Table 1 - available via license: Creative Commons Attribution 4.0 International
Content may be subject to copyright.
Oncolytic DNA and RNA viruses in clinical trials. A selected list includes viruses described in the text.
Source publication
In recent years, oncolytic virotherapy became a promising therapeutic approach, leading to the introduction of a novel generation of anticancer drugs. However, despite evoking an antitumor response, introducing an oncolytic virus (OV) to the patient is still inefficient to overcome both tumor protective mechanisms and the limitation of viral replic...
Context in source publication
Citations
... 165 In addition, part of the OV protein coat can block IFN-I response through various pathways, one of which is to avoid the start of the IFN-I signal cascade by finding that virus protein binds to viral RNA and RIG-I. 166 Some OV proteins can also directly prevent the stimulation of NF-kB and IRF3, thus preventing the transcription of IFN mRNA 167,168 and inhibiting the activation of IFN. Similarly, experiments have confirmed that herpes simplex virus 169 and reovirus 120 also have the above mechanisms, and they can also block the production of type III IFN. ...
Colorectal cancer (CRC) has the third highest incidence and the second highest mortality in the world, which seriously affects human health, while current treatments methods for CRC, including systemic therapy, preoperative radiotherapy, and surgical local excision, still have poor survival rates for patients with metastatic disease, making it critical to develop new strategies for treating CRC. In this article, we found that the gut microbiota can modulate the signaling pathways of cancer cells through direct contact with tumor cells, generate inflammatory responses and oxidative stress through interactions between the innate and adaptive immune systems, and produce diverse metabolic combinations to trigger specific immune responses and promote the initiation of systemic type I interferon (IFN-I) and anti-viral immunity. In addition, oncolytic virus-mediated immunotherapy for regulating oncolytic virus can directly lyse tumor cells, induce the immune activity of the body, interact with interferon, inhibit the anti-viral effect of IFN-I, and enhance the anti-tumor effect of IFN-II. Interferon plays an important role in the anti-tumor process. We put forward that exploring the effects of intestinal flora and oncolytic virus on interferon to treat CRC is a promising therapeutic option.
... The present study showed that immunomodulation targetting NF-kB, by blocking the protein via pimecrolimus showed complex stability towards the end of the 100ns simulation, with conformational changes induced, pointing towards a potential NF-kB inhibition in COVID-19 surge. Studies report that inhibitors of NF-kB reduce the cytokine storms, assuaging the severity of the disease and its effects [38]. Reports state that drugs such as Cromolyn can be repurposed against NF-kB-based targets [39]. ...
We selected fifty one drugs already known for their potential disease treatment roles in various studies and subjected to docking and molecular docking simulation (MDS) analyses. Five of them showed promising features that are discussed and suggested as potential candidates for repurposing for COVID-19. These top five compounds were boswellic acid, pimecrolimus, GYY-4137, BMS-345541 and triamcinolone hexacetonide that interacted with the chosen receptors 1R42, 4G3D, 6VW1, 6VXX and 7MEQ, respectively with binding energies of -9.2 kcal/mol, -9.1 kcal/mol, -10.3 kcal/mol, -10.1 kcal/mol and -8.7 kcal/mol, respectively. The MDS studies for the top 5 best complexes revealed binding features for the chosen receptor, human NF-kappa B transcription factor as an important drug target in COVID-19-based drug development strategies.
... Interestingly, studies showed that genistin administration decreased the levels of TNF-α, interleukin 6 (IL6), and Jun N-terminal kinase (JNK) (Shahmohammadi et al. 2018). Because NF-κB plays such a crucial role in tumor cells and the tumor microenvironment, it has been studied intensively as cancer therapeutic in recent decades (Struzik and Szulc-Dąbrowska 2018). In conjunction with other chemotherapies, NF-κB inhibitors remain promising. ...
Cancer is the world’s second-largest cause of death. Although there are numerous cancer treatment options, they are typically uncomfortable owing to side effects and ineffectual due to increased resistance to traditional anti-cancer medications or radiation therapy. A key method in cancer treatment is to target delayed/inhibited inflammation and apoptosis, which are very active areas of research. Natural chemicals originating from plants are of particular interest because of their high bioavailability, safety, few side effects, and, most importantly, cost-effectiveness. Flavonoids have become incredibly common as anti-cancer medications, with promising findings as cytotoxic anti-cancer agents that cause cancer cell death. Isolated compound (genistin) was evaluated for in vitro antiproliferative activity against breast cancer cell line (MCF-7 and MDA-MB-231). The compound exhibited good cytotoxic activities against both cell lines. In vivo antiproliferative efficacy was also investigated in Ehrlich’s ascites carcinoma (EAC). Compared to the control group, genistin revealed a significant decrease in tumor weight, volume, high-mobility group box1 (HMGB1), and nuclear factor-kappa B (NF-κB) contents. On the other hand, B-cell lymphoma 2 (Bcl-2) contents increase suggesting an anti-inflammatory and anti-apoptotic activity through inhibition of HMGB1 signaling and activating the Bcl-2 pathway.
... In general, oncolytic viruses have been administered intratumorally (IT) rather than intravenously (IV) to prevent inactivation by neutralizing antibodies (nAbs) and sequestration by the reticuloendothelial system [9]. However, like the widely cited dictum to "act locally but think globally", in situ replication of oncolytic virus abscopally activates the immune system, due to 1) the generation of so-called danger signals, which stimulate toll-like receptors (TLR) [10], and 2) the release of tumor-derived antigens, which may prime cytotoxic lymphocytes. Additionally, in the case of AdAPT-001, adenoviral particles are potentially small enough (~90 nm) [11] to extravasate from the leaky, tortuous tumor neovessels, seed the systemic circulation and infect distant metastases. ...
Transgene-enhanced oncolytic adenoviruses represent a promising novel therapeutic option for the treatment of cancer. A Phase 1 clinical trial featuring AdAPT-001 is ongoing (NCT04673942). AdAPT-001, a type 5 adenovirus, which carries a TGF-β trap transgene that neutralizes the immunosuppressive cytokine, TGF-β, has been shown in an immunocompetent mouse model to eradicate both locally injected and non-injected tumors. Single dose biodistribution of the TGF-β trap transgene was also evaluated in tumor bearing mice, providing an explanation for systemic activity. The biodistribution and toxicity of a single administration of mouse AdAPT-001 (mAdAPT-001) in 129S1 immunocompetent mice bearing ADS-12 tumors (mouse lung carcinoma) were assessed. mAdAPT-001 was injected intratumorally and intravenously in groups of 25 mice each at varying dose levels. Soluble TGF-β trap was detected in the serum using ELISA. A single AdAPT-001 injection resulted in non-negligible long-term TGF-β trap persistence in the serum over the 14-day study after intravenous and intratumoral administration. No TGF-β-related toxicity was observed. At clinically relevant doses, AdAPT-001 was safe and well tolerated. Systemic levels of the TGF-β trap transgene were observed from both local and intravenous dosing.
... Chemotherapy is a type of cancer treatment that exploits cytotoxic drugs in order to kill cancer cells. Unfortunately, in some cases the drugs are insufficiently effective due to poor penetration of the drugs into tumor cells [1][2][3][4]. To achieve the desirable level of biological efficiency, the drug must be administered in high doses, resulting in adverse cytotoxic effects of the drug [5]. ...
The combination of Ca²⁺ ions and electroporation has gained attention as potential alternative to electrochemotherapy. Ca²⁺ is an important component of the cell membrane repair system and its presence directly influences the dynamics of the pore cycle after electroporation which can be exploited for cancer therapies. Here, the influence of Ca²⁺ concentration is investigated on small molecule electrotransfer and release of Calcein from 4T1, MX-1, B16F10, U87 cancer cells after cell exposure to microsecond electric pulses. Moreover, we investigated simultaneous molecule electrotransfer and intracellular calcium ion influx when media was supplemented with different Ca²⁺ concentrations. Results show that increased concentrations of calcium ions reduce the electrotransfer of small molecules to different lines of cancer cells as well as the release of Calcein. These effects are related with an enhanced membrane repair mechanism. Overall, we show that the efficiency of molecular electrotransfer can be controlled by regulating Ca²⁺ concentration in the electroporation medium. For the first time, the cause of cancer cell death in vitro from 1 mM CaCl2 concentrations is related to the irreversible loss of Ca²⁺ homeostasis after cell electroporation. Our findings provide fundamental insight on the mechanisms of Ca²⁺ electroporation that might lead to improved therapeutic outcomes.
... NF-κB and IKK therefore play key roles in regulating the innate immune response against OVs. Indeed, two types of compounds enhance OV replication through very distinct mechanisms at different stages of NF-κB-mediated transcription [65]. For instance, fumaric and maleic acid esters, such as dimethyl fumarate (DMF), block the nuclear translocation of NF-κB and have been shown to improve replication of several OVs and subsequent therapeutic outcomes by inhibiting type I IFN [66]. ...
... NF-κB and IKK therefore play key roles in regulating the innate imm response against OVs. Indeed, two types of compounds enhance OV replication thro very distinct mechanisms at different stages of NF-κB-mediated transcription [65]. Fo stance, fumaric and maleic acid esters, such as dimethyl fumarate (DMF), block the clear translocation of NF-κB and have been shown to improve replication of several and subsequent therapeutic outcomes by inhibiting type I IFN [66]. ...
The focus of treating cancer with oncolytic viruses (OVs) has increasingly shifted towards achieving efficacy through the induction and augmentation of an antitumor immune response. However, innate antiviral responses can limit the activity of many OVs within the tumor and several immunosuppressive factors can hamper any subsequent antitumor immune responses. In recent decades, numerous small molecule compounds that either inhibit the immunosuppressive features of tumor cells or antagonize antiviral immunity have been developed and tested for. Here we comprehensively review small molecule compounds that can achieve therapeutic synergy with OVs. We also elaborate on the mechanisms by which these treatments elicit anti-tumor effects as monotherapies and how these complement OV treatment.
... Oncolytic viruses (OV) are a promising class of anti-cancer therapeutics that selectively infect, replicate within, and kill tumor cells. The unique susceptibility of cancer cells to OV infection is the result of defective immune responses and aberrant cellular signaling that accompanies tumorigenesis [27][28][29]. Following internalization, oncolytic viruses hijack the cell's transcriptional and translational machinery and trigger cell death by a variety of necrotic, apoptotic, and immune-mediated pathways. ...
Background
Cetuximab has been approved for use for first-line treatment of patients with wild-type KRAS metastatic colorectal cancer (CRC). However, treatment with cetuximab has shown limited efficacy as a CRC monotherapy. In addition, natural killer (NK) cell function is known to be severely attenuated in cancer patients. The goal of this study was to develop a new strategy to enhance antibody-dependent cell-mediated cytotoxicity (ADCC) mediated by NK cells, in combination with cetuximab against CRC cells.
Methods
Ex vivo expanded NK cells were stimulated with reovirus, and reovirus-activated NK cells mediated ADCC assay were performed on CRC cells in combination with cetuximab. The synergistic antitumor effects of reovirus-activated NK cells and cetuximab were tested on DLD-1 tumor-bearing mice. Finally, Toll-like receptor 3 (TLR3) knockdown in NK cells, along with chemical blockade of TLR3/dsRNA complex, and inhibition of the TLR3 downstream signaling pathway, were performed to explore the mechanisms by which reovirus enhances NK cell cytotoxicity.
Results
We first confirmed that exposure of NK cells to reovirus enhanced their cytotoxicity in a dose-dependent manner.We then investigated whether reovirus-activated NK cells exposed to cetuximab-bound CRC cells exhibited greater anti-tumor efficacy than either monotherapy. Co-culture of CRC cell lines with reovirus-activated NK cells indicated that NK cytotoxicity was significantly higher in combination with cetuximab, regardless of KRAS mutation status or EGFR expression level. We also found that reovirus activation of NK cells, in conjunction with cetuximab, resulted in significantly stronger anti-tumor efficacy.Finally, TLR3 knockdown, inhibition of TLR3/dsRNA complex or TBK1/IKKε demonstrated that activation of NK cells by reovirus was dependent on TLR3 and its downstream signaling pathway.
Conclusions
This study demonstrated that combination treatment of reovirus-activated NK cells with cetuximab synergistically enhances their anti-tumor cytotoxicity, suggesting a strong candidate strategy for clinical treatment of CRC.
... Targeting the inflammasomes may provide a promising opportunity for cancer prevention, either by controlling viral replication or preventing excessive virusinduced inflammation. In addition, drugs or inhibitors targeting inflammatory signalling pathways, such as NF-κB utilised by oncogenic viruses to establish persistent infections is expected to reduce the incidence of virus-mediated cancer, overcome tumour resistance, and enhance the synergistic effect of combination therapy [93,153]. Recently, cancer immunotherapy has evolved as a means to enhance antitumour response and therapeutic efficiency through increasing tumour antigenicity, reprogramming of TME, and systemic inhibition of immunosuppressive cells to checkpoint blockades [154]. ...
Simple Summary
Inflammasomes play a key role in mediating innate immunity by regulating the processing and production of pro-inflammatory cytokines and eliminating foreign pathogens via pyroptosis. The expression of Epstein–Barr virus (EBV) viral antigens during EBV infection, a known causative agent of nasopharyngeal carcinoma (NPC), can trigger host’s antiviral immune response through activation of the inflammasomes and subsequent production of pro-inflammatory cytokines. This review explores the roles of inflammasomes during viral infection, the possible impact of inflammasomes on oncogenesis in EBV-associated NPC, and current developments in targeting inflammasomes for cancer treatment. With the contrasting roles of inflammasomes reported in different types of cancers, this paper aims to inspire further investigations into the exact role and mechanism of inflammasomes in EBV-associated NPC, as well as the therapeutic potentials of targeting inflammasomes in NPC.
Abstract
Epstein–Barr virus (EBV) infection is recognised as one of the causative agents in most nasopharyngeal carcinoma (NPC) cases. Expression of EBV viral antigens can induce host’s antiviral immune response by activating the inflammasomes to produce pro-inflammatory cytokines, such as interleukin-1β (IL-1β) and IL-18. These cytokines are known to be detrimental to a wide range of virus-infected cells, in which they can activate an inflammatory cell death program, called pyroptosis. However, aberrant inflammasome activation and production of its downstream cytokines lead to chronic inflammation that may contribute to various diseases, including NPC. In this review, we summarise the roles of inflammasomes during viral infection, how EBV evades inflammasome-mediated immune response, and progress into tumourigenesis. The contrasting roles of inflammasomes in cancer, as well as the current therapeutic approaches used in targeting inflammasomes, are also discussed in this review. While the inflammasomes appear to have dual roles in carcinogenesis, there are still many questions that remain unanswered. In particular, the exact molecular mechanism responsible for the regulation of the inflammasomes during carcinogenesis of EBV-associated NPC has not been explored thoroughly. Furthermore, the current practical application of inflammasome inhibitors is limited to specific tumour types, hence, further studies are warranted to discover the potential of targeting the inflammasomes for the treatment of NPC.
... Globally, lung cancer accounts for one-fourth of cancer-related deaths [54][55][56][57][58][59]. Cardamonin has provided promising anticancer efficacy against lung cancer in vitro. ...
Cancer is one of the leading causes of mortality, contributing to 9.6 million deaths globally in 2018 alone. Although several cancer treatments exist, they are often associated with severe side effects and high toxicities, leaving room for significant advancements to be made in the field. In recent years, several phytochemicals from plants and natural bioresources have been extracted and tested against various human malignancies using both in vitro and in vivo preclinical model systems. Cardamonin, a chalcone extracted from the Alpinia species, is an example of a natural therapeutic agent that has anti-cancer and anti-inflammatory effects against human cancer cell lines, including breast, lung, colon, and gastric, in both in vitro culture systems as well as xenograft mouse models. Earlier, cardamonin was used as a natural medicine against stomach related issues, diarrhea, insulin resistance, nephroprotection against cisplatin treatment, vasorelaxant and antinociceptive. The compound is well-known to inhibit proliferation, migration, invasion, and induce apoptosis, through the involvement of Wnt/β-catenin, NF-κB, and PI3K/Akt pathways. The good biosafety and pharmacokinetic profiling of cardamonin satisfy it as an attractive molecule for the development of an anticancer agent. The present review has summarized the chemo-preventive ability of cardamonin as an anticancer agent against numerous human malignancies.
... The authors proposed a model of synergism based on available information. The third review focused on the therapeutic perspectives of NF-κB signaling in targeting tumor cells by oncolytic viruses (OV) [8]. ...
