Oncolytic Viruses for Cancer Therapy: Barriers and Recent Advances

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Abstract

Oncolytic viruses (OVs) are powerful new therapeutic agents in cancer therapy. With the first OV (talimogene laherparepvec [T-vec]) obtaining US Food and Drug Administration approval, interest in OVs has been boosted greatly. Nevertheless, despite extensive research, oncolytic virotherapy has shown limited efficacy against solid tumors. Recent advances in viral retargeting, genetic editing, viral delivery platforms, tracking strategies, OV-based gene therapy, and combination strategies have the potential to broaden the applications of oncolytic virotherapy in oncology. In this review, we present several insights into the limitations and challenges of oncolytic virotherapy, describe the strategies mentioned above, provide a summary of recent preclinical and clinical trials in the field of oncolytic virotherapy, and highlight the need to optimize current strategies to improve clinical outcomes.

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ONCOLYTIC VIROTHERAPY

Stephen J. Russell, Kah-Whye Peng, John Bell (2012)

Oncolytic virotherapy is an emerging treatment modality which uses replication competent viruses to destroy cancers. Advances in the past two years include preclinical proof of feasibility for a single-shot virotherapy cure, identification of drugs that accelerate intratumoral virus propagation, new strategies to maximize the immunotherapeutic potential of oncolytic virotherapy, and clinical confirmation of a critical viremic thereshold for vascular delivery and intratumoral virus replication. The primary clinical milestone was completion of accrual in a phase III trial of intratumoral herpes simplex virus therapy using talimogene laherparepvec for metastatic melanoma. Challenges for the field are to select ‘winners’ from a burgeoning number of oncolytic platforms and engineered derivatives, to transiently suppress but then unleash the power of the immune system to maximize both virus spread and anticancer immunity, to develop more meaningful preclinical virotherapy models and to manufacture viruses with orders of magnitude higher yields compared to established vaccine manufacturing processes.

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Recurrent Glioblastoma Treated with Recombinant Poliovirus

Darell D. Bigner, Dani Bolognesi, Allan Friedman … (2018)

BACKGROUND The prognosis of patients with recurrent World Health Organization (WHO) grade IV malignant glioma is dismal, and there is currently no effective therapy. We conducted a dose-finding and toxicity study in this population of patients, evaluating convection-enhanced, intratumoral delivery of the recombinant nonpathogenic polio–rhinovirus chimera (PVSRIPO). PVSRIPO recognizes the poliovirus receptor CD155, which is widely expressed in neoplastic cells of solid tumors and in major components of the tumor microenvironment. METHODS We enrolled consecutive adult patients who had recurrent supratentorial WHO grade IV malignant glioma, confirmed on histopathological testing, with measurable disease (contrast-enhancing tumor of ≥1 cm and ≤5.5 cm in the greatest dimension). The study evaluated seven doses, ranging between 10 7 and 10 10 50% tissue-culture infectious doses (TCID 50 ), first in a dose-escalation phase and then in a dose-expansion phase. RESULTS From May 2012 through May 2017, a total of 61 patients were enrolled and received a dose of PVSRIPO. Dose level −1 (5.0×10 7 TCID 50 ) was identified as the phase 2 dose. One dose-limiting toxic effect was observed; a patient in whom dose level 5 (10 10 TCID 50 ) was administered had a grade 4 intracranial hemorrhage immediately after the catheter was removed. To mitigate locoregional inflammation of the infused tumor with prolonged glucocorticoid use, dose level 5 was deescalated to reach the phase 2 dose. In the dose-expansion phase, 19% of the patients had a PVSRIPO-related adverse event of grade 3 or higher. Overall survival among the patients who received PVSRIPO reached a plateau of 21% (95% confidence interval, 11 to 33) at 24 months that was sustained at 36 months. CONCLUSIONS Intratumoral infusion of PVSRIPO in patients with recurrent WHO grade IV malignant glioma confirmed the absence of neurovirulent potential. The survival rate among patients who received PVSRIPO immunotherapy was higher at 24 and 36 months than the rate among historical controls.

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Integrating oncolytic viruses in combination cancer immunotherapy

Howard L. Kaufman, Praveen K. Bommareddy, Megha Shettigar (2018)

Oncolytic viruses can be usefully integrated into tumour immunotherapies, as they target multiple steps within the cancer-immunity cycle. Oncolytic viruses directly lyse tumour cells, leading to the release of soluble antigens, danger signals and type I interferons, which drive antitumour immunity. In addition, some oncolytic viruses can be engineered to express therapeutic genes or can functionally alter tumour-associated endothelial cells, further enhancing T cell recruitment into immune-excluded or immune-deserted tumour microenvironments. Oncolytic viruses can also utilize established tumours as an in situ source of neoantigen vaccination through cross-presentation, resulting in regression of distant, uninfected tumours. These features make oncolytic viruses attractive agents for combination strategies to optimize cancer immunotherapy.

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Hui Yang

Journal

Journal ID (nlm-ta): Mol Ther Oncolytics

Journal ID (iso-abbrev): Mol Ther Oncolytics

Title: Molecular Therapy Oncolytics

Publisher: American Society of Gene & Cell Therapy

ISSN (Electronic): 2372-7705

Publication date PMC-release: 02 November 2019

Publication date Collection: 20 December 2019

Publication date (Electronic): 02 November 2019

Volume: 15

Pages: 234-247

Affiliations

[1 ]Department of Otolaryngology, Head and Neck Surgery, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan Province, P.R. China

[2 ]State Key Laboratory of Biotherapy, West China Medical School, Sichuan University, Chengdu, Sichuan Province, P.R. China

[3 ]Department of Neurosurgery, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan Province, P.R. China

Author notes

[∗ ]Corresponding author: Hui Yang, PhD, Department of Otolaryngology, Head and Neck Surgery, West China Hospital, West China Medical School, Sichuan University, No. 37 Guo Xue Xiang, Chengdu, 610041, P.R. China. yh8806@ 123456163.com

[4]

These authors contributed equally to this work.

Article

Publisher ID: S2372-7705(19)30097-X

DOI: 10.1016/j.omto.2019.10.007

PMC ID: 6911943

PubMed ID: 31872046

SO-VID: 70d5824b-de42-430b-af8c-e30554456e1e

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This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Oncolytic Viruses for Cancer Therapy: Barriers and Recent Advances

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Most cited references 116

ONCOLYTIC VIROTHERAPY

Recurrent Glioblastoma Treated with Recombinant Poliovirus

Integrating oncolytic viruses in combination cancer immunotherapy

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