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Neurosurgical Focus Feb 2021High-grade gliomas (HGGs) inevitably recur and progress despite resection and standard chemotherapies and radiation. Viral therapies have emerged as a theoretically...
OBJECTIVE
High-grade gliomas (HGGs) inevitably recur and progress despite resection and standard chemotherapies and radiation. Viral therapies have emerged as a theoretically favorable adjuvant modality that might overcome intrinsic factors of HGGs that confer treatment resistance.
METHODS
The authors present the results of systematic searches of the MEDLINE and ClinicalTrials.gov databases that were performed for clinical trials published or registered up to July 15, 2020.
RESULTS
Fifty-one completed clinical trials were identified that made use of a virus-based therapeutic strategy to treat HGG. The two main types of viral therapies were oncolytic viruses and viral vectors for gene therapy. Among clinical trials that met inclusion criteria, 20 related to oncolytic viruses and 31 to gene therapy trials. No oncolytic viruses have progressed to phase III clinical trial testing, although there have been many promising early-phase results and no reported cases of encephalitis or death due to viral therapy. Three phase III trials in which viral gene therapy was used have been completed but have not resulted in any FDA-approved therapy. Recent efforts in this area have been focused on the delivery of suicide genes such as herpes simplex virus thymidine kinase and cytosine deaminase.
CONCLUSIONS
Decades of research efforts and an improving understanding of the immunomodulatory effects of viral therapies for gliomas are informing ongoing clinical efforts aimed at improving outcomes in patients with HGG. The available clinical data reveal varied efficacy among different virus-based treatment strategies.
Topics: Adult; Glioblastoma; Glioma; Humans; Neoplasm Recurrence, Local; Oncolytic Virotherapy; Oncolytic Viruses
PubMed: 33524943
DOI: 10.3171/2020.11.FOCUS20854 -
Cancers Jan 2022In Bacillus Calmette-Guérin (BCG) refractory non-muscle-invasive bladder cancer (NMIBC), radical cystectomy is the gold standard. The advent of immune checkpoint... (Review)
Review
From Interferon to Checkpoint Inhibition Therapy-A Systematic Review of New Immune-Modulating Agents in Bacillus Calmette-Guérin (BCG) Refractory Non-Muscle-Invasive Bladder Cancer (NMIBC).
BACKGROUND
In Bacillus Calmette-Guérin (BCG) refractory non-muscle-invasive bladder cancer (NMIBC), radical cystectomy is the gold standard. The advent of immune checkpoint inhibitors (CPIs) has permanently changed the therapy landscape of bladder cancer (BC). This article presents a systematic review of immune-modulating (IM) therapies (CPIs and others) in BCG-refractory NMIBC.
METHODS
In total, 406 articles were identified through data bank research in PubMed/Medline, with data cutoff in October 2021. Four full-text articles and four additional congress abstracts were included in the review.
RESULTS
Durvalumab plus Oportuzumab monatox, Pembrolizumab, and Nadofaragene firadenovec (NF) show complete response (CR) rates of 41.6%, 40.6%, and 59.6% after 3 months, with a long-lasting effect, especially for NF (12-month CR rate of 30.5%). Instillations with oncolytic viruses such as NF and CG0070 show good efficacy without triggering significant immune-mediated systemic adverse events. Recombinant BCG VPM1002BC could prove to be valid as an alternative to BCG in the future. The recombinant pox-viral vector vaccine PANVAC™ is not convincing in combination with BCG. Interleukin mediating therapies, such as ALT-803, are currently being studied.
CONCLUSION
CPIs and other IM agents now offer an increasing opportunity for bladder-preserving strategies. Studies on different substances are ongoing and will yield new findings.
PubMed: 35158964
DOI: 10.3390/cancers14030694 -
Future Science OA Aug 2021Thyroid cancer incidence and related mortality is increasing year-on-year, and although treatment for early disease with surgery and radioiodine results in a 98% 5-year... (Review)
Review
Thyroid cancer incidence and related mortality is increasing year-on-year, and although treatment for early disease with surgery and radioiodine results in a 98% 5-year survival rate, recurrence and treatment refractory disease is evident in an unacceptable number of patients. Alternative treatment regimens have therefore been sought in the form of tyrosine kinase inhibitors, immunotherapy, vaccines, chimeric antigen receptor T-cell therapy and oncolytic viruses. The current review aims to consolidate knowledge and highlight the latest clinical trials using secondary therapies in thyroid cancer treatment, focusing on both and studies, which have investigated therapies other than radioiodine.
PubMed: 34258030
DOI: 10.2144/fsoa-2021-0041 -
Anticancer Research Mar 2019Bladder-related diseases are among the most common and costly to the healthcare system, and therefore require new approaches to treatment. Organoids and spheroids are 3D...
Bladder-related diseases are among the most common and costly to the healthcare system, and therefore require new approaches to treatment. Organoids and spheroids are 3D cultures that mimic organ features ex vivo and offer novel approaches for diagnostic and therapeutic assessment. The aim of this article was to provide a systematic review of the literature related to bladder organoids and spheroids, applied to disease diagnosis, characterization, and treatment. PubMed and Web of Science were utilized in March 2018 to compile 191 articles satisfying search criteria related to bladder organoids or spheroids and 58 articles were included in the final review. Finally, cell types and techniques utilized for spheroid and organoid manufacture were characterized. The applications of bladder carcinoma spheroids and organoids followed three themes: cancer characterization, diagnosis, and treatment. Tumor characterization studies included a focus on extracellular matrix, microenvironment, genetics, and growth of tumor cells. Diagnostic studies explored the use of endogenous fluorophores and white light for photodiagnosis. Treatment studies investigated cancer chemotherapy, immunotherapy, oncolytic viruses, and gene therapy. Ten studies explored hypericin as a tool for diagnostics and photodynamic therapy. Additionally, two studies applied organoids to urinary tract infections.
Topics: Cell Culture Techniques; Humans; Neoplastic Stem Cells; Organoids; Regeneration; Spheroids, Cellular; Urinary Bladder; Urinary Bladder Neoplasms; Urothelium
PubMed: 30842139
DOI: 10.21873/anticanres.13219 -
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 -
Immunotherapy Aug 2018The standard of care for early hepatobiliary cancers (HBC) includes surgical resection. Liver transplantations or locoregional therapies are beneficial in early...
The standard of care for early hepatobiliary cancers (HBC) includes surgical resection. Liver transplantations or locoregional therapies are beneficial in early hepatocellular carcinoma (HCC) under certain circumstances. Systemic treatments have some benefit in advanced HBC, though long-term prognosis remains poor. We evaluated the role of oncolytic viruses in the treatment of HBCs through a systematic literature review. The recombinant vaccinia virus JX-594 improved median survival in patients with local/metastatic HCC more strongly at high dose than at low dose (14.1 vs 6.7 months; p = 0.08) in a Phase II study. A Phase III study with JX-594 and sorafenib in advanced HCC is ongoing. No survival benefit in HCC was seen with two other recombinant adenoviruses (Ad-TK and DL1520). Several preclinical trials using oncolytic viruses in HBC showed promising results, warranting clinical studies.
Topics: Animals; Carcinoma, Hepatocellular; Clinical Trials as Topic; Drug Evaluation, Preclinical; Hepatobiliary Elimination; Humans; Liver Neoplasms; Oncolytic Virotherapy; Oncolytic Viruses; Sorafenib; Treatment Outcome; Vaccinia virus
PubMed: 29900755
DOI: 10.2217/imt-2018-0048 -
Biomedicine & Pharmacotherapy =... Feb 2022Although tremendous advancements in cancer therapy over the last several years, cancer still is a complex illness to cure. Traditional cancer treatments, including...
Although tremendous advancements in cancer therapy over the last several years, cancer still is a complex illness to cure. Traditional cancer treatments, including chemotherapy, radiotherapy, and surgery, have a poor therapeutic effect, emphasizing the significance of employing innovative treatments like activated cell therapy. Chimeric antigen receptor T cell is one of the most prevalent types of activated cell therapy have been developed to direct T lymphocytes toward cancers (CAR-T cells). CAR-T cells therapy has illustrated poor impact versus solid tumors despite the remarkable success in patients suffering from hematological malignancies. CAR-T cells must overcome various hurdles to obtain full responses to solid tumors, including growth, stability, trafficking, and destiny inside tumors. As a result, novel treatment methods will entail overcoming the challenges that CAR-T cells face in solid tumors. The use of CAR-T cells in combination with other therapeutic approaches such as chemotherapy, radiotherapy, immuno-checkpoint inhibitors, and oncolytic viruses can promote the effectiveness of CAR-T cell therapy for the treatment of solid tumors. However, more research is needed to determine the safety and effectiveness of these therapies. CAR-T cell treatment success rates vary by type of disease, but are predicted to reach up to 90% in patients with leukemia. However, since this kind of immunotherapy is still in its infancy, there is much to learn about its efficacy. This review provided an in-depth examination of CAR-T cell therapy and its success and failure as a cancer treatment approach. We also discuss combination therapies with CAR-T Cell.
Topics: Antigenic Drift and Shift; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Combined Modality Therapy; Hematologic Neoplasms; Humans; Immune Checkpoint Inhibitors; Immunotherapy, Adoptive; Neoplasms; Oncolytic Virotherapy; Receptors, Chimeric Antigen; Tumor Microenvironment
PubMed: 34894519
DOI: 10.1016/j.biopha.2021.112512 -
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 -
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