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Order Reovirales
Published in Paul Pumpens, Peter Pushko, Philippe Le Mercier, Virus-Like Particles, 2022
Paul Pumpens, Peter Pushko, Philippe Le Mercier
The Spinareovirinae family also includes a well-known mammalian orthoreovirus type 3 Dearing (MRV-3De) of the Mammalian orthoreovirus species, which attracted special attention as an oncolytic virus and a prospective antitumor agent (for references see Black and Morris 2012). Reolysin® (pelareorep), a clinical formulation of the latter, was evaluated, for example, to treat melanoma (Galanis et al. 2012), head and neck cancer (Kyula et al. 2012), and advanced solid tumors (Morris et al. 2013).
Combining oncolytic virus with FDA approved pharmacological agents for cancer therapy
Published in Expert Opinion on Biological Therapy, 2021
Wei Zhang, Clark C. Chen, Jianfang Ning
Due to the promising efficacy demonstrated by preclinical studies in combining OVs and other modalities, OVs have been extensively tested in clinic for different types of cancer therapies. A phase 1b trial studied the safety and effectiveness of an oncolytic reovirus Pelareorep in combination with immunotherapy anti-PD1 antibody Pembrolizumab and chemotherapy either 5-fluorouracil, gemcitabine, or irinotecan [47]. Disease control was observed in three of the ten efficacy-evaluable patients, one with partial response for 17.4 months and the other two with stable disease over 9 and 4 months, respectively, while treatment was well tolerated [47]. Viral replication was observed in on-treatment tumor biopsies [47]. New T-cell clones during treatment were revealed by T-cell receptor sequencing analyzing peripheral blood and changes in the expression of immune genes were observed in patients with clinical benefit [47]. This trial demonstrated that pelareorep and pembrolizumab combined with chemotherapy did not induce significant toxicity and showed encouraging efficacy. In addition to immune checkpoint inhibitors, clinical trials are testing combinational immunotherapy of OVs and cytokines such as IFN-γ to augment overall anti-tumor immune response or immunosuppressant drugs such as cyclophosphamide to protect the activity of OV in tumors (Table 1). In addition, encouraging anti-tumor efficacy was reported from clinical trials by combing oncolytic vaccinia virus, reovirus, HSV, or adenovirus with chemotherapy in patients with advanced malignancies [6,48–50].
Engineered oncolytic viruses to treat melanoma: where are we now and what comes next?
Published in Expert Opinion on Biological Therapy, 2018
Luke D. Rothermel, Jonathan S. Zager
Pelareorep [39] is a live, replication-competent Reovirus Type 3 Dearing strain. This virus is considered nonpathogenic in humans due to inactivation in cells with normal Ras-pathway signaling. In cancer cells with Ras-activating mutations, this virus utilizes this pathway for its own replication and multiplies until cell lysis occurs. This mechanism is of significant interest in the realm of oncolytic virotherapy due to the presence of Ras-activation in ~2/3 of all tumors. Vidal et al. published a phase I study in 2008 demonstrating the safety of intravenous administration of pelareorep in patients with advanced cancers, including some anti-tumor immune response in patients with melanoma [40]. This immune targeting of tumors was reaffirmed in a phase II trial that did not meet its primary endpoint, noting no objective responses [41]. Nonetheless, an improvement in response was seen when combined with carboplatin and paclitaxel in a phase I/II trial for head and neck cancers, including melanomas [42]. The combination demonstrated improved viral penetration of pelareorep due to the chemotherapeutic effect of attenuating neutralizing antibodies. A phase II, single-arm, open-label trial of intravenous administration of pelareorep combined with carboplatin and paclitaxel with advanced melanomas subsequently demonstrated ORR of 21% (3 of 14 patients) with a 1-year OS of 43% and a disease control rate of 85%. No complete responses occurred [43]. Whereas clinical trials with pelareorep are ongoing in multiple other tumor types including malignant gliomas, pancreatic cancer, and ovarian epithelial cancers, no trials are currently active for the treatment of melanoma.
Combination immunotherapy for pancreatic cancer: challenges and future considerations
Published in Expert Review of Clinical Immunology, 2022
Gustavo C. L. Gössling, David B. Zhen, Venu G. Pillarisetty, E. Gabriela Chiorean
Oncolytic viruses, either naturally occurring such as reoviruses or genetically engineered, may specifically induce cancer cells cytotoxicity while sparing normal cells, and some can induce adaptive immune responses [53]. Main limitations regarding their efficacy have been difficult target infiltration and preexistent neutralizing antibodies. Pelareorep, an oncolytic reovirus capable of inducing a T-cell inflamed phenotype in PDA, has been tested in several clinical trials in PDA. An initial study with gemcitabine noted median OS of 10 months [54]. Given the upregulation of PD-L1 from virochemotherapy, pelareorep with pembrolizumab plus gemcitabine, irinotecan or 5-FU chemotherapy has been studied in the second line treatment of metastatic PDA [55]. Unfortunately, no significant efficacy was observed, with ORR of 10%, and median PFS and OS of 2 and 3 months, respectively. Nevertheless, changes in the immune TME were observed, with increased CD8+ T cells priming, and increased peripheral T cell receptor (TCR) clonality. VCN-01 is an oncolytic adenovirus genetically modified to express hyaluronidase (PH20) to degrade extracellular matrix and improve delivery of other therapeutic agents, including immunotherapeutics. To date, VCN-01 has been safely administered intratumorally to PDA patients where it elicited stroma disruption [56], and in a small study in combination with GnP resulted in ORR of 50% and median PFS and OS of 7.2 and 13.4 months [57]. Another oncolytic adenovirus, LOAd703, genetically engineered to express 4-1-BB, completed a study in combination with GnP with and without atezolizumab (NCT02705196). Other oncolytic viruses such as herpes simplex virus (HSV)-1 have been combined with chemotherapy with modest results [58].