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. 2018 May 25;10(6):160.
doi: 10.3390/cancers10060160.

A Phase II Study of Pelareorep (REOLYSIN®) in Combination with Gemcitabine for Patients with Advanced Pancreatic Adenocarcinoma

Devalingam Mahalingam  1   2 , Sanjay Goel  3 , Santiago Aparo  4 , Sukeshi Patel Arora  5 , Nicole Noronha  6 , Hue Tran  7 , Romit Chakrabarty  8 , Giovanni Selvaggi  9 , Andres Gutierrez  10 , Matthew Coffey  11 , Steffan T Nawrocki  12 , Gerard Nuovo  13 , Monica M Mita  14
Affiliations

A Phase II Study of Pelareorep (REOLYSIN®) in Combination with Gemcitabine for Patients with Advanced Pancreatic Adenocarcinoma

Devalingam Mahalingam et al. Cancers (Basel). .

Abstract

Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis, with 1 and 5-year survival rates of ~18% and 7% respectively. FOLFIRINOX or gemcitabine in combination with nab-paclitaxel are standard treatment options for metastatic disease. However, both regimens are more toxic than gemcitabine alone. Pelareorep (REOLYSIN®), a proprietary isolate of reovirus Type 3 Dearing, has shown antitumor activity in clinical and preclinical models. In addition to direct cytotoxic effects, pelareorep can trigger antitumor immune responses. Due to the high frequency of RAS mutations in PDAC, we hypothesized that pelareorep would promote selective reovirus replication in pancreatic tumors and enhance the anticancer activity of gemcitabine. Chemotherapy-naïve patients with advanced PDAC were eligible for the study. The primary objective was Clinical Benefit Rate (complete response (CR) + partial response (PR) + stable disease (SD) ≥ 12 weeks) and secondary objectives include overall survival (OS), toxicity, and pharmacodynamics (PD) analysis. The study enrolled 34 patients; results included one partial response, 23 stable disease, and 5 progressive disease. The median OS was 10.2 months, with a 1- and 2-year survival rate of 45% and 24%, respectively. The treatment was well tolerated with manageable nonhematological toxicities. PD analysis revealed reovirus replication within pancreatic tumor and associated apoptosis. Upregulation of immune checkpoint marker PD-L1 suggests future consideration of combining oncolytic virus therapy with anti-PD-L1 inhibitors. We conclude that pelareorep complements single agent gemcitabine in PDAC.

Keywords: PD-L1; REOLYSIN®; immuno-oncolytic virus; pancreatic cancer; pelareorep; reovirus.

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Conflict of interest statement

Nicole Noronha, Hue Tran, Romit Chakrabarty, Giovanni Selvaggi, Andres Gutierrez, and Matt Coffey are employees of Oncolytics Biotech Inc. with stock options and/or stock. The other authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Survival of patients with advanced pancreatic cancer receiving pelareorep in combination with gemcitabine. (A) Spider plot showing the change in tumor size at each 6 week time point for 29 patients; (B) progression free survival and overall survival for all patients on study.
Figure 2
Figure 2
Tumor biopsy from the primary pancreatic tumor of a single patient with a KRAS G12D mutation following treatment with pelareorep and gemcitabine. (A) Immunohistochemistry (IHC) analysis of HCT116 colon cancer cells treated with pelareorep serves as a positive control for reoviral protein replication (brown). The uninfectecd HCT116 cell line is the negative control (inset); (B) IHC shows positive staining for reoviral protein and activated caspase-3 protein localized to cancer cells; (C) Fluorescent in situ hybridization (FISH) demonstrates coexpression of reoviral protein and caspase-3 consistent with productive lytic infection in the patient’s tumor. Yellow indicates colocalizaiton of reovirus (green) and caspase-3 (red) in the same cancer cells; (D) analysis of the tumor also reveals upregulation of programmed death ligand 1 (PD-L1) on IHC following pelareorep therapy (left panel represents the baseline; right panel represents pelareorep with gemcitabine). Scale bar: 50 µm.
Figure 2
Figure 2
Tumor biopsy from the primary pancreatic tumor of a single patient with a KRAS G12D mutation following treatment with pelareorep and gemcitabine. (A) Immunohistochemistry (IHC) analysis of HCT116 colon cancer cells treated with pelareorep serves as a positive control for reoviral protein replication (brown). The uninfectecd HCT116 cell line is the negative control (inset); (B) IHC shows positive staining for reoviral protein and activated caspase-3 protein localized to cancer cells; (C) Fluorescent in situ hybridization (FISH) demonstrates coexpression of reoviral protein and caspase-3 consistent with productive lytic infection in the patient’s tumor. Yellow indicates colocalizaiton of reovirus (green) and caspase-3 (red) in the same cancer cells; (D) analysis of the tumor also reveals upregulation of programmed death ligand 1 (PD-L1) on IHC following pelareorep therapy (left panel represents the baseline; right panel represents pelareorep with gemcitabine). Scale bar: 50 µm.
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