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Oncolytic virus-based hepatocellular carcinoma treatment: Current status, intravenous delivery strategies, and emerging combination therapeutic solutions.

Current treatments for advanced hepatocellular carcinoma (HCC) have limited success in improving patients' quality of life and prolonging life expectancy. The clinical need for more efficient and safe therapies has contributed to the exploration of emerging strategies. Recently, there has been increased interest in oncolytic viruses (OVs) as a therapeutic modality for HCC. OVs undergo selective replication in cancerous tissues and kill tumor cells. Strikingly, pexastimogene devacirepvec (Pexa-Vec) was granted an orphan drug status in HCC by the U.S. Food and Drug Administration (FDA) in 2013.

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… The deletion of the thymidine kinase (TK) gene of VVs and host p53 mutation contribute to selective replication in tumor cells. In RNA viruses, the sensitivity of VSV to HCV-infected HCC is increased, and the Reo-associated immune response can inhibit HCV replication. … A preclinical trial verified the feasibility of the combination therapy of RFH and HSV thymidine kinase/ganciclovir (HSV-TK/GCV) in HCC treatment. The results showed that nonablative RFH as a local therapy could improve the antitumor effects of HSV-TK/GCV in an HCC xenograft mouse model [151] . …

Chimeric Antigen Receptor Design and Efficacy in Ovarian Cancer Treatment.

Our increased understanding of tumour biology gained over the last few years has led to the development of targeted molecular therapies, e.g., vascular endothelial growth factor A (VEGF-A) antagonists, poly[ADP-ribose] polymerase 1 (PARP1) inhibitors in hereditary breast and ovarian cancer syndrome (BRCA1 and BRCA2 mutants), increasing survival and improving the quality of life. However, the majority of ovarian cancer (OC) patients still do not have access to targeted molecular therapies that would be capable of controlling their disease, especially resistant or relapsed. Chimeric antigen rece

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… To reduce ‘on-target, off-tumour toxicity’, an idea of introducing a regulated suicide gene into CARs such as the HSV-TK (herpes simplex virus I–derived thymidine kinase) or iCasp9 (caspase 9) has been proposed. … A Phase I Trial of in vivo Gene Therapy with the Herpes Simplex Thymidine Kinase/Ganciclovir System for the Treatment of Refractory or Recurrent Ovarian Cancer. Hum. Gene Ther. 1996;7:1161–1179. doi: 10.1089/hum.1996.7.9-1161. 51. Hu W.S., Pathak V.K. …

A rare case of post-transplant lymphoproliferative disorder (Hodgkins lymphoma) post autologous stem cell transplantation: A case report and review of literature.

IntroductionPost-transplant lymphoproliferative disorders(PTLD) include a mix of rare yet life endangering complications.Case presentation and conclusionHere, we report a case of a 63-year-old man who was the victim of post-transplant lymphoproliferative disorder (Hodgkin's lymphoma). The patient was initially diagnosed with multiple myeloma, for which chemotherapy and the autologous stem cell transplant was carried out. Post transplant patient was stable but on a follow up visit 6 months after the transplant he presented with generalized lymphadenopathy.His subsequent workup was done includin

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… been shown to have therapeutic efficacy for keeping EBV viral loads at bay and our patient had been on antivirals and anti -Pneumocystis pneumonia prophylaxis for 6 months, but the treatment of latent EBV with antivirals has shown to be futile as B cells with latent infection do not express the EBV thymidine …

Harnessing the Therapeutic Potential of Mesenchymal Stem Cells in Cancer Treatment.

Cancer, as a complicated disease, is considered to be one of the major leading causes of death globally. Although various cancer therapeutic strategies have been established, however, some issues confine the efficacies of the treatments. In recent decades researchers for finding efficient therapeutic solutions have extensively focused on the abilities of stem cells in cancer inhibition. Mesenchymal stem cells (MSCs) are multipotent stromal cells that can the most widely extracted from various sources such as the bone marrow (BM), placenta, umbilical cord (UC), menses blood, Wharton's jelly (WJ

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… can trigger complete tumor regression in prostate cancer models. 110 CD::UPRT can convert the non-toxic 5-fluorocytosine into the cytotoxic anti-tumor drug known as 5-fluorouracil. 111 , 112 Recent findings showed the safety of adipose tissue–derived allogeneic MSCs which carry herpes simplex virus-thymidine … Suicide gene therapy by canine mesenchymal stem cell transduced with thymidine kinase in a u-87 glioblastoma murine model: secretory profile and antitumor activity. PLoS One. 2022;17(2):e0264001. doi: 10.1371/journal.pone.0264001. 115. Gao Z, Zhang L, Hu J, Sun Y. …

Correlative analysis from a phase I clinical trial of intrapleural administration of oncolytic vaccinia virus (Olvi-vec) in patients with malignant pleural mesothelioma.

BackgroundThe attenuated, genetically engineered vaccinia virus has been shown to be a promising oncolytic virus for the treatment of patients with solid tumors, through both direct cytotoxic and immune-activating effects. Whereas systemically administered oncolytic viruses can be neutralized by pre-existing antibodies, locoregionally administered viruses can infect tumor cells and generate immune responses. We conducted a phase I clinical trial to investigate the safety, feasibility and immune activating effects of intrapleural administration of oncolytic vaccinia virus (NCT01766739).MethodsE

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… GLV-1h68 was derived from the LIVP strain by inserting RUC-GFP (a fusion gene of Renilla luciferase and green fluorescent protein), LacZ (beta-galactosidase), and gusA (beta-glucuronidase) expression cassettes into F14.5L (located between F14L and F15L ), thymidine kinase (TK), and hemagglutinin loci … Long-term follow-up of patients with malignant pleural mesothelioma receiving high-dose adenovirus herpes simplex thymidine Kinase/Ganciclovir suicide gene therapy. Clin Cancer Res (2005) 11(20):7444–53. doi: 10.1158/1078-0432.CCR-05-0405 42. Sun Y, Zhang Z, Zhang C, Zhang N, Wang P, Chu Y, et al. …

Gene therapy for people with hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma is the most common type of liver cancer, accounting for 70% to 85% of individuals with primary liver ca … fe and time to symptomatic progression was confounded by the high patient dropout rate." Adenovirus-thymidine kinase with ganciclovir (ADV-TK/GCV) plus liver transplantation versus liver transplantation alone There is uncertainty about whether ADV-TK/GCV plus liver transplantation may benefit all-cause mortality at the two-year follow-up (RR 0.39, 95% CI 0. …

Stochasticity of anticancer mechanisms underlying clinical effectiveness of vorinostat.

The Food and Drug Administration (FDA) has approved vorinostat, also called Zolinza®, for its effectiveness in fighting cancer. This drug is a suberoyl-anilide hydroxamic acid belonging to the class of histone deacetylase inhibitors (HDACis). Its HDAC inhibitory potential allows it to accumulate acetylated histones. This, in turn, can restore normal gene expression in cancer cells and activate multiple signaling pathways. Experiments have proven that vorinostat induces histone acetylation and cytotoxicity in many cancer cell lines, increases the level of p21 cell cycle proteins, and enhances p

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… TP: thymidine phosphorylase. TS: thymidylate synthase. Annexin V: a protein that has a high affinity for phosphatidylserine. PI: propidium iodide. TUNEL assay: Terminal deoxynucleotidyl transferase dUTP nick end labeling assay. EGCG: epigallocatechin-3-gallate. … Additionally, vorinostat down-regulated TS in cancer cells and up-regulated thymidine phosphorylase (TP) ( in vivo and in vitro ). Overall, combination therapy with vorinostat and other chemotherapeutic agents can be a colossal option in the clinical treatment of CRC. …

Exogenous α-ketoglutarate Modulates Redox Metabolism and Functions of Human Dendritic Cells, Altering Their Capacity to Polarise T Cell Response.

Alpha-ketoglutarate (αKG) emerged as a key regulator of energetic and redox metabolism in cells, affecting the immune response in various conditions. However, it remained unclear how the exogenous αKG modulates the functions of dendritic cells (DCs), key cells regulating T-cell response. Here we found that non-toxic doses of αKG display anti-inflammatory properties in human APC-T cell interaction models. In a model of monocyte-derived (mo)DCs, αKG impaired the differentiation, and the maturation of moDCs induced with lipopolysaccharide (LPS)/interferon (IFN)-γ, and decreased their capacity to

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… The proliferation of PBMCs was determined in [ 3 H]-thymidine assay, as described previously 36 . … B) The proliferation of PBMCs, according to [ 3 H]-thymidine incorporation during the last 18h of culture, was determined by β-scintillation counting, and the data is shown as counts per minute (CPM) ± SEM (n=3 different donors). …

Metabolic crosstalk between stromal and malignant cells in the bone marrow niche.

Bone marrow is the primary site of blood cell production in adults and serves as the source of osteoblasts and osteoclasts that maintain bone homeostasis. The medullary microenvironment is also involved in malignancy, providing a fertile soil for the growth of blood cancers or solid tumors metastasizing to bone. The cellular composition of the bone marrow is highly complex, consisting of hematopoietic stem and progenitor cells, maturing blood cells, skeletal stem cells, osteoblasts, mesenchymal stromal cells, adipocytes, endothelial cells, lymphatic endothelial cells, perivascular cells, and n

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… Some MM cells express high levels of thymidine phosphorylase, which converts thymidine into thymine and 2-deoxy- d -ribose-1-phosphate that is further dephosphorylated into 2-deoxy- d -ribose (2DDR) ( Liu et al., 2016 ). … Thymidine phosphorylase exerts complex effects on bone resorption and formation in myeloma. Sci. Transl. Med. 2016;8(353):353ra113. doi: 10.1126/scitranslmed.aad8949. Liu H., et al. Reprogrammed marrow adipocytes contribute to myeloma-induced bone disease. Sci. Transl. …

Looking for the Holy Grail-Drug Candidates for Glioblastoma Multiforme Chemotherapy.

Glioblastoma multiforme (GBM) is the deadliest and the most heterogeneous brain cancer. The median survival time of GBM patients is approximately 8 to 15 months after initial diagnosis. GBM development is determined by numerous signaling pathways and is considered one of the most challenging and complicated-to-treat cancer types. Standard GBM therapy consist of surgery followed by radiotherapy or chemotherapy, and combined treatment. Current standard of care (SOC) does not offer a significant chance for GBM patients to combat cancer, and the selection of available drugs is limited. For almost

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… The methylation of the O-6 position of guanine is the most cytotoxic, which results in a ‘mismatch’ incorporation of thymidine instead of cytosine [ 10 ]. Consequently, proper DNA replication is altered, leading to cell death induction. … On the other hand, thymidine incorporation is recognized by the mismatch repair (MMR) enzymes, such as o-6-methylguanine-DNA methyltransferase (MGMT), which repair the guanine methylation, leading to the escape of GBM cells from TMZ-dependent apoptosis [ 11 ]. …

Treatment-induced mucositis: an old problem with new remedies.

Mucositis may be a painful, debilitating, dose-limiting side-effect of both chemotherapy and radiotherapy for which there is no widely accepted prophylaxis or effective treatment. The basis of management is pain relief, prevention of dehydration and adequate nutrition. When tested vigorously, most antiseptic mouthwashes and anti-ulcer agents are ineffective. Simple mechanical cleansing by saline is the most effective traditional measure. A variety of new agents are effective. Granulocyte macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF) act outwith

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… Interleukin 1 increases thymidine labeling index of normal tissues of mice but not the tumor. 29 4 1 7 1994 805 811 Int J Radiat Oncol Biol Phys 8040027 10.1016/0360-3016(94)90569-x van Saene H. K. Martin M. V. Do microorganisms play a role in irradiation mucositis? …

Oncolytic Viruses for Cancer Therapy in Dogs.

Cancer remains the leading cause of death in domestic dogs. Conventional therapeutic approaches, including surgery, chemotherapy, and radiotherapy, frequently fail to achieve sustained remission or stabilization. Oncolytic virotherapy, a rapidly advancing therapeutic modality in human oncology, is emerging as a novel strategy in veterinary medicine. This systematic review summarizes current knowledge on the application of oncolytic viruses (OVs) in canine cancer treatment, focusing on their mechanisms of action, safety profiles, and clinical efficacy. We evaluate diverse OV platforms, includin

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… Inactivation of J2R (encoding viral thymidine kinase) reduces VACV’s toxicity, while enhancing its tumor tropism. The I4L and F4L genes encode ribonucleotide reductase-like proteins, modifications that further increase tumor selectivity. … Adenovirus-mediated thymidine kinase gene therapy for recurrent ovarian cancer: Expression of coxsackie-adenovirus receptor and integrins alphavbeta3 and alphavbeta5 J. Soc. Gynecol. Investig. 2002 9 174 180 10.1177/107155760200900310 12009393 81. Martin T.A. Watkins G. Jiang W.G. …

Managing allorejection in off-the-shelf CAR-engineered cell therapies.

Chimeric antigen receptor (CAR)-engineered T (CAR-T) cell therapy has revolutionized the treatment of various diseases, including cancers and autoimmune disorders. However, all US Food and Drug Administration (FDA)-approved CAR-T cell therapies are autologous, and their widespread clinical application is limited by several challenges, such as complex individualized manufacturing, high costs, and the need for patient-specific selection. Allogeneic off-the-shelf CAR-engineered cell therapy offers promising potential due to its immediate availability, consistent quality, potency, and scalability

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… Figure 2 In vitro and in vivo assays assessing allorejection A range of assays has been employed to assess host-cell-mediated allorejection of grafted cells, including flow cytometry in mixed lymphocyte reaction (MLR) assays (A), carboxyfluorescein succinimidyl ester (CFSE) staining (B), 3 H-thymidine … As 3H-thymidine incorporates into the DNA of the proliferating effector cells, it provides a quantitative measure of allorejection by indicating the alloreactive proliferation of recipient cells. 46 Furthermore, IFN-γ enzyme linked immunosorbent spot (ELISPOT) assay is used to detect the presence of …

Metabolic Reprogramming of Cancer Cells and Therapeutics Targeting Cancer Metabolism.

BackgroundCancer metabolism is a field focused on the unique alterations in metabolic pathways that occur in cancer cells, distinguishing them from the metabolic processes in normal cells.MethodsAn extensive review of the current literature on the metabolic adaptation of cancer cells was carried out in the current study.ResultsThe rapidly proliferating cells require high levels of molecules, such as glucose, amino acids, lipids, and nucleotides, along with increased energy demand (ATP). These requirements are met through alterations in the processes involving glucose, amino acid, lipid, and nu

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… In addition, thymidine kinase 1 (TK1) mediates the alteration of thymidine to deoxythymidine monophosphate (dTMP) in the salvage pathway, whereas thymidylate synthase (TYMS) in the de novo pathway [ 24 , 110 , 111 ]. … Floxuridine is transformed into floxuridine‐5′‐monophosphate II via thymidine kinase; hence, floxuridine inhibits TYMS, and the FDA approved it for metastatic colorectal malignancies in 1970 [ 292 ]. …

Mesenchymal stem cells lineage and their role in disease development.

BackgroundMesenchymal stem cells (MSCs) are widely dispersed in vivo and are isolated from several tissues, including bone marrow, heart, body fluids, skin, and perinatal tissues. Bone marrow MSCs have a multidirectional differentiation potential, which can be induced to differentiate the medium in a specific direction or by adding specific regulatory factors. MSCs repair damaged tissues through lineage differentiation, and the ex vivo transplantation of bone marrow MSCs can heal injured sites. MSCs have different propensities for lineage differentiation and pathological evolution for differen

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… localization | example | Merits | Limitations Embryo | Embryo transplantations | Embryo natural body color [Spemann and Mangold 1924 ] | Intuitive graphics and simple operation | Nonclonal, dilution, accessibility to cells Chemical dye | CM-Dil [Ben - Yair et al. 2003 ] Radioactive dye | Tritiated thymidine … In addition to the embryo’s color and chemical dyes, radioactive dyes have been used to label embryos, such as deuterated thymidine as a DNA probe to track DNA synthesis, which is vital in the study of murine neurodevelopment (Kaplan and Hinds 1977 ). …

Bioengineered Mesenchymal Stem/Stromal Cells in Anti-Cancer Therapy: Current Trends and Future Prospects.

Mesenchymal stem/stromal cells (MSCs) are one of the most widely used cell types in advanced therapies due to their therapeutic potential in the regulation of tissue repair and homeostasis, and immune modulation. However, their use in cancer therapy is controversial: they can inhibit cancer cell proliferation, but also potentially promote tumour growth by supporting angiogenesis, modulation of the immune milieu and increasing cancer stem cell invasiveness. This opposite behaviour highlights the need for careful and nuanced use of MSCs in cancer treatment. To optimize their anti-cancer effects,

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… The most common example of this approach is the combination of the thymidine kinase (TK) gene from herpes simplex virus (HSV) with ganciclovir (GCV) as a prodrug. … Tumor chemosensitivity conferred by inserted herpes thymidine kinase genes: Paradigm for a prospective cancer control strategy Cancer Res. 1986 46 5276 5281 3019523 216. Fillat C. Carrio M. Cascante A. Sangro B. …

New light on chemotherapy toxicity and its prevention.

Most patients with cancer receive chemotherapy. Unfortunately, chemotherapy is associated with a number of potentially life-threatening side effects. There is a need to ameliorate chemotoxicity to improve therapeutic outcomes and quality of life. Chemotoxicity arises from systemic DNA damage and inflammation in healthy cells due to chemotherapy drugs. Traditionally, these processes are believed to be caused by the direct death of normal cells by chemotherapeutic drugs. However, new research has challenged this dogma by suggesting that chemotoxicity is a secondary effect associated with the rel

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… When experiments in the same study were performed using dead Jurkat cells that had been pre-labelled with the thymidine analogue bromodeoxyuridine (BrdU) prior to Adriamycin treatment, numerous BrdU-labelled fluorescent particles representing DNA were found to have accumulated in the nuclei of NIH3T3 …

CD4-Positive T-Cell Responses to MOG Peptides in MOG Antibody-Associated Disease.

To clarify T-cell responses in myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD), we cultured the peripheral blood mononuclear cells of 24 patients with MOGAD and 20 with aquaporin-4 (AQP4) antibody-positive neuromyelitis optica spectrum disorders (NMOSD), and those of 17 healthy controls (HCs), in the presence of fourteen MOG peptides covering the full-length MOG, five AQP4 peptides, two myelin basic protein peptides, or two proteolipid protein peptides. Then, we measured T-cell activation markers, such as cell surface CD69 and the intracellular production of granu

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… Third, we focused on early T-cell activation with MOG peptides; however, we did not analyze late T-cell activation markers such as CD154, nor did we conduct a T-cell proliferation using the CSFE proliferation assay or [3H] the thymidine uptake assay. …

Gene and Cell Therapy for Sarcomas: A Review.

Background: The heterogeneity of sarcomas and resulting distinct sub-type specific characteristics, their high recurrence rates, and tendency for distant metastasis, continue to present significant challenges to providing optimal treatments. Objective: To provide a comprehensive review of current literature and clinical trials in gene and cell therapies for sarcomas. Methods: A comprehensive literature search was conducted utilizing the following databases: PubMed, Medline, Google Scholar and clinicaltrials.gov. Search terms included "gene therapy", "cell therapy", "NK cell therapy, "CAR-T the

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… dual-targeted gene therapy regimen, combining (1) Rexin-G, a tumor-targeted retrovector encoding a cytocidal gene to destroy the cancer cells and tumor vasculature and expose tumor neoantigens, and (2) Reximmune-C, a tumor-targeted retrovector encoding a regulatable GM-CSF/Herpes simplex virus Type 1 thymidine … The vector payload encodes for a suicide gene, an enhanced viral thymidine kinase enzyme (HSV-eTK), which in the presence of a prodrug, valganciclovir, causes the tumor to release patient-specific tumor antigens. …

Keyword Index for Volume 91

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… squamous cell carcinoma 2005 health anxiety 893 height 519 Helicobacter pylori 929 heparin 30 hepatoblastoma 972 hepatocarcinogenesis 1955 hepatocellular carcinoma 753, 1561 HER-2 430, 795 HER2/neu 959, 1195, 1308 HER3 2034 HER4 2034 Herceptin 1190 heregulins 2034 herpes simplex virus thymidine …