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Pembrolizumab in Combination with the Oncolytic Virus Pelareorep And Published OnlineFirst November 6, 2019; DOI: 10.1158/1078-0432.CCR-19-2078 CLINICAL CANCER RESEARCH | CLINICAL TRIALS: IMMUNOTHERAPY Pembrolizumab in Combination with the Oncolytic Virus Pelareorep and Chemotherapy in Patients with Advanced Pancreatic Adenocarcinoma: A Phase Ib Study A C Devalingam Mahalingam1,2, Grey A. Wilkinson3, Kevin H. Eng4, Paul Fields5, Patrick Raber5, Jennifer L. Moseley2, Karol Cheetham3, Matt Coffey3, Gerard Nuovo6, Pawel Kalinski4, Bin Zhang1, Sukeshi Patel Arora2, and Christos Fountzilas4 ABSTRACT ◥ Background: Pelareorep is an intravenously delivered oncolytic achieved partial response for 17.4 months. Two additional patients reovirus that can induce a T-cell–inflamed phenotype in pancreatic achieved stable disease, lasting 9 and 4 months, respectively. ductal adenocarcinoma (PDAC). Tumor tissues from patients Treatment was well tolerated, with mostly grade 1 or 2 treat- treated with pelareorep have shown reovirus replication, T-cell ment-related adverse events, including flu-like symptoms. Viral infiltration, and upregulation of PD-L1. We hypothesized that replication was observed in on-treatment tumor biopsies. T-cell pelareorep in combination with pembrolizumab and chemotherapy receptor sequencing from peripheral blood revealed the creation of in patients with PDAC would be safe and effective. new T-cell clones during treatment. High peripheral clonality and Methods: A phase Ib single-arm study enrolled patients with changes in the expression of immune genes were observed in PDAC who progressed after first-line treatment. Patients received patients with clinical benefit. pelareorep, pembrolizumab, and either 5-fluorouracil, gemcitabine, Conclusions: Pelareorep and pembrolizumab added to che- or irinotecan until disease progression or unacceptable toxicity. motherapy did not add significant toxicity and showed encour- Study objectives included safety and dose-limiting toxicities, tumor aging efficacy. Further evaluation of pelareorep and anti–PD-1 response, evaluation for reovirus replication, and immune analysis therapy is ongoing in follow-up studies. This research high- in peripheral blood and tumor biopsies. lights the potential utility of several pretreatment and on- Results: Eleven patients were enrolled. Disease control was treatment biomarkers for pelareorep therapy warranting further achieved in three of the 10 efficacy-evaluable patients. One patient investigation. Introduction stream mediators of RAS and PKR signaling pathways (6). Preclinical and clinical studies have revealed that reovirus replication and lysis is Pancreatic ductal adenocarcinoma (PDAC) is the third-leading enhanced by combination treatments with several chemotherapies, cause of cancer-related death in the United States (1) with a 5-year including taxanes, gemcitabine, and irinotecan (7–9). overall survival (OS) of only 5% (2). Most patients present with Pelareorep was safely combined with gemcitabine in a phase I study advanced disease (3) and, despite recent advances in manage- in patients with advanced cancer (8). Overall, the combination was ment (4, 5), almost all patients will eventually succumb to their disease. assessed as safe, and the most common toxicities were manageable Therefore, new treatment options are urgently needed. One novel “flu-like” and gastrointestinal symptoms (8). The combination dis- option is oncolytic virus immunotherapy, which uses wild-type or played clinical activity in this highly pretreated patient population. In a genetically modified viruses to selectively kill tumor cells and promote follow-up phase II, single-arm, open-label study pelareorep was tumor-directed innate and adaptive immune responses (6). The administered in combination with gemcitabine in 34 chemothera- oncolytic reovirus pelareorep is a proprietary isolate of the reovirus py-na€ve patients with advanced PDAC (9). Treatment was well type III Dearing strain. Selective viral replication and lysis in cancer tolerated with manageable nonhematologic toxicities (9). One patient cells is influenced by multiple factors, including upstream and down- attained a partial response (PR), while 23 patients had stable disease (SD) as best response. The median OS was 10.2 months, with a 1- and 2-year survival rate of 45% and 24%, respectively. Despite modest 1Robert H. Lurie Comprehensive Cancer Center, Northwestern University, advances in pelareorep plus chemotherapy combinations, the immu- 2 Chicago, Illinois. Mays Cancer Center, University of Texas Health San Antonio, nogenic properties of pelareorep have spurred investigations that San Antonio, Texas. 3Oncolytics Biotech Inc, Calgary, Alberta, Canada. 4Roswell 5 examine combinations with immune checkpoint blockade inhibitors Park Comprehensive Cancer Center, Buffalo, New York. Adaptive Biotechno- – logies, Seattle, Washington. 6Ohio State University Arthur G. James Cancer (ICI; refs. 10 12). Hospital and Richard J. Solove Research Institute, Columbus, Ohio. Antiviral immune responses help trigger antitumor immunity (13). Antiviral immune responses to pelareorep are mediated by Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). the detection of dsRNA (via Toll-like receptors and pattern recog- nition receptors), which stimulate the secretion of IFNs, inflam- Corresponding Author: Devalingam Mahalingam, Robert H. Lurie Comprehen- sive Cancer Center, Northwestern University, 233 E Superior, Chicago, IL 60611. matory cytokines, and upregulate innate immune response genes Phone: 210-413-1723; E-mail: [email protected] such as PD-L1 and antigen processing genes such as TAP1/2 and HLAs (14–16). Moreover, innate activation leads to T- and natural Clin Cancer Res 2019;XX:XX–XX killer (NK) cell infiltration into the tumor microenvironment doi: 10.1158/1078-0432.CCR-19-2078 (TME), priming the TME, and serving as an adjunct to Ó2019 American Association for Cancer Research. ICIs (13, 17–20). On-treatment primary pancreatic tumor biopsies AACRJournals.org | OF1 Downloaded from clincancerres.aacrjournals.org on October 1, 2021. © 2019 American Association for Cancer Research. Published OnlineFirst November 6, 2019; DOI: 10.1158/1078-0432.CCR-19-2078 Mahalingam et al. Trial design, treatment, and procedures Translational Relevance This was a single-arm, open-label, nonrandomized phase Ib trial This study demonstrates that combination therapy with pelar- (Fig. 1A). Patients were treated on a 21-day cycle with one of three eorep, an intravenously delivered oncolytic virus, in combination chemotherapy backbone regimens based on physician preference: with pembrolizumab and chemotherapy is safe and well tolerated (i) gemcitabine 1,000 mg/m2 intravenously on day 1, (ii) irinotecan in patients with pancreatic ductal adenocarcinoma. Efficacy results 125 mg/m2 i.v. on day 1, or (iii) leucovorin 200 mg/m2 and are encouraging in this difficult to treat patient population. Bio- 5-fluorouracil (5-FU) 200 mg/m2 i.v. bolus on day 1, followed by marker analysis reveals striking changes to the peripheral T-cell 5-FU 1,200 mg/m2 continuous intravenous infusion over 22 hours repertoire, with early and durable clonal expansion being associ- on day 1. The choice for chemotherapy backbone was based on the ated with longer overall survival. Changes in peripheral T-cell patient's prior chemotherapy exposure and investigator preference. Â 10 clonality should be examined as a dynamic predictive biomarker in Pelareorep was administered at 4.5 10 TCID50 (50% tissue future studies with oncolytic viruses. Upregulation of CCR5 path- culture infective dose) intravenously on days 1 and 2 after chemo- way and CCR5 ligands should also be evaluated as a potential therapy infusion. Pembrolizumab was administered at 2 mg/kg i.v. on negative predictive biomarker. day 8 (dosing based on the package insert at the time of the study design). After three patients were initially enrolled with no dose-limiting toxicity (DLT), the study was expanded by the addition of eight patients. in the phase II study of pelareorep in combination with gemcitabine Patients were treated until disease progression or intolerable toxicity showed viral replication and upregulation of PD-L1 and apoptosis (that did not respond to either supportive care or dose reduction). in cancer cells (9). Chemotherapy and pelareorep dose modifications were allowed We hypothesized that, as PD-L1 is upregulated in nonneoplastic (Supplementary Table S1); the dose of chemotherapy or pelareorep tissue after chronic viral infection to minimize immune system- was decreased by one dose level for ANC < 0.5 Â 109/L lasting for induced damage (21), PD-L1 upregulation in PDAC after oncolytic >7 days, ANC < 0.5 Â 109/L with sepsis, platelet count <25 Â 109/L, virotherapy can be an inducible defense mechanism that can be grade 2 neurotoxicity or cardiotoxicity. The dose was also decreased for exploited for ICI therapy. Furthermore, we hypothesized that active any other drug-related nonhematologic grade 3 or 4 toxicity (with viral replication in PDAC can promote a favorable antitumor immune exception of flu-like symptoms, nausea, vomiting, and diarrhea in the response and “prime” PDAC, a notoriously “immune-cold” tumor, for absence of appropriate prophylactic or therapeutic measures) or ICI therapy. To test our hypothesis, we designed a phase Ib trial to inability to tolerate one course of therapy due to toxicity. No dose evaluate the efficacy and safety of combination therapy with intra- modifications were
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