres. Ultimately, researchers have found neurons and astrocytes originating from ESCs in the area around the hematoma, highlighting the therapeutic potential of ESCs [39]. Owing to its low migratory ability, cell therapy for ICH remains a challenge.…”

Combination Immunotherapies to Overcome Intrinsic Resistance to Checkpoint Blockade in Microsatellite Stable Colorectal Cancer

“…Moreover, RC402 cooperated with PD1 blockade to completely regress colon cancer and prolong the survival of tumor-bearing mice [114]. Parakrama et al also reported that an intravenous administration of reovirus to patients with mCRC resulted in antigen-presenting cell stimulation and CD8 + T cell activation, which can be used as an immunomodulator [115].…”

Molecular Tools for Metastatic Colorectal Cancer Characterization

“…In our recent publication [1], we have explored at the molecular level the consequences of reovirus administration to patients with KRAS mutated colorectal cancer (CRC). This was the first reported study where transcriptome assay was performed on KRAS mutated CRC patients receiving reovirus (pelareorep) therapy.…”