Pembrolizumab in Combination with the Oncolytic Virus Pelareorep and Chemotherapy in Patients with Advanced Pancreatic Adenocarcinoma: A Phase Ib Study

Abstract

Purpose: Pelareorep is an intravenously delivered oncolytic reovirus that can induce a T-cell-inflamed phenotype in pancreatic ductal adenocarcinoma (PDAC). Tumor tissues from patients treated with pelareorep have shown reovirus replication, T-cell infiltration, and upregulation of PD-L1. We hypothesized that pelareorep in combination with pembrolizumab and chemotherapy in patients with PDAC would be safe and effective. Patients and Methods: A phase Ib single-arm study enrolled patients with PDAC who progressed after first-line treatment. Patients received pelareorep, pembrolizumab, and either 5-fluorouracil, gemcitabine, or irinotecan until disease progression or unacceptable toxicity. Study objectives included safety and doselimiting toxicities, tumor response, evaluation for reovirus replication, and immune analysis in peripheral blood and tumor biopsies. Results: Eleven patients were enrolled. Disease control was achieved in three of the 10 efficacy-evaluable patients. One patient achieved partial response for 17.4 months. Two additional patients achieved stable disease, lasting 9 and 4 months, respectively. Treatment was well tolerated, with mostly grade 1 or 2 treatment-related adverse events, including flu-like symptoms. Viral replication was observed in on-treatment tumor biopsies. T-cell receptor sequencing from peripheral blood revealed the creation of new T-cell clones during treatment. High peripheral clonality and changes in the expression of immune genes were observed in patients with clinical benefit. Conclusions: Pelareorep and pembrolizumab added to chemotherapy did not add significant toxicity and showed encouraging efficacy. Further evaluation of pelareorep and anti-PD-1 therapy is ongoing in follow-up studies. This research highlights the potential utility of several pretreatment and ontreatment biomarkers for pelareorep therapy warranting further investigation.

An Immunological Glance on Pancreatic Ductal Adenocarcinoma

“…Although this therapeutic approach leads to a measurable response in PDAC, it becomes evident again that the therapy only leads to a short extension of survival. Again, the analysis of the T cell receptor clonality in this study revealed the most extended survival for one patient, which was corroborated with the induction of the highest number of new clonal T cells following the combination therapy [86]. This highlights the dependency of PD-1 blockade success in PDAC on pre-existing patients' TCR repertoire.…”

“…In the following, we would like to address the PD-1/PD-L1 axis. Eleven PDAC patients still exhibiting progression under the first-line therapy exhibited an observable response to the combination therapy with pembrolizumab (a PD-1 blocker) and the oncolytic reovirus pelareorep, resulting in median overall survival of 3.1 months [86]. Although this therapeutic approach leads to a measurable response in PDAC, it becomes evident again that the therapy only leads to a short extension of survival.…”

Combining Oncolytic Viruses With Cancer Immunotherapy: Establishing a New Generation of Cancer Treatment

“…For example, in 2017 a phase I trial of intravenous oncolytic vaccinia virus combined with cisplatin and radiotherapy was shown to improve 1-year progress-free survival (74.4%) of locally advanced head and neck cancer patients (148). To make it even further, most recently Mahalingam et al reported phase Ib single-arm study demonstrating that combination of oncolytic reovirus, pembrolizumab and chemotherapy showed encouraging treatment efficacy for patients with pancreatic ductal adenocarcinoma (PDAC) who progressed after first-line treatment (149). More promising results could be expected in the future with multiple combination of OVs, cancer immunotherapies and standard cancer therapies.…”

Molecular Mechanisms and Potential Therapeutic Reversal of Pancreatic Cancer-Induced Immune Evasion

“…Moreover, oncolytic virus infection can increase the expression of PD-L1 receptors on tumor cells [ 121 ]. In a recently published phase Ib trial incorporating intravenous reolysin and pembrolizumab for patients with metastatic pancreatic adenocarcinoma, treatment was well-tolerated with durable efficacies [ 122 ]. A follow-up phase II study using pelareorep and pembrolizumab on patients with advanced pancreatic cancer is underway (NCT03723915).…”