-
International Journal of Molecular... Oct 2020Leveraging the immune system to thwart cancer is not a novel strategy and has been explored via cancer vaccines and use of immunomodulators like interferons. However, it... (Meta-Analysis)
Meta-Analysis
Leveraging the immune system to thwart cancer is not a novel strategy and has been explored via cancer vaccines and use of immunomodulators like interferons. However, it was not until the introduction of immune checkpoint inhibitors that we realized the true potential of immunotherapy in combating cancer. Oncolytic viruses are one such immunotherapeutic tool that is currently being explored in cancer therapeutics. We present the most comprehensive systematic review of all oncolytic viruses in Phase 1, 2, and 3 clinical trials published to date. We performed a systematic review of all published clinical trials indexed in PubMed that utilized oncolytic viruses. Trials were reviewed for type of oncolytic virus used, method of administration, study design, disease type, primary outcome, and relevant adverse effects. A total of 120 trials were found; 86 trials were available for our review. Included were 60 phase I trials, five phase I/II combination trials, 19 phase II trials, and two phase III clinical trials. Oncolytic viruses are feverously being evaluated in oncology with over 30 different types of oncolytic viruses being explored either as a single agent or in combination with other antitumor agents. To date, only one oncolytic virus therapy has received an FDA approval but advances in bioengineering techniques and our understanding of immunomodulation to heighten oncolytic virus replication and improve tumor kill raises optimism for its future drug development.
Topics: Clinical Trials as Topic; Combined Modality Therapy; Disease Management; Gene Transfer Techniques; Genetic Vectors; Humans; Neoplasms; Oncolytic Virotherapy; Oncolytic Viruses; Treatment Outcome
PubMed: 33053757
DOI: 10.3390/ijms21207505 -
Cancers May 2020Oncolytic virotherapy is a promising antitumor therapeutic strategy. It is based on the ability of viruses to selectively kill cancer cells and induce host antitumor... (Review)
Review
Oncolytic virotherapy is a promising antitumor therapeutic strategy. It is based on the ability of viruses to selectively kill cancer cells and induce host antitumor immune responses. However, the clinical outcomes of oncolytic viruses (OVs) vary widely. Therefore, we performed a meta-analysis to illustrate the efficacy and safety of oncolytic viruses. The Cochrane Library, PubMed, and EMBASE databases were searched for randomized controlled trials (RCTs) published up to January 31, 2020. The data for objective response rate (ORR), overall survival (OS), progression-free survival (PFS), and adverse events (AEs) were independently extracted by two investigators from 11 studies that met the inclusion criteria. In subgroup analyses, the objective response rate benefit was observed in patients treated with oncolytic DNA viruses (odds ratio (OR) = 4.05; 95% confidence interval (CI): 1.96-8.33; = 0.0002), but not in those treated with oncolytic RNA viruses (OR = 1.00, 95% CI: 0.66-1.52, = 0.99). Moreover, the intratumoral injection arm yielded a statistically significant improvement (OR = 4.05, 95% CI: 1.96-8.33, = 0.0002), but no such improvement was observed for the intravenous injection arm (OR = 1.00, 95% CI: 0.66-1.52, = 0.99). Among the five OVs investigated in RCTs, only talimogene laherparepvec (T-VEC) effectively prolonged the OS of patients (hazard ratio (HR), 0.79; 95% CI: 0.63-0.99; = 0.04). None of the oncolytic virotherapies improved the PFS (HR = 1.00, 95% CI: 0.85-1.19, = 0.96). Notably, the pooled rate of severe AEs (grade ≥3) was higher for the oncolytic virotherapy group (39%) compared with the control group (27%) (risk difference (RD), 12%; risk ratio (RR), 1.44; 95% CI: 1.17-1.78; = 0.0006). This review offers a reference for fundamental research and clinical treatment of oncolytic viruses. Further randomized controlled trials are needed to verify these results.
PubMed: 32486227
DOI: 10.3390/cancers12061416 -
BMJ Open Dec 2019This study aimed to conduct a systematic review of preclinical and clinical evidence to chart the successful trajectory of talimogene laherparepvec (T-VEC) from the...
OBJECTIVE
This study aimed to conduct a systematic review of preclinical and clinical evidence to chart the successful trajectory of talimogene laherparepvec (T-VEC) from the bench to the clinic.
DESIGN
This study was a systematic review. The primary outcome of interest was the efficacy of treatment, determined by complete response. Abstract and full-text selection as well as data extraction were done by two independent reviewers. The Cochrane risk of bias tool was used to assess the risk of bias in studies.
SETTING
Embase, Embase Classic and OvidMedline were searched from inception until May 2016 to assess its development trajectory to approval in 2015.
PARTICIPANTS
Preclinical and clinical controlled comparison studies, as well as observational studies.
INTERVENTIONS
T-VEC for the treatment of any malignancy.
RESULTS
8852 records were screened and five preclinical (n=150 animals) and seven clinical studies (n=589 patients) were included. We saw large decreases in T-VEC's efficacy as studies moved from the laboratory to patients, and as studies became more methodologically rigorous. Preclinical studies reported complete regression rates up to 100% for injected tumours and 80% for contralateral tumours, while the highest degree of efficacy seen in the clinical setting was a 24% complete response rate, with one study experiencing a complete response rate of 0%. We were unable to reliably assess safety due to the lack of reporting, as well as the heterogeneity seen in adverse event definitions. All preclinical studies had high or unclear risk of bias, and all clinical studies were at a high risk of bias in at least one domain.
CONCLUSIONS
Our findings illustrate that even successful biotherapeutics may not demonstrate a clear translational road map. This emphasises the need to consider increasing rigour and transparency along the translational pathway.
PROSPERO REGISTRATION NUMBER
CRD42016043541.
Topics: Animals; Biological Products; Disease Models, Animal; Herpesvirus 1, Human; Humans; Melanoma; Neoplasms; Oncolytic Virotherapy; Oncolytic Viruses; Randomized Controlled Trials as Topic
PubMed: 31796474
DOI: 10.1136/bmjopen-2019-029475 -
Critical Reviews in Oncology/hematology Jun 2019Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive soft tissue sarcomas. Once metastasized, prognosis is poor despite regular treatment with conventional...
BACKGROUND
Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive soft tissue sarcomas. Once metastasized, prognosis is poor despite regular treatment with conventional cytotoxic drugs. This study reviews the preclinical and clinical results of non-cytotoxic systemic therapy in MPNST.
METHODS
A systematic search was performed in PubMed and Embase databases according to the PRISMA guidelines. Search terms related to 'MPNST', 'targeted therapy', 'immunotherapy', and 'viral therapy' were used. Only in vivo studies and clinical trials were included. Clinicaltrials.gov was also searched for any ongoing trials including MPNST patients. Qualitative synthesis was performed on all studies stratifying per target: membrane, cytoplasmic, nuclear, immunotherapy and oncolytic viruses, and other. In vivo studies were assessed for treatment effect on tumor growth (low/intermediate/high), survival, and metastases. Clinical trials were assessed on response rate, progression-free survival, and overall survival.
RESULTS
After full-text screening, 60 in vivo studies and 19 clinical trials were included. A total of 13 trials are ongoing and unpublished. The included trials displayed relatively poor response rates thus far, with patients achieving stable disease at best. Inhibiting cytoplasmic targets most commonly yielded high treatment effect, predominantly after mTOR inhibition. Oncolytic viruses and angiogenesis inhibition also demonstrate intermediate to high effect. Therapies including a combination of drugs were most effective in controlling tumor growth. Several ongoing trials investigate potentially promising pathways, while others have yet to be established.
CONCLUSION
Targeting the PI3K/Akt/mTOR pathway seems most promising in the treatment of MPNSTs. Oncolytic viruses and angiogenesis inhibition represent emerging therapies that require further study. Combinations of targeted therapies are most likely key to maximize treatment effect.
Topics: Animals; Antineoplastic Agents; Humans; Immunotherapy; Nerve Sheath Neoplasms; Oncolytic Virotherapy; Protein Kinase Inhibitors
PubMed: 31092379
DOI: 10.1016/j.critrevonc.2019.04.007 -
Cancers Apr 2019Despite that the impact of immune checkpoint inhibitors on malignancies treatment is unprecedented, a lack of response to these molecules is observed in several cases.... (Review)
Review
Despite that the impact of immune checkpoint inhibitors on malignancies treatment is unprecedented, a lack of response to these molecules is observed in several cases. Differently from melanoma and non-small cell lung cancer, where the use of immune checkpoint inhibitors results in a high efficacy, the response rate in other tumors, such as gastrointestinal cancers, breast cancer, sarcomas, and part of genitourinary cancers remains low. The first strategy evaluated to improve the response rate to immune checkpoint inhibitors is the use of predictive factors for the response such as PD-L1 expression, tumor mutational burden, and clinical features. In addition to the identification of the patients with a higher expression of immune checkpoint molecules, another approach currently under intensive investigation is the use of therapeutics in a combinatory manner with immune checkpoint inhibitors in order to obtain an enhancement of efficacy through the modification of the tumor immune microenvironment. In addition to the abscopal effect induced by radiotherapy, a lot of studies are evaluating several drugs able to improve the response rate to immune checkpoint inhibitors, including microbiota modifiers, drugs targeting co-inhibitory receptors, anti-angiogenic therapeutics, small molecules, and oncolytic viruses. In view of the rapid and extensive development of this research field, we conducted a systematic review of the literature identifying which of these drugs are closer to achieving validation in the clinical practice.
PubMed: 30991686
DOI: 10.3390/cancers11040539 -
Cancer Immunology, Immunotherapy : CII Sep 2016Several immunomodulatory checkpoint inhibitors have been approved for the treatment of patients with advanced melanoma, including ipilimumab, nivolumab and... (Review)
Review
Several immunomodulatory checkpoint inhibitors have been approved for the treatment of patients with advanced melanoma, including ipilimumab, nivolumab and pembrolizumab. Talimogene laherparepvec is the first oncolytic virus to gain regulatory approval in the USA; it is also approved in Europe. Talimogene laherparepvec expresses granulocyte-macrophage colony-stimulating factor (GM-CSF), and with other GM-CSF-expressing oncolytic viruses in development, understanding the clinical relevance of this cytokine in treating advanced melanoma is important. Results of trials of GM-CSF in melanoma have been mixed, and while GM-CSF has the potential to promote anti-tumor responses, some preclinical data suggest that GM-CSF may sometimes promote tumor growth. GM-CSF has not been approved as a melanoma treatment. We undertook a systematic literature review of studies of GM-CSF in patients with advanced melanoma (stage IIIB-IV). Of the 503 articles identified, 26 studies met the eligibility criteria. Most studies investigated the use of GM-CSF in combination with another treatment, such as peptide vaccines or chemotherapy, or as an adjuvant to surgery. Some clinical benefit was reported in patients who received GM-CSF as an adjuvant to surgery, or in combination with other treatments. In general, outcomes for patients receiving peptide vaccines were not improved with the addition of GM-CSF. GM-CSF may be a valuable therapeutic adjuvant; however, further studies are needed, particularly head-to-head comparisons, to confirm the optimal dosing regimen and clinical effectiveness in patients with advanced melanoma.
Topics: Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Melanoma; Skin Neoplasms; Treatment Outcome
PubMed: 27372293
DOI: 10.1007/s00262-016-1860-3