-
Acta Pharmaceutica Sinica. B Jun 2024Oncolytic viruses (OVs), a group of replication-competent viruses that can selectively infect and kill cancer cells while leaving healthy cells intact, are emerging as...
Oncolytic viruses (OVs), a group of replication-competent viruses that can selectively infect and kill cancer cells while leaving healthy cells intact, are emerging as promising living anticancer agents. Unlike traditional drugs composed of non-replicating compounds or biomolecules, the replicative nature of viruses confer unique pharmacokinetic properties that require further studies. Despite some pharmacokinetics studies of OVs, mechanistic insights into the connection between OV pharmacokinetics and antitumor efficacy remain vague. Here, we characterized the pharmacokinetic profile of oncolytic virus M1 (OVM) in immunocompetent mouse tumor models and identified the JAK‒STAT pathway as a key modulator of OVM pharmacokinetics. By suppressing the JAK‒STAT pathway, early OVM pharmacokinetics are ameliorated, leading to enhanced tumor-specific viral accumulation, increased AUC and , and improved antitumor efficacy. Rather than compromising antitumor immunity after JAK‒STAT inhibition, the improved pharmacokinetics of OVM promotes T cell recruitment and activation in the tumor microenvironment, providing an optimal opportunity for the therapeutic outcome of immune checkpoint blockade, such as anti-PD-L1. Taken together, this study advances our understanding of the pharmacokinetic-pharmacodynamic relationship in OV therapy.
PubMed: 38828147
DOI: 10.1016/j.apsb.2024.03.007 -
International Immunopharmacology Jul 2024The second-leading cause of death, cancer, poses a significant threat to human life. Innovations in cancer therapies are crucial due to limitations in traditional...
The second-leading cause of death, cancer, poses a significant threat to human life. Innovations in cancer therapies are crucial due to limitations in traditional approaches. Newcastle disease virus (NDV), a nonpathogenic oncolytic virus, exhibits multifunctional anticancer properties by selectively infecting, replicating, and eliminating tumor cells. To enhance NDV's antitumor activity, four oncolytic NDV viruses were developed, incorporating IL24 and/or GM-CSF genes at different gene loci using reverse genetics. In vitro experiments revealed that oncolytic NDV virus augmented the antitumor efficacy of the parental virus rClone30, inhibiting tumor cell proliferation, inducing tumor cell fusion, and promoting apoptosis. Moreover, NDV carrying the IL24 gene inhibited microvessel formation in CAM experiments. Evaluation in a mouse model of liver cancer confirmed the therapeutic efficacy of oncolytic NDV viral therapy. Tumors in mice treated with oncolytic NDV virus significantly decreased in size, accompanied by tumor cell detachment and apoptosis evident in pathological sections. Furthermore, oncolytic NDV virus enhanced T cell and dendritic cell production and substantially improved the survival rate of mice with hepatocellular carcinoma, with rClone30-IL24(P/M) demonstrating significant therapeutic effects. This study establishes a basis for utilizing oncolytic NDV virus as an antitumor agent in clinical practice.
Topics: Animals; Newcastle disease virus; Oncolytic Virotherapy; Oncolytic Viruses; Humans; Mice; Cell Line, Tumor; Interleukins; Liver Neoplasms; Mice, Inbred BALB C; Carcinoma, Hepatocellular; Apoptosis; Neovascularization, Pathologic; Cell Proliferation; Granulocyte-Macrophage Colony-Stimulating Factor; Dendritic Cells; T-Lymphocytes
PubMed: 38823178
DOI: 10.1016/j.intimp.2024.112305 -
Journal For Immunotherapy of Cancer May 2024Cytokines are small proteins that regulate the growth and functional activity of immune cells, and several have been approved for cancer therapy. Oncolytic viruses are... (Review)
Review
Cytokines are small proteins that regulate the growth and functional activity of immune cells, and several have been approved for cancer therapy. Oncolytic viruses are agents that mediate antitumor activity by directly killing tumor cells and inducing immune responses. Talimogene laherparepvec is an oncolytic herpes simplex virus type 1 (oHSV), approved for the treatment of recurrent melanoma, and the virus encodes the human cytokine, granulocyte-macrophage colony-stimulating factor (GM-CSF). A significant advantage of oncolytic viruses is the ability to deliver therapeutic payloads to the tumor site that can help drive antitumor immunity. While cytokines are especially interesting as payloads, the optimal cytokine(s) used in oncolytic viruses remains controversial. In this review, we highlight preliminary data with several cytokines and chemokines, including GM-CSF, interleukin 12, FMS-like tyrosine kinase 3 ligand, tumor necrosis factor α, interleukin 2, interleukin 15, interleukin 18, chemokine (C-C motif) ligand 2, chemokine (C-C motif) ligand 5, chemokine (C-X-C motif) ligand 4, or their combinations, and show how these payloads can further enhance the antitumor immunity of oHSV. A better understanding of cytokine delivery by oHSV can help improve clinical benefit from oncolytic virus immunotherapy in patients with cancer.
Topics: Humans; Oncolytic Virotherapy; Oncolytic Viruses; Cytokines; Immunotherapy; Neoplasms; Animals; Simplexvirus; Herpesvirus 1, Human
PubMed: 38821716
DOI: 10.1136/jitc-2023-008025 -
Molecular Therapy. Oncology Jun 2024The immune response plays a crucial role in the functionality of oncolytic viruses. In this study, Albendazole, an antihelminthic drug known to modulate the immune...
The immune response plays a crucial role in the functionality of oncolytic viruses. In this study, Albendazole, an antihelminthic drug known to modulate the immune checkpoint PD-L1, was combined with the oncolytic virus M1 (OVM1) to treat mice with either prostate cancer (RM-1) or glioma (GL261) tumors. This combination therapy enhanced anti-tumor effects in immunocompetent mice, but not in immunodeficient ones, without increasing OVM1 replication. Instead, it led to an increase in the number of CD8 T cells within the tumor, downregulated the expression of PD1 on CD8 T cells, and upregulated activation markers such as Ki67, CD44, and CD69 and the secretion of cytotoxic factors including interferon (IFN)-γ, granzyme B, and tumor necrosis factor (TNF)-α. Consistently, it enhanced the tumor-killing activity of lymphocytes from tumor-draining lymph nodes or spleens. The synergistic effect of Albendazole on OVM1 was abolished by depleting CD8 T cells, suggesting a CD8 T cell-dependent mechanism. In addition, Albendazole and OVM1 therapy increased CTLA4 expression in the spleen, and the addition of CTLA4 antibodies further enhanced the anti-tumor efficacy . In summary, Albendazole can act synergistically with oncolytic viruses via CD8 T cell activation, and the Albendazole/OVM1 combination can overcome resistance to CTLA4-based immune checkpoint blockade therapy.
PubMed: 38817541
DOI: 10.1016/j.omton.2024.200813 -
Frontiers in Immunology 2024Bladder cancer is a common type of cancer around the world, and the majority of patients are diagnosed with non-muscle-invasive bladder cancer (NMIBC). Although low-risk...
Bladder cancer is a common type of cancer around the world, and the majority of patients are diagnosed with non-muscle-invasive bladder cancer (NMIBC). Although low-risk NMIBC has a good prognosis, the disease recurrence rate and development of treatment-refractory disease remain high in intermediate- to high-risk NMIBC patients. To address these challenges for the treatment of NMIBC, a novel combination therapy composed of an oncolytic adenovirus (oAd) co-expressing interleukin (IL)-12, granulocyte-macrophage colony-stimulating factor (GM-CSF), and relaxin (RLX; HY-oAd) and a clinical-stage glycogen synthase kinase (GSK)-3β inhibitor (9-ING-41; elraglusib) was investigated in the present report. Our findings demonstrate that HY-oAd and 9-ING-41 combination therapy (HY-oAd+9-ING-41) exerted superior inhibition of tumor growth compared with respective monotherapy in a syngeneic NMIBC tumor model. HY-oAd+9-ING-41 induced high-level tumor extracellular matrix (ECM) degradation and a more potent antitumor immune response than the respective monotherapy. In detail, HY-oAd+9-ING-41 induced superior accumulation of intratumoral T cells, prevention of immune cell exhaustion, and induction of tumor-specific adaptive immune response compared to either monotherapy. Collectively, these results demonstrate that the combination of HY-oAd and 9-ING-41 may be a promising approach to elicit a potent antitumor immune response against bladder cancer.
Topics: Urinary Bladder Neoplasms; Tumor Microenvironment; Animals; Adenoviridae; Oncolytic Virotherapy; Oncolytic Viruses; Mice; Humans; Glycogen Synthase Kinase 3 beta; Cell Line, Tumor; Combined Modality Therapy; Female
PubMed: 38812516
DOI: 10.3389/fimmu.2024.1360436 -
Journal of Neurovirology May 2024Managing malignant brain tumors remains a significant therapeutic hurdle that necessitates further research to comprehend their treatment potential fully. Oncolytic... (Review)
Review
Managing malignant brain tumors remains a significant therapeutic hurdle that necessitates further research to comprehend their treatment potential fully. Oncolytic viruses (OVs) offer many opportunities for predicting and combating tumors through several mechanisms, with both preclinical and clinical studies demonstrating potential. OV therapy has emerged as a potent and effective method with a dual mechanism. Developing innovative and effective strategies for virus transduction, coupled with immune checkpoint inhibitors or chemotherapy drugs, strengthens this new technique. Furthermore, the discovery and creation of new OVs that can seamlessly integrate gene therapy strategies, such as cytotoxic, anti-angiogenic, and immunostimulatory, are promising advancements. This review presents an overview of the latest advancements in OVs transduction for brain cancer, focusing on the safety and effectiveness of G207, G47Δ, M032, rQNestin34.5v.2, C134, DNX-2401, Ad-TD-nsIL12, NSC-CRAd-S-p7, TG6002, and PVSRIPO. These are evaluated in both preclinical and clinical models of various brain tumors.
PubMed: 38806994
DOI: 10.1007/s13365-024-01209-8 -
Journal of Colloid and Interface Science Oct 2024Colorectal cancer (CRC) is a prevalent malignancy with insidious onset and diagnostic challenges, highlighting the need for therapeutic approaches to enhance theranostic...
Colorectal cancer (CRC) is a prevalent malignancy with insidious onset and diagnostic challenges, highlighting the need for therapeutic approaches to enhance theranostic outcomes. In this study, we elucidated the unique temperature-resistant properties of the oncolytic vaccinia virus (OVV), which can synergistically target tumors under photothermal conditions. To capitalize on this characteristic, we harnessed the potential of the OVV by surface-loading it with indocyanine green (ICG) and encapsulating it within a platelet membrane (PLTM), resulting in the creation of PLTM-ICG-OVV (PIOVV). This complex seamlessly integrates virotherapy, photodynamic therapy (PDT), and photothermal therapy (PTT). The morphology, size, dispersion stability, optical properties, and cellular uptake of PIOVV were evaluated using transmission electron microscopy (TEM). In vitro and in vivo experiments revealed specificity of PIOVV for cancer cells; it effectively induced apoptosis and suppressed CT26 cell proliferation. In mouse models, PIOVV exhibits enhanced fluorescence at tumor sites, accompanied by prolonged blood circulation. Under 808 nm laser irradiation, PIOVV significantly inhibited tumor growth. This strategy holds the potential for advancing phototherapy, oncolytic virology, drug delivery, and tumor-specific targeting, particularly in the context of CRC theranostics.
Topics: Indocyanine Green; Animals; Colorectal Neoplasms; Mice; Vaccinia virus; Oncolytic Viruses; Humans; Oncolytic Virotherapy; Photochemotherapy; Blood Platelets; Cell Line, Tumor; Mice, Inbred BALB C; Apoptosis; Cell Proliferation; Optical Imaging; Photothermal Therapy; Combined Modality Therapy; Particle Size; Surface Properties; Infrared Rays; Mice, Nude
PubMed: 38801796
DOI: 10.1016/j.jcis.2024.05.175 -
Advances in Experimental Medicine and... 2024Despite the significant advancement of new tools and technology in the field of medical biology and molecular biology, the challenges in the treatment of most cancer... (Review)
Review
Despite the significant advancement of new tools and technology in the field of medical biology and molecular biology, the challenges in the treatment of most cancer types remain constant with the problem of developing resistance toward drugs and no substantial enhancement in the overall survival rate of cancer patients. Immunotherapy has shown the most promising results in different clinical and preclinical trials in the treatment of various cancer due to its higher efficacy and minimum collateral damage in many cancer patients as compared to conventional chemotherapy and radiotherapy. An oncolytic virus is a new class of immunotherapy that can selectively replicate in tumor cells and destroy them by the process of cell lysis while exerting minimum or no effect on a normal cell. Besides this, it can also activate the host's innate immune system, which generates an anti-tumor immune response to eliminate the tumor cells. Several wild types and genetically modified viruses have been investigated to show oncolytic behavior. Vaccinia virus has been studied extensively and tested for its promising oncolytic nature on various model systems and clinical trials. Recently, several engineered vaccinia viruses have been developed that express the desired genes encoded for selective penetration in tumor cells and enhanced activation of the immune system for generating anti-tumor immunity. However, further investigation is required to prove their potential and enhance their therapeutic efficacy.
Topics: Humans; Oncolytic Virotherapy; Neoplasms; Oncolytic Viruses; Animals; Poxviridae; Immunotherapy; Vaccinia virus
PubMed: 38801591
DOI: 10.1007/978-3-031-57165-7_24 -
IScience Jun 2024As therapies, oncolytic viruses regress tumors and have the potential to induce antitumor immune responses that clear hard-to-treat and late-stage cancers. Despite this...
As therapies, oncolytic viruses regress tumors and have the potential to induce antitumor immune responses that clear hard-to-treat and late-stage cancers. Despite this promise, clearance from the blood prevents treatment of internal solid tumors. To address this issue, we developed virus-delivering Salmonella (VDS) to carry oncolytic viruses into cancer cells. The VDS strain contains the delivery circuit and has deletions in four homologous recombination genes (Δ, Δs, Δ, and Δ) to preserve essential hairpins in the viral genome required for replication and infectivity. VDS delivered the genome for minute virus of mice (MVMp) to multiple cancers, including breast, pancreatic, and osteosarcoma. Viral delivery produced functional viral particles that are cytotoxic and infective to neighboring cells. The release of mature virions initiated new rounds of infection and amplified the infection. Using Salmonella for delivery will circumvent the limitations of oncolytic viruses and will provide a new therapy for many cancers.
PubMed: 38799578
DOI: 10.1016/j.isci.2024.109813 -
Vaccines May 2024Merkel cell carcinoma is a rare, aggressive skin cancer that mainly occurs in elderly and immunocompromised patients. Due to the success of immune checkpoint inhibition... (Review)
Review
Merkel cell carcinoma is a rare, aggressive skin cancer that mainly occurs in elderly and immunocompromised patients. Due to the success of immune checkpoint inhibition in MCC, the importance of immunotherapy and vaccines in MCC has increased in recent years. In this article, we aim to present the current progress and perspectives in the development of vaccines for this disease. Here, we summarize and discuss the current literature and ongoing clinical trials investigating vaccines against MCC. We identified 10 articles through a PubMed search investigating a vaccine against MCC. From the international clinical trial database Clinical.Trials.gov, we identified nine studies on vaccines for the management of MCC, of which seven are actively recruiting. Most of the identified studies investigating a vaccine against MCC are preclinical or phase 1/2 trials. The vaccine principles mainly included DNA- and (synthetic) peptide-based vaccines, but RNA-based vaccines, oncolytic viruses, and the combination of vaccines and immunotherapy are also under investigation for the treatment of MCC. Although the management of MCC is changing, when compared to times before the approval of immune checkpoint inhibitors, it will still take some time before the first MCC vaccine is ready for approval.
PubMed: 38793784
DOI: 10.3390/vaccines12050533