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Signal Transduction and Targeted Therapy May 2024Immunotherapy represented by anti-PD-(L)1 and anti-CTLA-4 inhibitors has revolutionized cancer treatment, but challenges related to resistance and toxicity still remain.... (Review)
Review
Immunotherapy represented by anti-PD-(L)1 and anti-CTLA-4 inhibitors has revolutionized cancer treatment, but challenges related to resistance and toxicity still remain. Due to the advancement of immuno-oncology, an increasing number of novel immunoregulatory targets and mechanisms are being revealed, with relevant therapies promising to improve clinical immunotherapy in the foreseeable future. Therefore, comprehending the larger picture is important. In this review, we analyze and summarize the current landscape of preclinical and translational mechanistic research, drug development, and clinical trials that brought about next-generation pharmacological immunoregulatory anti-cancer agents and drug candidates beyond classical immune checkpoint inhibitors. Along with further clarification of cancer immunobiology and advances in antibody engineering, agents targeting additional inhibitory immune checkpoints, including LAG-3, TIM-3, TIGIT, CD47, and B7 family members are becoming an important part of cancer immunotherapy research and discovery, as are structurally and functionally optimized novel anti-PD-(L)1 and anti-CTLA-4 agents and agonists of co-stimulatory molecules of T cells. Exemplified by bispecific T cell engagers, newly emerging bi-specific and multi-specific antibodies targeting immunoregulatory molecules can provide considerable clinical benefits. Next-generation agents also include immune epigenetic drugs and cytokine-based therapeutics. Cell therapies, cancer vaccines, and oncolytic viruses are not covered in this review. This comprehensive review might aid in further development and the fastest possible clinical adoption of effective immuno-oncology modalities for the benefit of patients.
Topics: Humans; Neoplasms; Immunotherapy; Immune Checkpoint Inhibitors
PubMed: 38773064
DOI: 10.1038/s41392-024-01826-z -
Journal of Virology Jun 2024Many functions of viral attachment proteins are established, but less is known about the biological importance of viral attachment protein encapsidation efficiency. The...
UNLABELLED
Many functions of viral attachment proteins are established, but less is known about the biological importance of viral attachment protein encapsidation efficiency. The mammalian orthoreovirus (reovirus) σ1 attachment protein forms filamentous trimers that incorporate into pentamers of the λ2 capsid protein. Reovirus strains vary in the efficiency of σ1 encapsidation onto progeny virions, which influences viral stability during entry into cells and the efficacy of tumor cell lysis. While the role of σ1 encapsidation has been evaluated in studies using cultured cells, the contribution of attachment protein encapsidation efficiency to viral infection in animals is less clear. Polymorphisms in reovirus σ1 at residues 22 and 249 have been implicated in viral dissemination in mice and susceptibility to proteolysis in the murine intestine, respectively. To determine whether these residues contribute to σ1 encapsidation efficiency, we engineered σ1 mutant viruses with single- and double-residue substitutions at sites 22 and 249. We found that substitutions at these sites alter the encapsidation of σ1 and that reoviruses encapsidating higher amounts of σ1 bind cells more avidly and have a modest replication advantage in a cell-type-specific manner relative to low σ1-encapsidating reoviruses. Furthermore, we found that a high σ1-encapsidating reovirus replicates and disseminates more efficiently in mice relative to a low σ1-encapsidating reovirus. These findings provide evidence of a relationship between viral attachment protein encapsidation efficiency and viral replication in cell culture and animal hosts.
IMPORTANCE
Viral attachment proteins can serve multiple functions during viral replication, including attachment to host cells, cell entry and disassembly, and modulation of host immune responses. The relationship between viral attachment protein encapsidation efficiency and viral replication in cells and animals is poorly understood. We engineered and characterized a panel of reoviruses that differ in the capacity to encapsidate the σ1 attachment protein. We found that strains encapsidating σ1 with higher efficiency bind cells more avidly and replicate and spread more efficiently in mice relative to those encapsidating σ1 with lower efficiency. These results highlight a function for σ1 attachment protein capsid abundance in viral replication in cells and animals, which may inform future use of reovirus as an oncolytic therapeutic.
Topics: Animals; Mice; Virus Replication; Capsid Proteins; Reoviridae Infections; Virus Attachment; Polymorphism, Genetic; Orthoreovirus, Mammalian; Virus Assembly; Cell Line; Capsid; Humans
PubMed: 38771042
DOI: 10.1128/jvi.00305-24 -
Nature Protocols May 2024Oncolytic viruses (OVs) represent a novel class of cancer immunotherapy agents that preferentially infect and kill cancer cells and promote protective antitumor... (Review)
Review
Oncolytic viruses (OVs) represent a novel class of cancer immunotherapy agents that preferentially infect and kill cancer cells and promote protective antitumor immunity. Furthermore, OVs can be used in combination with established or upcoming immunotherapeutic agents, especially immune checkpoint inhibitors, to efficiently target a wide range of malignancies. The development of OV-based therapy involves three major steps before clinical evaluation: design, production and preclinical testing. OVs can be designed as natural or engineered strains and subsequently selected for their ability to kill a broad spectrum of cancer cells rather than normal, healthy cells. OV selection is further influenced by multiple factors, such as the availability of a specific viral platform, cancer cell permissivity, the need for genetic engineering to render the virus non-pathogenic and/or more effective and logistical considerations around the use of OVs within the laboratory or clinical setting. Selected OVs are then produced and tested for their anticancer potential by using syngeneic, xenograft or humanized preclinical models wherein immunocompromised and immunocompetent setups are used to elucidate their direct oncolytic ability as well as indirect immunotherapeutic potential in vivo. Finally, OVs demonstrating the desired anticancer potential progress toward translation in patients with cancer. This tutorial provides guidelines for the design, production and preclinical testing of OVs, emphasizing considerations specific to OV technology that determine their clinical utility as cancer immunotherapy agents.
PubMed: 38769145
DOI: 10.1038/s41596-024-00985-1 -
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 -
Advances in Protein Chemistry and... 2024Discovering a therapeutic that can counteract the aggressiveness of this disease's mechanism is crucial for improving survival rates for cancer patients and for better... (Review)
Review
Discovering a therapeutic that can counteract the aggressiveness of this disease's mechanism is crucial for improving survival rates for cancer patients and for better understanding the most different types of cancer. In recent years, using these viruses as an anticancer therapy has been thought to be successful. They mostly work by directly destroying cancer cells, activating the immune system to fight cancer, and expressing exogenous effector genes. For the treatment of tumors, oncolytic viruses (OVs), which can be modified to reproduce only in tumor tissues and lyse them while preserving the healthy non-neoplastic host cells and reinstating antitumor immunity which present a novel immunotherapeutic strategy. OVs can exist naturally or be created in a lab by altering existing viruses. These changes heralded the beginning of a new era of less harmful virus-based cancer therapy. We discuss three different types of oncolytic viruses that have already received regulatory approval to treat cancer as well as clinical research using oncolytic adenoviruses. The primary therapeutic applications, mechanism of action of oncolytic virus updates, future views of this therapy will be covered in this chapter.
Topics: Humans; Oncolytic Viruses; Neoplasms; Immunotherapy; Oncolytic Virotherapy; Animals
PubMed: 38762277
DOI: 10.1016/bs.apcsb.2023.12.007 -
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 -
Biochimica Et Biophysica Acta. Reviews... Jul 2024Oncolytic viruses (OVs) are increasingly recognized as potent tools in cancer therapy, effectively targeting and eradicating oncogenic conditions while sparing healthy... (Review)
Review
Oncolytic viruses (OVs) are increasingly recognized as potent tools in cancer therapy, effectively targeting and eradicating oncogenic conditions while sparing healthy cells. They enhance antitumor immunity by triggering various immune responses throughout the cancer cycle. Genetically engineered OVs swiftly destroy cancerous tissues and activate the immune system by releasing soluble antigens like danger signals and interferons. Their ability to stimulate both innate and adaptive immunity makes them particularly attractive in cancer immunotherapy. Recent advancements involve combining OVs with other immune therapies, yielding promising results. Transgenic OVs, designed to enhance immunostimulation and specifically target cancer cells, further improve immune responses. This review highlights the intrinsic mechanisms of OVs and underscores their synergistic potential with other immunotherapies. It also proposes strategies for optimizing armed OVs to bolster immunity against tumors.
Topics: Humans; Neoplasms; Oncolytic Viruses; Oncolytic Virotherapy; Immunotherapy; Animals
PubMed: 38754793
DOI: 10.1016/j.bbcan.2024.189110 -
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