Octyl itaconate enhances VSVΔ51 oncolytic virotherapy by multitarget inhibition of antiviral and inflammatory pathways.

The presence of heterogeneity in responses to oncolytic virotherapy poses a barrier to clinical effectiveness, as resistance to this treatment can occur through the inhibition of viral spread within the tumor, potentially leading to treatment failures. Here we show that 4-octyl itaconate (4-OI), a chemical derivative of the Krebs cycle-derived metabolite itaconate, enhances oncolytic virotherapy with VSVΔ51 in various models including human and murine resistant cancer cell lines, three-dimensional (3D) patient-derived colon tumoroids and organotypic brain tumor slices. Furthermore, 4-OI in combination with VSVΔ51 improves therapeutic outcomes in a resistant murine colon tumor model. Mechanistically, we find that 4-OI suppresses antiviral immunity in cancer cells through the modification of cysteine residues in MAVS and IKKß independently of the NRF2/KEAP1 axis. We propose that the combination of a metabolite-derived drug with an oncolytic virus agent can greatly improve anticancer therapeutic outcomes by direct interference with the type I IFN and NF-κB-mediated antiviral responses.

High-Pressure Delivery of Oncolytic Viruses via Needle-Free Injection Preserves Therapeutic Activity.

Intratumoural delivery of oncolytic viruses (OVs) to solid tumours is currently performed via multiple percutaneous methods of needle injections (NI). In this study, we investigated the potential use of a novel delivery approach, needle-free injection (NFI), to administer OVs to subcutaneous tumours. The stability and genetic integrity of several RNA and DNA viruses exposed to high-pressure jet injectors were first evaluated in vitro. We demonstrate that replication competence and infectivity of the viruses remained unchanged after NFI, as compared to traditional NI. Using the oncolytic Vesicular Stomatitis Virus expressing luciferase (VSVΔ51-Luc) in the syngeneic CT26 subcutaneous tumour model, we show that NFI administration not only successfully delivers infectious particles but also increases the dissemination of the virus within the tumour tissues when compared to NI. Furthermore, mice treated with VSVΔ51-Luc by NFI delivery showed similar reduction in tumour growth and survival compared to those with needle-administered virus. These results indicate that NFI represents a novel approach to administer and potentially increase the spread of OVs within accessible solid tumours, highlighting its usefulness in virotherapy.

Adaptation of transgene mRNA translation boosts the anticancer efficacy of oncolytic HSV1.

BACKGROUND: Transgenes deliver therapeutic payloads to improve oncolytic virus immunotherapy. Transgenes encoded within oncolytic viruses are designed to be highly transcribed, but protein synthesis is often negatively affected by viral infection, compromising the amount of therapeutic protein expressed. Studying the oncolytic herpes simplex virus-1 (HSV1), we found standard transgene mRNAs to be suboptimally translated in infected cells. METHODS: Using RNA-Seq reads, we determined the transcription start sites and 5'leaders of HSV1 genes and uncovered the US11 5'leader to confer superior activity in translation reporter assays. We then incorporated this 5'leader into GM-CSF expression cassette in oncolytic HSV1 and compared the translationally adapted oncolytic virus with the conventional, leaderless, virus in vitro and in mice. RESULTS: Inclusion of the US11 5'leader in the GM-CSF transgene incorporated into HSV1 boosted translation in vitro and in vivo. Importantly, treatment with US11 5'leader-GM-CSF oncolytic HSV1 showed superior antitumor immune activity and improved survival in a syngeneic mouse model of colorectal cancer as compared with leaderless-GM-CSF HSV1. CONCLUSIONS: Our study demonstrates the therapeutic value of identifying and integrating platform-specific cis-acting sequences that confer increased protein synthesis on transgene expression.

Kinase inhibitors with viral oncolysis: Unmasking pharmacoviral approaches for cancer therapy.

There are more than 500 kinases in the human genome, many of which are oncogenic once constitutively activated. Fortunately, numerous hyperactive kinases are druggable, and several targeted small molecule kinase inhibitors have demonstrated impressive clinical benefits in cancer treatment. However, their often cytostatic rather than cytotoxic effect on cancer cells, and the development of resistance mechanisms, remain significant limitations to these targeted therapies. Oncolytic viruses are an emerging class of immunotherapeutic agents with a specific oncotropic nature and excellent safety profile, highlighting them as a promising alternative to conventional therapeutic modalities. Nonetheless, the clinical efficacy of oncolytic virotherapy is challenged by immunological and physical barriers that limit viral delivery, replication, and spread within tumours. Several of these barriers are often associated with oncogenic kinase activity and, in some cases, worsened by the action of oncolytic viruses on kinase signaling during infection. What if inhibiting these kinases could potentiate the cancer-lytic and anti-tumour immune stimulating properties of oncolytic virotherapies? This could represent a paradigm shift in the use of specific kinase inhibitors in the clinic and provide a novel therapeutic approach to the treatment of cancers. A phase III clinical trial combining the oncolytic Vaccinia virus Pexa-Vec with the kinase inhibitor Sorafenib was initiated. While this trial failed to show any benefits over Sorafenib monotherapy in patients with advanced liver cancer, several pre-clinical studies demonstrate that targeting kinases combined with oncolytic viruses have synergistic effects highlighting this strategy as a unique avenue to cancer therapy. Herein, we review the combinations of oncolytic viruses with kinase inhibitors reported in the literature and discuss the clinical opportunities that represent these pharmacoviral approaches.

Engineering and combining oncolytic measles virus for cancer therapy.

Cancer immunotherapy using tumor-selective, oncolytic viruses is an emerging therapeutic option for solid and hematologic malignancies. A considerable variety of viruses ranging from small picornaviruses to large poxviruses are currently being investigated as potential candidates. In the early days of virotherapy, non-engineered wild-type or vaccine-strain viruses were employed. However, these viruses often did not fully satisfy the major criteria of safety and efficacy. Since the advent of reverse genetics systems for manipulating various classes of viruses, the field has shifted to developing genetically engineered viruses with an improved therapeutic index. In this review, we will summarize the concepts and strategies of multi-level genetic engineering of oncolytic measles virus, a prime candidate for cancer immunovirotherapy. Furthermore, we will provide a brief overview of measles virus-based multimodal combination therapies for improved tumor control and clinical efficacy.

Combining Cost-Efficient Cellulose and Short-Chain Carboxylic Acid Production: The Polyoxometalate (POM)-Ionosolv Concept.

Full cost-effective exploitation of all wood components is key to growing a commercially successful biorefining industry. An innovative process is reported that combines fractionation of lignocellulosic biomass using a low-cost ionic liquid (Ionosolv) and production of bio-derived formic acid using polyoxometalates and molecular oxygen (OxFA process). We show that the hemicellulose and part of the lignin were selectively dissolved into the ionic liquid triethylammonium hydrogen sulfate and oxidised in situ to short-chain, distillable carboxylic acids by a Keggin-type polyoxometalate with high yields and selectivities. Characterization by several techniques, including ICP-OES, FTIR, GC, HPLC and NMR spectroscopy confirmed stability of the catalyst over three consecutive POM-Ionosolv recycles and stable formic acid yields.High formic acid yields of 26 % (pine chips), 23 % (beech chips), and 18 % (Miscanthus) were obtained with respect to the initial carbon content of the biomass, with unprecedented oxidation selectivities for formic acid of 54-62 % depending on vanadium substitution in the polyoxometalate, the processing temperature and the water content in the reaction mixture.. We also demonstrate that the cellulose rich pulp is a suitable source of glucose via enzymatic saccharification. We report cellulose yields of 37% for Miscanthus (from originally 48% glucan content), 33% for pine (from originally 49%) and 31% for beech (from originally 41%) were achieved, and a saccharification yield of up to 25% without optimisation. With further optimisation, this concept has the potential to generate two chemical products directly from lignocellulose in high yields and selectivities and hence a novel avenue for full utilisation of cellulose, hemicellulose and lignin.

Abuse and Effects of Salvia divinorum in a Sample of Patients Hospitalized for Substance Dependence.

The study goal is to document the prevalence of salvia use among patients admitted for detoxification of other illicit drug use and to determine its effect. This cross-sectional study included 47 heavy drug users who were admitted for detoxification of other illicit drug abuse at a psychiatric hospital in Lebanon. The prevalence of salvia use was 66%. The salvia effect started and dissipated rapidly (15 min). No significant difference was found between salvia and non-salvia users in terms of affect, cognition and somaesthesia subscales of the Hallucinogen Rating Scale. Ratings of intensity and volition subscales were higher in non-salvia users than salvia users, while perception score was higher in users. Salvia use was correlated with perceptual alteration and hallucinogenic effects.