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Trends in Cancer Feb 2023Oncolytic viruses (OVs) provide novel and promising therapeutic options for patients with cancers resistant to traditional therapies. Natural or genetically modified OVs... (Review)
Review
Oncolytic viruses (OVs) provide novel and promising therapeutic options for patients with cancers resistant to traditional therapies. Natural or genetically modified OVs are multifaceted tumor killers. They directly lyse tumor cells while sparing normal cells, and indirectly potentiate antitumor immunity by releasing antigens and activating inflammatory responses in the tumor microenvironment. However, some limitations, such as limited penetration of OVs into tumors, short persistence, and the host antiviral immune response, are impeding the broad translation of oncolytic virotherapy into the clinic. If these challenges can be overcome, combination therapies, such as OVs plus immune checkpoint blockade (ICB), chimeric antigen receptor (CAR) T cells, or CAR natural killer (NK) cells, may provide powerful therapeutic platforms in the clinic.
Topics: Humans; Oncolytic Viruses; Immunotherapy; Oncolytic Virotherapy; Neoplasms; Killer Cells, Natural; Tumor Microenvironment
PubMed: 36402738
DOI: 10.1016/j.trecan.2022.10.003 -
Advanced Drug Delivery Reviews Nov 2021Extracellular vesicles (EVs) are natural nanoparticles containing biologically active molecules. They are important mediators of intercellular communication and can be... (Review)
Review
Extracellular vesicles (EVs) are natural nanoparticles containing biologically active molecules. They are important mediators of intercellular communication and can be exploited therapeutically by various bioengineering approaches. To accurately determine the therapeutic potential of EVs in pre-clinical and clinical settings, dependable dosing strategies are of utmost importance. However, the field suffers from inconsistencies comprising all areas of EV production and characterisation. Therefore, a standardised and well-defined process in EV quantification, key to reliable therapeutic EV dosing, remains to be established. Here, we examined 64 pre-clinical studies for EV-based therapeutics with respect to their applied EV dosing strategies. We identified variations in effective dosing strategies irrespective of the applied EV purification method and cell source. Moreover, we found dose discrepancies depending on the disease model, where EV doses were selected without accounting for published EV pharmacokinetics or biodistribution patterns. We therefore propose to focus on qualitative aspects when dosing EV-based therapeutics, such as the potency of the therapeutic cargo entity. This will ensure batch-to-batch reliability and enhance reproducibility between applications. Furthermore, it will allow for the successful benchmarking of EV-based therapeutics compared to other nanoparticle drug delivery systems, such as viral vector-based or lipid-based nanoparticle approaches.
Topics: Drug Delivery Systems; Extracellular Vesicles; Humans; Lipids; Nanoparticles
PubMed: 34481030
DOI: 10.1016/j.addr.2021.113961 -
International Journal of Molecular... Feb 2021Around 77 new oncology drugs were approved by the FDA in the past five years; however, most cancers remain untreated. Small molecules and antibodies are dominant... (Review)
Review
Around 77 new oncology drugs were approved by the FDA in the past five years; however, most cancers remain untreated. Small molecules and antibodies are dominant therapeutic modalities in oncology. Antibody-drug conjugates, bispecific antibodies, peptides, cell, and gene-therapies are emerging to address the unmet patient need. Advancement in the discovery and development platforms, identification of novel targets, and emergence of new technologies have greatly expanded the treatment options for patients. Here, we provide an overview of various therapeutic modalities and the current treatment options in oncology, and an in-depth discussion of the therapeutics in the preclinical stage for the treatment of breast cancer, lung cancer, and multiple myeloma.
Topics: Antibodies, Monoclonal; Cell- and Tissue-Based Therapy; Genetic Therapy; Humans; Immunoconjugates; Immunotherapy; Medical Oncology; Molecular Targeted Therapy; Neoplasms; Small Molecule Libraries
PubMed: 33670524
DOI: 10.3390/ijms22042008 -
Cell Jan 2023Increasing antimicrobial resistance rates have revitalized bacteriophage (phage) research, the natural predators of bacteria discovered over 100 years ago. In order to... (Review)
Review
Increasing antimicrobial resistance rates have revitalized bacteriophage (phage) research, the natural predators of bacteria discovered over 100 years ago. In order to use phages therapeutically, they should (1) preferably be lytic, (2) kill the bacterial host efficiently, and (3) be fully characterized to exclude side effects. Developing therapeutic phages takes a coordinated effort of multiple stakeholders. Herein, we review the state of the art in phage therapy, covering biological mechanisms, clinical applications, remaining challenges, and future directions involving naturally occurring and genetically modified or synthetic phages.
Topics: Phage Therapy; Bacteriophages; Bacteria
PubMed: 36608652
DOI: 10.1016/j.cell.2022.11.017 -
Frontiers in Immunology 2020The use of biomarkers in diagnosis, therapy and prognosis has gained increasing interest over the last decades. In particular, the analysis of biomarkers in cancer... (Review)
Review
The use of biomarkers in diagnosis, therapy and prognosis has gained increasing interest over the last decades. In particular, the analysis of biomarkers in cancer patients within the pre- and post-therapeutic period is required to identify several types of cells, which carry a risk for a disease progression and subsequent post-therapeutic relapse. Cancer stem cells (CSCs) are a subpopulation of tumor cells that can drive tumor initiation and can cause relapses. At the time point of tumor initiation, CSCs originate from either differentiated cells or adult tissue resident stem cells. Due to their importance, several biomarkers that characterize CSCs have been identified and correlated to diagnosis, therapy and prognosis. However, CSCs have been shown to display a high plasticity, which changes their phenotypic and functional appearance. Such changes are induced by chemo- and radiotherapeutics as well as senescent tumor cells, which cause alterations in the tumor microenvironment. Induction of senescence causes tumor shrinkage by modulating an anti-tumorigenic environment in which tumor cells undergo growth arrest and immune cells are attracted. Besides these positive effects after therapy, senescence can also have negative effects displayed post-therapeutically. These unfavorable effects can directly promote cancer stemness by increasing CSC plasticity phenotypes, by activating stemness pathways in non-CSCs, as well as by promoting senescence escape and subsequent activation of stemness pathways. At the end, all these effects can lead to tumor relapse and metastasis. This review provides an overview of the most frequently used CSC markers and their implementation as biomarkers by focussing on deadliest solid (lung, stomach, liver, breast and colorectal cancers) and hematological (acute myeloid leukemia, chronic myeloid leukemia) cancers. Furthermore, it gives examples on how the CSC markers might be influenced by therapeutics, such as chemo- and radiotherapy, and the tumor microenvironment. It points out, that it is crucial to identify and monitor residual CSCs, senescent tumor cells, and the pro-tumorigenic senescence-associated secretory phenotype in a therapy follow-up using specific biomarkers. As a future perspective, a targeted immune-mediated strategy using chimeric antigen receptor based approaches for the removal of remaining chemotherapy-resistant cells as well as CSCs in a personalized therapeutic approach are discussed.
Topics: Animals; Biomarkers; Biomarkers, Tumor; Cellular Senescence; Combined Modality Therapy; Disease Management; Disease Progression; Disease Susceptibility; Drug Resistance, Neoplasm; Humans; Immunotherapy, Adoptive; Molecular Diagnostic Techniques; Molecular Targeted Therapy; Neoplasms; Neoplastic Stem Cells; Organ Specificity; Precision Medicine; Prognosis
PubMed: 32849491
DOI: 10.3389/fimmu.2020.01280 -
International Journal of Molecular... Apr 2021Coronary artery disease (CAD) and its complications are the leading cause of death worldwide. Inflammatory activation and dysfunction of the endothelium are key events... (Review)
Review
Coronary artery disease (CAD) and its complications are the leading cause of death worldwide. Inflammatory activation and dysfunction of the endothelium are key events in the development and pathophysiology of atherosclerosis and are associated with an elevated risk of cardiovascular events. There is great interest to further understand the pathophysiologic mechanisms underlying endothelial dysfunction and atherosclerosis progression, and to identify novel biomarkers and therapeutic strategies to prevent endothelial dysfunction, atherosclerosis and to reduce the risk of developing CAD and its complications. The use of liquid biopsies and new molecular biology techniques have allowed the identification of a growing list of molecular and cellular markers of endothelial dysfunction, which have provided insight on the molecular basis of atherosclerosis and are potential biomarkers and therapeutic targets for the prevention and or treatment of atherosclerosis and CAD. This review describes recent information on normal vascular endothelium function, as well as traditional and novel potential biomarkers of endothelial dysfunction and inflammation, and pharmacological and non-pharmacological therapeutic strategies aimed to protect the endothelium or reverse endothelial damage, as a preventive treatment for CAD and related complications.
Topics: Animals; Biomarkers; Capillary Permeability; Coronary Artery Disease; Disease Management; Disease Susceptibility; Endothelium, Vascular; Hemostasis; Humans; Molecular Targeted Therapy; Vasculitis
PubMed: 33917744
DOI: 10.3390/ijms22083850 -
Nature Nanotechnology Apr 2020CRISPR-Cas gene editing and messenger RNA-based protein replacement therapy hold tremendous potential to effectively treat disease-causing mutations with diverse...
CRISPR-Cas gene editing and messenger RNA-based protein replacement therapy hold tremendous potential to effectively treat disease-causing mutations with diverse cellular origin. However, it is currently impossible to rationally design nanoparticles that selectively target specific tissues. Here, we report a strategy termed selective organ targeting (SORT) wherein multiple classes of lipid nanoparticles are systematically engineered to exclusively edit extrahepatic tissues via addition of a supplemental SORT molecule. Lung-, spleen- and liver-targeted SORT lipid nanoparticles were designed to selectively edit therapeutically relevant cell types including epithelial cells, endothelial cells, B cells, T cells and hepatocytes. SORT is compatible with multiple gene editing techniques, including mRNA, Cas9 mRNA/single guide RNA and Cas9 ribonucleoprotein complexes, and is envisioned to aid the development of protein replacement and gene correction therapeutics in targeted tissues.
Topics: Animals; CRISPR-Cas Systems; Drug Delivery Systems; Gene Editing; Mice; Nanoparticles; Organ Specificity; RNA, Messenger
PubMed: 32251383
DOI: 10.1038/s41565-020-0669-6 -
RNA Biology 2022RNA-based therapeutics have entered the mainstream with seemingly limitless possibilities to treat all categories of neurological disease. Here, common RNA-based drug... (Review)
Review
RNA-based therapeutics have entered the mainstream with seemingly limitless possibilities to treat all categories of neurological disease. Here, common RNA-based drug modalities such as antisense oligonucleotides, small interfering RNAs, RNA aptamers, RNA-based vaccines and mRNA drugs are reviewed highlighting their current and potential applications. Rapid progress has been made across rare genetic diseases and neurodegenerative disorders, but safe and effective delivery to the brain remains a significant challenge for many applications. The advent of individualized RNA-based therapies for ultra-rare diseases is discussed against the backdrop of the emergence of this field into more common conditions such as Alzheimer's disease and ischaemic stroke. There remains significant untapped potential in the use of RNA-based therapeutics for behavioural disorders and tumours of the central nervous system; coupled with the accelerated development expected over the next decade, the true potential of RNA-based therapeutics to transform the therapeutic landscape in neurology remains to be uncovered.
Topics: Animals; Aptamers, Nucleotide; Disease Management; Disease Susceptibility; Gene Expression Regulation; Genetic Therapy; Humans; Nervous System Diseases; RNA; RNA Interference; RNA, Small Interfering; RNAi Therapeutics; Targeted Gene Repair
PubMed: 35067193
DOI: 10.1080/15476286.2021.2021650 -
Science Translational Medicine May 2019Extracellular vesicles (EVs) are nanometer-sized, lipid membrane-enclosed vesicles secreted by most, if not all, cells and contain lipids, proteins, and various nucleic... (Review)
Review
Extracellular vesicles (EVs) are nanometer-sized, lipid membrane-enclosed vesicles secreted by most, if not all, cells and contain lipids, proteins, and various nucleic acid species of the source cell. EVs act as important mediators of intercellular communication that influence both physiological and pathological conditions. Given their ability to transfer bioactive components and surmount biological barriers, EVs are increasingly being explored as potential therapeutic agents. EVs can potentiate tissue regeneration, participate in immune modulation, and function as potential alternatives to stem cell therapy, and bioengineered EVs can act as delivery vehicles for therapeutic agents. Here, we cover recent approaches and advances of EV-based therapies.
Topics: Animals; Bioengineering; Disease; Drug Delivery Systems; Extracellular Vesicles; Humans; Immunotherapy
PubMed: 31092696
DOI: 10.1126/scitranslmed.aav8521 -
Nature Immunology Sep 2022Eosinophils are important effector cells and therapeutic targets in allergic diseases. Emerging data indicate that eosinophils infiltrate a variety of solid tumor types... (Review)
Review
Eosinophils are important effector cells and therapeutic targets in allergic diseases. Emerging data indicate that eosinophils infiltrate a variety of solid tumor types and have pleiotropic activities by at least two non-mutually exclusive mechanisms: direct interactions with tumor cells, and intricate cross-talk with lymphocytes. In light of the immune checkpoint inhibition revolution in cancer therapy, we review eosinophil-lymphocyte interactions in the tumor microenvironment. We also analyze potential interactions between eosinophils and lymphocyte subsets, including T cells, natural killer cells and innate lymphoid cells. We provide perspectives on the consequences of these interactions and how eosinophils are accessory cells that can affect the response to various forms of T cell-mediated immunotherapies and might be therapeutically targeted to improve cancer immunotherapy.
Topics: Eosinophils; Humans; Immune Checkpoint Inhibitors; Immunity, Innate; Immunotherapy; Killer Cells, Natural; Neoplasms; Tumor Microenvironment
PubMed: 36002647
DOI: 10.1038/s41590-022-01291-2