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NPJ Vaccines May 2024Antigenic characterization of newly emerging SARS-CoV-2 variants is important to assess their immune escape and judge the need for future vaccine updates. To bridge data...
Antigenic characterization of newly emerging SARS-CoV-2 variants is important to assess their immune escape and judge the need for future vaccine updates. To bridge data obtained from animal sera with human sera, we analyzed neutralizing antibody titers in human and hamster single infection sera in a highly controlled setting using the same authentic virus neutralization assay performed in one laboratory. Using a Bayesian framework, we found that titer fold changes in hamster sera corresponded well to human sera and that hamster sera generally exhibited higher reactivity.
PubMed: 38762525
DOI: 10.1038/s41541-024-00888-y -
Molecular Medicine Reports Jul 2024Ovarian cancer is a multifactorial and deadly disease. Despite significant advancements in ovarian cancer therapy, its incidence is on the rise and the molecular...
Ovarian cancer is a multifactorial and deadly disease. Despite significant advancements in ovarian cancer therapy, its incidence is on the rise and the molecular mechanisms underlying ovarian cancer invasiveness, metastasis and drug resistance remain largely elusive, resulting in poor prognosis. Oncolytic viruses armed with therapeutic transgenes of interest offer an attractive alternative to chemical drugs, which often face innate and acquired drug resistance. The present study constructed a novel oncolytic adenovirus carrying short interfering (si)RNA, regulated by and promoters, termed Ad‑siERCC1. The findings demonstrated that this oncolytic adenovirus effectively inhibits the proliferation, migration and invasion of ovarian cancer cells. Furthermore, the downregulation of expression by siRNA ameliorates drug resistance to cisplatin (DDP) chemotherapy. It was found that Ad‑siERCC1 blocks the cell cycle in the G phase and enhances apoptosis through the PI3K/AKT‑caspase‑3 signaling pathways in SKOV3 cells. The results of the present study highlighted the critical effect of oncolytic virus Ad‑siERCC1 in inhibiting the survival of ovarian cancer cells and increasing chemotherapy sensitivity to DDP. These findings underscore the potent antitumor effect of Ad‑siERCC1 on ovarian cancers
Topics: Humans; Female; Ovarian Neoplasms; Adenoviridae; Cell Line, Tumor; RNA, Small Interfering; Endonucleases; Apoptosis; Cell Proliferation; Oncolytic Virotherapy; Oncolytic Viruses; DNA-Binding Proteins; Cisplatin; Cell Movement; Drug Resistance, Neoplasm; Genetic Vectors; Phosphatidylinositol 3-Kinases; Signal Transduction; Proto-Oncogene Proteins c-akt; Antineoplastic Agents
PubMed: 38757346
DOI: 10.3892/mmr.2024.13245 -
Breast Cancer Research : BCR May 2024Metastatic breast cancer is a leading cause of cancer death in woman. Current treatment options are often associated with adverse side effects and poor outcomes,...
BACKGROUND
Metastatic breast cancer is a leading cause of cancer death in woman. Current treatment options are often associated with adverse side effects and poor outcomes, demonstrating the need for effective new treatments. Immunotherapies can provide durable outcomes in many cancers; however, limited success has been achieved in metastatic triple negative breast cancer. We tested whether combining different immunotherapies can target metastatic triple negative breast cancer in pre-clinical models.
METHODS
Using primary and metastatic 4T1 triple negative mammary carcinoma models, we examined the therapeutic effects of oncolytic vesicular stomatitis virus (VSVΔM51) engineered to express reovirus-derived fusion associated small transmembrane proteins p14 (VSV-p14) or p15 (VSV-p15). These viruses were delivered alone or in combination with natural killer T (NKT) cell activation therapy mediated by adoptive transfer of α-galactosylceramide-loaded dendritic cells.
RESULTS
Treatment of primary 4T1 tumors with VSV-p14 or VSV-p15 alone increased immunogenic tumor cell death, attenuated tumor growth, and enhanced immune cell infiltration and activation compared to control oncolytic virus (VSV-GFP) treatments and untreated mice. When combined with NKT cell activation therapy, oncolytic VSV-p14 and VSV-p15 reduced metastatic lung burden to undetectable levels in all mice and generated immune memory as evidenced by enhanced in vitro recall responses (tumor killing and cytokine production) and impaired tumor growth upon rechallenge.
CONCLUSION
Combining NKT cell immunotherapy with enhanced oncolytic virotherapy increased anti-tumor immune targeting of lung metastasis and presents a promising treatment strategy for metastatic breast cancer.
Topics: Animals; Female; Mice; Natural Killer T-Cells; Oncolytic Virotherapy; Humans; Cell Line, Tumor; Oncolytic Viruses; Immunotherapy; Vesicular stomatitis Indiana virus; Triple Negative Breast Neoplasms; Combined Modality Therapy; Neoplasm Metastasis; Vesiculovirus; Dendritic Cells; Breast Neoplasms; Disease Models, Animal
PubMed: 38750591
DOI: 10.1186/s13058-024-01818-5 -
Nature Communications May 2024The presence of heterogeneity in responses to oncolytic virotherapy poses a barrier to clinical effectiveness, as resistance to this treatment can occur through the...
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 IKKβ 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.
Topics: Animals; Humans; Oncolytic Virotherapy; Succinates; Mice; Cell Line, Tumor; Oncolytic Viruses; Interferon Type I; NF-E2-Related Factor 2; Colonic Neoplasms; Antiviral Agents; NF-kappa B; I-kappa B Kinase; Kelch-Like ECH-Associated Protein 1; Inflammation; Female; Vesicular stomatitis Indiana virus; Signal Transduction
PubMed: 38750019
DOI: 10.1038/s41467-024-48422-x -
Molecular Therapy. Oncology Jun 2024Intraperitoneal tumor-associated macrophages (TAMs) are involved in evading anti-tumor immunity and promoting the peritoneal metastasis (PM) of gastric cancer (GC)....
Intraperitoneal tumor-associated macrophages (TAMs) are involved in evading anti-tumor immunity and promoting the peritoneal metastasis (PM) of gastric cancer (GC). Oncolytic viruses are known to induce the activation of host anti-tumor immunity in addition to tumor lysis. This study investigated whether a wild-type -loading telomerase-specific oncolytic adenovirus (OBP-702) could elicit the remodeling of intraperitoneal macrophages and enhance the efficacy of immune therapy. Increased numbers of CD163 TAMs and few CD8 lymphocytes were immunohistochemically observed in clinical samples with PM, which suggested that TAMs were associated with the suppression of anti-tumor immunity. OBP-702 induced immunogenic cell death and upregulated PD-L1 expression in human and murine GC cell lines. Intraperitoneal administration of OBP-702 increased recruitment of CD8 lymphocytes into the PM via the functional remodeling of intraperitoneal macrophages from TAM toward a pro-inflammatory phenotype, resulting in significantly suppressed tumor growth for the model. Furthermore, the combination of intraperitoneal OBP-702 with anti-programmed cell death-1 antibody enhanced anti-tumor immunity and prolonged the survival of mice bearing PM. Intraperitoneal immunotherapy using OBP-702 restores anti-tumor immunity via the remodeling of intraperitoneal macrophages in addition to direct tumor lysis and cooperates with immune checkpoint inhibitors to suppress PM in GC.
PubMed: 38745748
DOI: 10.1016/j.omton.2024.200806 -
Molecular Therapy : the Journal of the... May 2024Vaccinia viruses (VACVs) are versatile therapeutic agents and different features of various VACV strains allow for a broad range of therapeutic applications. Modified...
Vaccinia viruses (VACVs) are versatile therapeutic agents and different features of various VACV strains allow for a broad range of therapeutic applications. Modified VACV Ankara (MVA) is a particularly altered VACV strain that is highly immunogenic, incapable of replicating in mammalian hosts, and broadly used as a safe vector for vaccination. Alternatively, Western Reserve (WR) or Copenhagen (Cop) are VACV strains that efficiently replicate in cancer cells and, therefore, are used to develop oncolytic viruses. However, the immune evasion capacity of WR or Cop hinders their ability to elicit antitumor immune responses, which is crucial for efficacy in the clinic. Here, we describe a new VACV strain named Immune-Oncolytic VACV Ankara (IOVA), which combines efficient replication in cancer cells with induction of immunogenic tumor cell death (ICD). IOVA was engineered from an MVA ancestor and shows superior cytotoxicity in tumor cells. In addition, the IOVA genome incorporates mutations that lead to massive fusogenesis of tumor cells, which contributes to improved antitumor effects. In syngeneic mouse tumor models, the induction of ICD results in robust antitumor immunity directed against tumor neo-epitopes and eradication of large established tumors. These data present IOVA as an improved immunotherapeutic oncolytic vector.
PubMed: 38734899
DOI: 10.1016/j.ymthe.2024.05.014 -
International Journal of Molecular... May 2024Oncolytic viruses (OVs) are characterised by their preference for infecting and replicating in tumour cells either naturally or after genetic modification, resulting in... (Review)
Review
Oncolytic viruses (OVs) are characterised by their preference for infecting and replicating in tumour cells either naturally or after genetic modification, resulting in oncolysis. Furthermore, OVs can elicit both local and systemic anticancer immune responses while specifically infecting and lysing tumour cells. These characteristics render them a promising therapeutic approach for paediatric brain tumours (PBTs). PBTs are frequently marked by a cold tumour immune microenvironment (TIME), which suppresses immunotherapies. Recent preclinical and clinical studies have demonstrated the capability of OVs to induce a proinflammatory immune response, thereby modifying the TIME. In-depth insights into the effect of OVs on different cell types in the TIME may therefore provide a compelling basis for using OVs in combination with other immunotherapy modalities. However, certain limitations persist in our understanding of oncolytic viruses' ability to regulate the TIME to enhance anti-tumour activity. These limitations primarily stem from the translational limitations of model systems, the difficulties associated with tracking reliable markers of efficacy throughout the course of treatment and the role of pre-existing viral immunity. In this review, we describe the different alterations observed in the TIME in PBTs due to OV treatment, combination therapies of OVs with different immunotherapies and the hurdles limiting the development of effective OV therapies while suggesting future directions based on existing evidence.
Topics: Humans; Brain Neoplasms; Oncolytic Virotherapy; Tumor Microenvironment; Oncolytic Viruses; Child; Immunotherapy; Combined Modality Therapy; Animals
PubMed: 38732225
DOI: 10.3390/ijms25095007 -
International Journal of Molecular... Apr 2024Oncolytic virotherapy is a promising immunotherapy approach for cancer treatment that utilizes viruses to preferentially infect and eliminate cancer cells while... (Review)
Review
Oncolytic virotherapy is a promising immunotherapy approach for cancer treatment that utilizes viruses to preferentially infect and eliminate cancer cells while stimulating the immune response. In this review, we synthesize the current literature on the molecular circuits of immune sensing and response to oncolytic virotherapy, focusing on viral DNA or RNA sensing by infected cells, cytokine and danger-associated-signal sensing by neighboring cells, and the subsequent downstream activation of immune pathways. These sequential sense-and-response mechanisms involve the triggering of molecular sensors by viruses or infected cells to activate transcription factors and related genes for a breadth of immune responses. We describe how the molecular signals induced in the tumor upon virotherapy can trigger diverse immune signaling pathways, activating both antigen-presenting-cell-based innate and T cell-based adaptive immune responses. Insights into these complex mechanisms provide valuable knowledge for enhancing oncolytic virotherapy strategies.
Topics: Humans; Oncolytic Virotherapy; Neoplasms; Oncolytic Viruses; Animals; Signal Transduction; Immunity, Innate; Immunotherapy
PubMed: 38731910
DOI: 10.3390/ijms25094691 -
International Journal of Oral Science May 2024N-methyladenosine (mA) RNA methylation is critical for regulating mRNA translation; however, its role in the development, progression, and immunotherapy response of head...
N-methyladenosine (mA) RNA methylation is critical for regulating mRNA translation; however, its role in the development, progression, and immunotherapy response of head and neck squamous cell carcinoma (HNSCC) remains largely unknown. Using Tgfbr1 and Pten conditional knockout (2cKO) mice, we found the neoplastic transformation of oral mucosa was accompanied by increased mA modification levels. Analysis of mA-associated genes identified TRMT61A as a key mA writer linked to cancer progression and poor prognosis. Mechanistically, TRMT61A-mediated tRNA-mA modification promotes MYC protein synthesis, upregulating programmed death-ligand 1 (PD-L1) expression. Moreover, mA modification levels were also elevated in tumors treated with oncolytic herpes simplex virus (oHSV), contributing to reactive PD-L1 upregulation. Therapeutic mA inhibition sustained oHSV-induced antitumor immunity and reduced tumor growth, representing a promising strategy to alleviate resistance. These findings indicate that mA inhibition can prevent immune escape after oHSV therapy by reducing PD-L1 expression, providing a mutually reinforcing combination immunotherapy approach.
Topics: Animals; B7-H1 Antigen; Mice; Proto-Oncogene Proteins c-myc; Oncolytic Viruses; Signal Transduction; Humans; Adenosine; Down-Regulation; Squamous Cell Carcinoma of Head and Neck; Oncolytic Virotherapy; PTEN Phosphohydrolase; Mice, Knockout; Head and Neck Neoplasms; Simplexvirus; Cell Line, Tumor
PubMed: 38730256
DOI: 10.1038/s41368-024-00304-0 -
Cells Apr 2024Chimeric antigen receptor (CAR)-T cell therapy has proven to be a powerful treatment for hematological malignancies. The situation is very different in the case of solid... (Review)
Review
Chimeric antigen receptor (CAR)-T cell therapy has proven to be a powerful treatment for hematological malignancies. The situation is very different in the case of solid tumors, for which no CAR-T-based therapy has yet been approved. There are many factors contributing to the absence of response in solid tumors to CAR-T cells, such as the immunosuppressive tumor microenvironment (TME), T cell exhaustion, or the lack of suitable antigen targets, which should have a stable and specific expression on tumor cells. Strategies being developed to improve CAR-T-based therapy for solid tumors include the use of new-generation CARs such as TRUCKs or bi-specific CARs, the combination of CAR therapy with chemo- or radiotherapy, the use of checkpoint inhibitors, and the use of oncolytic viruses. Furthermore, despite the scarcity of targets, a growing number of phase I/II clinical trials are exploring new solid-tumor-associated antigens. Most of these antigens are of a protein nature; however, there is a clear potential in identifying carbohydrate-type antigens associated with tumors, or carbohydrate and proteoglycan antigens that emerge because of aberrant glycosylations occurring in the context of tumor transformation.
Topics: Humans; Neoplasms; Immunotherapy, Adoptive; Receptors, Chimeric Antigen; Tumor Microenvironment; Antigens, Neoplasm; T-Lymphocytes; Animals
PubMed: 38727261
DOI: 10.3390/cells13090725