Clinical landscape of oncolytic virus research in 2020

Abstract

Oncolytic viruses (OVs) are a new class of cancer therapeutics. This review was undertaken to provide insight into the current landscape of OV clinical trials. A PubMed search identified 119 papers from 2000 to 2020 with 97 studies reporting data on 3233 patients. The viruses used, presence of genetic modifications and/or transgene expression, cancer types targeted, inclusion of combination strategies and safety profile were reported. In addition, information on viral bioshedding across the studies, including which tissues or body fluids were evaluated and how virus was detected (eg, PCR, plaque assay or both), is also reported. Finally, the number of studies evaluating antiviral and antitumor humoral and cellular immune responses were noted. We found that adenovirus (n=30) is the most common OV in clinical trials with approximately two-thirds (n=63) using modified or recombinant viral backbones and granulocyte-macrophage colony-stimulating factor (n=24) was the most common transgene. The most common tumors targeted were melanoma (n=1000) and gastrointestinal (GI; n=577) cancers with most using monotherapy OVs given by intratumoral (n=1482) or intravenous (n=1347) delivery. The most common combination included chemotherapy (n=36). Overall, OV treatment-related adverse events were low-grade constitutional and local injection site reactions. Viral shedding was frequently measured although many studies restricted this to blood and tumor tissue and used PCR only. While most studies did report antiviral antibody titers (n=63), only a minority of studies reported viral-specific T cell responses (n=10). Tumor immunity was reported in 48 studies and largely relied on general measures of immune activation (eg, tumor biopsy immunohistochemistry (n=25) and serum cytokine measurement (n=19)) with few evaluating tumor-specific immune responses (n=7). Objective responses were reported in 292 (9%) patients and disease control was achieved in 681 (21.1%) patients, although standard reporting criteria were only used in 53% of the trials. Completed clinical trials not reported in the peer-reviewed literature were not included in this review potentially underestimating the impact of OV treatment. These data provide insight into the current profile of OV clinical trials reporting and identifies potential gaps where further studies are needed to better define the role of OVs, alone and in combination, for patients with cancer.

Keywords: clinical trials as topic; immunotherapy; oncolytic virotherapy.

Figure 1

Pie chart showing the distribution of oncolytic viruses by clinical stage. The majority of studies were phase I (n=49; 51%) or not specified (n-=29; 30%). There were 6 (6%) phase I/II trials, 11 (11%) phase 2 and only two phase 3 clinical trials.

Figure 2

Characterization of viruses used in oncolytic virus clinical trials. (A) The type (family) of viruses reported in clinical trials were dominated by adenovirus (n=30), HSV-1 (n=23), reovirus (n=19) and poxviruses (n=12) with several other viruses as shown. (B) Table showing the viral backbone used in clinical oncolytic virus studies (eg, native virus, modified viruses, including recombinant or attenuated viruses, or activation of latent intracellular viruses). (C) Transgenes used as payloads in oncolytic viruses. Of the 97 independent clinical trials, 57 used oncolytic viruses without transgenes while 40 had recombinant transgene(s) expressed with GM-CSF (n=24) and LacZ (n=8) being the most common. GM-CSF, granulocyte-macrophage colony-stimulating factor; HSV-1, herpes simplex virus, type 1; HSP70, heat shock protein 70; hTERT, human telomerase reverse transcriptase; HVJ-E, hemagglutinating virus of Japan—Envelope; IL-2, interleukin 2; ICAM-1, intercellular adhesion molecule 1; LFA-3, lymphocyte function associated antigen 3 gene; NDV, Newcastle Disease virus; NIS, sodium iodide symporter; SVV, Seneca Valley virus.

Figure 3

Types of cancer being targeted in oncolytic virus (OV) clinical trials. The histological type of cancer being treated by OVs in clinical trials is shown by (A) number of clinical studies and by (B) patients enrolled. Melanoma and GI cancers were the most common. CSCC, cutaneous squamous cell carcinoma; GI, gastrointestinal; N.S., not specified; NOS, not otherwise specified.

Figure 4

Combination agents used with oncolytic viruses (OVs) in clinical trials. (A) The number of clinical studies using monotherapy OVs (n=61) or combination trials (n=36) with the breakdown by types of other drugs or regimens combined with OVs. The specific agents are listed for immunotherapy, prodrugs and targeted therapy; (B) chemotherapy agents used in combination OV clinical trials. IL-2, interleukin 2; 5-FU, 5-fluorouracil.

Figure 5

Routes of administration for oncolytic viruses in clinical trials. Method of oncolytic virus delivery in clinical trials; most were by intratumoral (n=48) or intravenous (n=34) routes of administration with 18% using alternative delivery routes. CED, convection-enhanced delivery.

Figure 6

Summary of viral bioshedding assessment in oncolytic virus clinical trials. (A) The number of studies that collected information on viral shedding (n=71) while 21 studies did not assess viral shedding and five could not be determined. (B) Pie chart of the anatomic sites or fluid biospecimens collected for virus determination showing that blood/serum and urine were the most commonly tested sites followed by tumor tissue. (C) The frequency of positive viral detection and by method of detection (PCR, plaque assay or both).

Figure 7

Summary of antiviral humoral and cellular immunity reported in oncolytic virus clinical studies. Detection of antiviral antibody titers was performed in 63 studies with 36 reporting non-neutralizing antibody titers, 5 reporting neutralizing titers and 22 reporting both neutralizing and non-neutralizing titers. Only 10 studies reported viral-specific T cell responses.

Figure 8

Antitumor activity of oncolytic viruses (OVs) in clinical studies. (A) Pie chart showing the endpoint response criteria used to monitor clinical responses in the OV trials. (B) The number of patients with specific clinical responses in clinical trials using RECIST criteria (left panel) and in all studies (right panel). (C) Responses by type of OV used in the clinical study. (D) Responses by route of administration. Abbreviations: CR, complete response; DCR, disease control rate; irRC, immune-related RECIST criteria; Minor, minor response; mWHO, modified WHO criteria; NR, not reported; ORR, objective response rate; PR, partial response; RECIST, Response Endpoint Criteria in Solid Tumors; Stable, stable response.