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Cell Communication and Signaling : CCS Apr 2024Cancer, ranked as the second leading cause of mortality worldwide, leads to the death of approximately seven million people annually, establishing itself as one of the... (Review)
Review
Cancer, ranked as the second leading cause of mortality worldwide, leads to the death of approximately seven million people annually, establishing itself as one of the most significant health challenges globally. The discovery and identification of new anti-cancer drugs that kill or inactivate cancer cells without harming normal and healthy cells and reduce adverse effects on the immune system is a potential challenge in medicine and a fundamental goal in Many studies. Therapeutic bacteria and viruses have become a dual-faceted instrument in cancer therapy. They provide a promising avenue for cancer treatment, but at the same time, they also create significant obstacles and complications that contribute to cancer growth and development. This review article explores the role of bacteria and viruses in cancer treatment, examining their potential benefits and drawbacks. By amalgamating established knowledge and perspectives, this review offers an in-depth examination of the present research landscape within this domain and identifies avenues for future investigation.
Topics: Humans; Neoplasms; Bacteria; Animals; Oncolytic Virotherapy; Viruses
PubMed: 38654309
DOI: 10.1186/s12964-024-01622-w -
Endokrynologia Polska 2024Glioblastoma multiforme (GBM) is the most aggressive malignant brain tumour. The average survival time for a patient diagnosed with GBM, using standard treatment... (Review)
Review
Glioblastoma multiforme (GBM) is the most aggressive malignant brain tumour. The average survival time for a patient diagnosed with GBM, using standard treatment methods, is several months. Authors of the article pose a direct question: Is it possible to treat GBM solely with radioactive iodine (¹³¹I) therapy without employing the sodium iodide symporter (NIS) gene? After all, NIS has been detected not only in the thyroid but also in various tumours. The main author of this article (A.C.), with the assistance of her colleagues (physicians and pharmacologists), underwent ¹³¹I therapy after prior iodine inhibition, resulting in approximately 30% reduction in tumour size as revealed by magnetic resonance imaging (MRI). Classical therapy for GBM encompasses neurosurgery, conventional radiotherapy, and chemotherapy (e.g. temozolomide). Currently, tyrosine kinase inhibitors (imatinib, sunitinib, and sorafenib) are being used. Additionally, novel drugs such as crizotinib, entrectinib, or larotrectinib are being applied. Recently, personalised multimodal immunotherapy (IMI) based on anti-tumour vaccines derived from oncolytic viruses has been developed, concomitant with the advancement of cellular and molecular immunology. Thus, ¹³¹I therapy has been successfully employed for the first time in the case of GBM recurrence.
Topics: Humans; Glioblastoma; Iodine Radioisotopes; Brain Neoplasms; Neoplasm Recurrence, Local; Combined Modality Therapy
PubMed: 38646982
DOI: 10.5603/ep.98240 -
MedRxiv : the Preprint Server For... Apr 2024Glutamatergic neuron-glioma synaptogenesis and peritumoral hyperexcitability promote glioma growth in a positive feedback loop. The objective of this study was to...
BACKGROUND
Glutamatergic neuron-glioma synaptogenesis and peritumoral hyperexcitability promote glioma growth in a positive feedback loop. The objective of this study was to evaluate the feasibility and estimated effect sizes of the AMPA-R antagonist, perampanel, on intraoperative electrophysiologic hyperexcitability and clinical outcomes.
METHODS
An open-label trial was performed comparing perampanel to standard of care (SOC) in patients undergoing resection of newly-diagnosed radiologic high-grade glioma. Perampanel was administered as a pre-operative loading dose followed by maintenance therapy until progressive disease or up to 12-months. SOC treatment involved levetiracetam for 7-days or as clinically indicated. The primary outcome of hyperexcitability was defined by intra-operative electrocorticography high frequency oscillation (HFO) rates. Seizure-freedom and overall survival (OS) were estimated by the Kaplan-Meier method. Tissue concentrations of perampanel, levetiracetam, and metabolites were measured by mass spectrometry.
RESULTS
HFO rates were similar between perampanel-treated and SOC cohorts. The trial was terminated early after interim analysis for futility, and outcomes assessed in 11 patients (7 perampanel-treated, 4 SOC). Over a median 281 days of post-enrollment follow-up, 27% of patients had seizures, including 14% treated with perampanel and 50% treated with SOC. OS in perampanel-treated patients was similar to a glioblastoma reference cohort (p=0.81). Glutamate concentrations in surface biopsies were positively correlated with HFO rates in adjacent electrode contacts and were not significantly associated with treatment assignment or drug concentrations.
CONCLUSIONS
A peri-operative loading regimen of perampanel was safe and well-tolerated, with similar peritumoral hyperexcitability as in levetiracetam-treated patients. Maintenance anti-glutamatergic therapy was not observed to impact survival outcomes.
PubMed: 38645003
DOI: 10.1101/2024.04.11.24305666 -
Cells Apr 2024Glioblastoma is the most aggressive, malignant, and lethal brain tumor of the central nervous system. Its poor prognosis lies in its inefficient response to currently... (Review)
Review
Glioblastoma is the most aggressive, malignant, and lethal brain tumor of the central nervous system. Its poor prognosis lies in its inefficient response to currently available treatments that consist of surgical resection, radiotherapy, and chemotherapy. Recently, the use of mesenchymal stem cells (MSCs) as a possible kind of cell therapy against glioblastoma is gaining great interest due to their immunomodulatory properties, tumor tropism, and differentiation into other cell types. However, MSCs seem to present both antitumor and pro-tumor properties depending on the tissue from which they come. In this work, the possibility of using MSCs to deliver therapeutic genes, oncolytic viruses, and miRNA is presented, as well as strategies that can improve their therapeutic efficacy against glioblastoma, such as CAR-T cells, nanoparticles, and exosomes.
Topics: Humans; Glioblastoma; Mesenchymal Stem Cell Transplantation; Glioma; Brain Neoplasms; Mesenchymal Stem Cells
PubMed: 38607056
DOI: 10.3390/cells13070617 -
Journal For Immunotherapy of Cancer Apr 2024Glioblastoma (GBM), a highly immunosuppressive and often fatal primary brain tumor, lacks effective treatment options. GBMs contain a subpopulation of GBM stem-like...
BACKGROUND
Glioblastoma (GBM), a highly immunosuppressive and often fatal primary brain tumor, lacks effective treatment options. GBMs contain a subpopulation of GBM stem-like cells (GSCs) that play a central role in tumor initiation, progression, and treatment resistance. Oncolytic viruses, especially oncolytic herpes simplex virus (oHSV), replicate selectively in cancer cells and trigger antitumor immunity-a phenomenon termed the "in situ vaccine" effect. Although talimogene laherparepvec (T-VEC), an oHSV armed with granulocyte macrophage-colony stimulating factor (GM-CSF), is Food and Drug Administration (FDA)-approved for melanoma, its use in patients with GBM has not been reported. Interleukin 2 (IL-2) is another established immunotherapy that stimulates T cell growth and orchestrates antitumor responses. IL-2 is FDA-approved for melanoma and renal cell carcinoma but has not been widely evaluated in GBM, and IL-2 treatment is limited by its short half-life, minimal tumor accumulation, and significant systemic toxicity. We hypothesize that local intratumoral expression of IL-2 by an oHSV would avoid the systemic IL-2-related therapeutic drawbacks while simultaneously producing beneficial antitumor immunity.
METHODS
We developed G47Δ-mIL2 (an oHSV expressing IL-2) using the flip-flop HSV BAC system to deliver IL-2 locally within the tumor microenvironment (TME). We then tested its efficacy in orthotopic mouse GBM models (005 GSC, CT-2A, and GL261) and evaluated immune profiles in the treated tumors and spleens by flow cytometry and immunohistochemistry.
RESULTS
G47Δ-mIL2 significantly prolonged median survival without any observable systemic IL-2-related toxicity in the 005 and CT-2A models but not in the GL261 model due to the non-permissive nature of GL261 cells to HSV infection. The therapeutic activity of G47Δ-mIL2 in the 005 GBM model was associated with increased intratumoral infiltration of CD8 T cells, critically dependent on the release of IL-2 within the TME, and CD4 T cells as their depletion completely abrogated therapeutic efficacy. The use of anti-PD-1 immune checkpoint blockade did not improve the therapeutic outcome of G47Δ-mIL2.
CONCLUSIONS
Our findings illustrate that G47Δ-mIL2 is efficacious, stimulates antitumor immunity against orthotopic GBM, and may also target GSC. OHSV expressing IL-2 may represent an agent that merits further exploration in patients with GBM.
Topics: Animals; Humans; Mice; Brain Neoplasms; CD8-Positive T-Lymphocytes; Glioblastoma; Herpes Simplex; Herpesvirus 2, Human; Interleukin-2; Melanoma; Oncolytic Virotherapy; Tumor Microenvironment; United States
PubMed: 38599661
DOI: 10.1136/jitc-2024-008880 -
Computational and Structural... Dec 2024Identifying potential cancer-associated genes and drug targets from omics data is challenging due to its diverse sources and analyses, requiring advanced skills and...
Identifying potential cancer-associated genes and drug targets from omics data is challenging due to its diverse sources and analyses, requiring advanced skills and large amounts of time. To facilitate such analysis, we developed Cat-E (ncer arget xplorer), a novel R/Shiny web tool designed for comprehensive analysis with evaluation according to cancer-related omics data. Cat-E is accessible at https://cat-e.bioinfo-wuerz.eu/. Cat-E compiles information on oncolytic viruses, cell lines, gene markers, and clinical studies by integrating molecular datasets from key databases such as OvirusTB, TCGA, DrugBANK, and PubChem. Users can use all datasets and upload their data to perform multiple analyses, such as differential gene expression analysis, metabolic pathway exploration, metabolic flux analysis, GO and KEGG enrichment analysis, survival analysis, immune signature analysis, single nucleotide variation analysis, dynamic analysis of gene expression changes and gene regulatory network changes, and protein structure prediction. Cancer target evaluation by Cat-E is demonstrated here on lung adenocarcinoma (LUAD) datasets. By offering a user-friendly interface and detailed user manual, Cat-E eliminates the need for advanced computational expertise, making it accessible to experimental biologists, undergraduate and graduate students, and oncology clinicians. It serves as a valuable tool for investigating genetic variations across diverse cancer types, facilitating the identification of novel diagnostic markers and potential therapeutic targets.
PubMed: 38596315
DOI: 10.1016/j.csbj.2024.03.024 -
Molecular Therapy. Oncology Mar 2024Lung cancer's intractability is enhanced by its frequent resistance to (chemo)therapy and often high relapse rates that make it the leading cause of cancer death... (Review)
Review
Lung cancer's intractability is enhanced by its frequent resistance to (chemo)therapy and often high relapse rates that make it the leading cause of cancer death worldwide. Improvement of therapy efficacy is a crucial issue that might lead to a significant advance in the treatment of lung cancer. Oncolytic viruses are desirable combination partners in the developing field of cancer immunotherapy due to their direct cytotoxic effects and ability to elicit an immune response. Systemic oncolytic virus administration through intravenous injection should ideally lead to the highest efficacy in oncolytic activity. However, this is often hampered by the prevalence of host-specific, anti-viral immune responses. One way to achieve more efficient systemic oncolytic virus delivery is through better protection against neutralization by several components of the host immune system. Carrier cells, which can even have innate tumor tropism, have shown their appropriateness as effective vehicles for systemic oncolytic virus infection through circumventing restrictive features of the immune system and can warrant oncolytic virus delivery to tumors. In this overview, we summarize promising results from studies in which carrier cells have shown their usefulness for improved systemic oncolytic virus delivery and better oncolytic virus therapy against lung cancer.
PubMed: 38596310
DOI: 10.1016/j.omton.2024.200788 -
Molecular Therapy. Oncology Mar 2024Pancreatic cancer will soon become the second cause of death by cancer in Western countries. The main barrier to increase the survival of patients with this disease...
Pancreatic cancer will soon become the second cause of death by cancer in Western countries. The main barrier to increase the survival of patients with this disease requires the development of novel and efficient therapeutic strategies that better consider tumor biology. In this context, oncolytic viruses emerge as promising therapeutics. Among them, the fibrotropic minute virus of mice prototype (MVMp) preferentially infects migrating and undifferentiated cells that highly resemble poorly differentiated, basal-like pancreatic tumors showing the worst clinical outcome. We report here that MVMp specifically infects, replicates in, and kills pancreatic cancer cells from murine and human origin with a mesenchymal, basal-like profile, while sparing cancer cells with an epithelial phenotype. Remarkably, MVMp infection, at a dose that does not provoke tumor growth inhibition in athymic mice, shows significant antitumoral effect in immune-competent models; extended mouse survival; and promoted the massive infiltration of tumors by innate, myeloid, and cytotoxic T cells that exhibit a less terminally exhausted phenotype. Collectively, we demonstrate herein for the first time that MVMp is specific and oncolytic for pancreatic tumors with mesenchymal, basal-like profile, paving the way for precision-medicine opportunities for the management of the most aggressive and lethal form of this disease.
PubMed: 38596307
DOI: 10.1016/j.omton.2024.200780 -
Molecular Therapy. Oncology Mar 2024Oncolytic viruses are engineered to selectively kill tumor cells and have demonstrated promising results in early-phase clinical trials. To further modulate the innate...
Oncolytic viruses are engineered to selectively kill tumor cells and have demonstrated promising results in early-phase clinical trials. To further modulate the innate and adaptive immune system, we generated AZD4820, a vaccinia virus engineered to express interleukin-12 (IL-12), a potent cytokine involved in the activation of natural killer (NK) and T cells and the reprogramming of the tumor immune microenvironment. Testing in cultured human tumor cell lines demonstrated broad oncolytic activity and IL-12 transgene expression. A surrogate virus expressing murine IL-12 demonstrated antitumor activity in both MC38 and CT26 mouse syngeneic tumor models that responded poorly to immune checkpoint inhibition. In both models, AZD4820 significantly upregulated interferon-gamma (IFN-γ) relative to control mice treated with oncolytic vaccinia virus (VACV)-luciferase. In the CT26 study, 6 of 10 mice had a complete response after treatment with AZD4820 murine surrogate, whereas control VACV-luciferase-treated mice had 0 of 10 complete responders. AZD4820 treatment combined with anti-PD-L1 blocking antibody augmented tumor-specific T cell immunity relative to monotherapies. These findings suggest that vaccinia virus delivery of IL-12, combined with immune checkpoint blockade, elicits antitumor immunity in tumors that respond poorly to immune checkpoint inhibitors.
PubMed: 38596304
DOI: 10.1016/j.omton.2023.200758 -
Molecular Therapy. Oncology Mar 2024Cancer immunotherapy requires a specific antitumor CD8 T cell-driven immune response; however, upon genetic and epigenetic alterations of the antigen processing and...
Cancer immunotherapy requires a specific antitumor CD8 T cell-driven immune response; however, upon genetic and epigenetic alterations of the antigen processing and presenting components, cancer cells escape the CD8 T cell recognition. As a result, poorly immunogenic tumors are refractory to conventional immunotherapy. In this context, the use of viral cancer vaccines in combination with hypomethylating agents represents a promising strategy to prevent cancer from escaping immune system recognition. In this study, we evaluated the sensitivity of melanoma (B16-expressing ovalbumin) and metastatic triple-negative breast cancer (4T1) cell lines to FDA-approved low-dose decitabine in combination with PeptiCRAd, an adenoviral anticancer vaccine. The two models showed different sensitivity to decitabine and when combined with PeptiCRAd. In particular, mice bearing syngeneic 4T1 cancer showed higher tumor growth control when receiving the combinatorial treatment compared to single controls in association with a higher expression of MHC class I on cancer cells and reduction in Tregs within the tumor microenvironment. Furthermore, remodeling of the CD8 T cell infiltration and cytotoxic activity toward cancer cells confirmed the effect of decitabine in enhancing anticancer vaccines in immunotherapy regimens.
PubMed: 38596301
DOI: 10.1016/j.omton.2024.200766