Understanding the Interplay between oHSV and the Host Immune System: Implications for Therapeutic Oncolytic Virus Development.

Oncolytic herpes simplex viruses (oHSV) preferentially replicate in cancer cells while inducing antitumor immunity, and thus, they are often referred to as in situ cancer vaccines. OHSV infection of tumors elicits diverse host immune responses comprising both innate and adaptive components. Although the innate/adaptive immune responses primarily target the tumor, they also contribute to antiviral immunity, limiting viral replication/oncolysis.

Tumor Microenvironment: A Niche for Cancer Stem Cell Immunotherapy.

Tumorigenic Cancer Stem Cells (CSCs), often called tumor-initiating cells (TICs), represent a unique subset of cells within the tumor milieu. They stand apart from the bulk of tumor cells due to their exceptional self-renewal, metastatic, and differentiation capabilities. Despite significant progress in classifying CSCs, these cells remain notably resilient to conventional radiotherapy and chemotherapy, contributing to cancer recurrence.

An evolving perspective on novel modified release drug delivery systems for inhalational therapy.

Introduction: Drugs delivered via the lungs are predominantly used to treat various respiratory disorders, including asthma, chronic obstructive pulmonary diseases, respiratory tract infections and lung cancers, and pulmonary vascular diseases such as pulmonary hypertension. To treat respiratory diseases, targeted, modified or controlled release inhalation formulations are desirable for improved patient compliance and superior therapeutic outcome.

Areas Covered: This review summarizes the important factors that have an impact on the inhalable modified release formulation approaches with a focus toward various formulation strategies, including dissolution rate-controlled systems, drug complexes, site-specific delivery, drug-polymer conjugates, and drug-polymer matrix systems, lipid matrix particles, nanosystems, and formulations that can bypass clearance via mucociliary system and alveolar macrophages.

A Protocol for Fabrication and on-Chip Cell Culture to Recreate PAH-Afflicted Pulmonary Artery on a Microfluidic Device.

Pulmonary arterial hypertension (PAH) is a rare pulmonary vascular disease that affects people of all ethnic origins and age groups including newborns. In PAH, pulmonary arteries and arterioles undergo a series of pathological changes including remodeling of the entire pulmonary vasculatures and extracellular matrices, mis-localized growth of pulmonary arterial cells, and development of glomeruloid-like lesions called plexiform lesions. Traditionally, various animal and cellular models have been used to understand PAH pathophysiology, investigate sex-disparity in PAH and monitor therapeutic efficacy of PAH medications.

Multilayer Soft Photolithography Fabrication of Microfluidic Devices Using a Custom-Built Wafer-Scale PDMS Slab Aligner and Cost-Efficient Equipment.

We present a robust, low-cost fabrication method for implementation in multilayer soft photolithography to create a PDMS microfluidic chip with features possessing multiple height levels. This fabrication method requires neither a cleanroom facility nor an expensive UV exposure machine. The central part of the method stays on the alignment of numerous PDMS slabs on a wafer-scale instead of applying an alignment for a photomask positioned right above a prior exposure layer using a sophisticated mask aligner.

Multicellular Cell Seeding on a Chip: New Design and Optimization towards Commercialization.

This paper shows both experimental and in-depth theoretical studies (including simulations and analytical solutions) on a microfluidic platform to optimize its design and use for 3D multicellular co-culture applications, e.g., creating a tissue-on-chip model for investigating diseases such as pulmonary arterial hypertension (PAH).

3D Printing in Solid Dosage Forms and Organ-on-Chip Applications.

3D printing (3DP) can serve not only as an excellent platform for producing solid dosage forms tailored to individualized dosing regimens but can also be used as a tool for creating a suitable 3D model for drug screening, sensing, testing and organ-on-chip applications. Several new technologies have been developed to convert the conventional dosing regimen into personalized medicine for the past decade. With the approval of Spritam, the first pharmaceutical formulation produced by 3DP technology, this technology has caught the attention of pharmaceutical researchers worldwide.

Growth, Purification, and Titration of Oncolytic Herpes Simplex Virus.

Oncolytic viruses (OVs), such as the oncolytic herpes simplex virus (oHSV), are a rapidly growing treatment strategy in the field of cancer immunotherapy. OVs, including oHSV, selectively replicate in and kill cancer cells (sparing healthy/normal cells) while inducing anti-tumor immunity. Because of these unique properties, oHSV-based treatment strategies are being increasingly used for the treatment of cancer, preclinically and clinically, including FDA-approved talimogene laherparevec (T-Vec).

Optimal timing of PD-1 blockade in combination with oncolytic virus therapy.

Anti-PD-1 and oncolytic viruses (OVs) have non-overlapping anti-tumor mechanisms, since each agent works at different steps of the cancer-immunity cycle. Evidence suggests that OVs improve therapeutic responses to anti-PD-1 therapy by reversing immunosuppressive factors, increasing the number and diversity of infiltrating lymphocytes, and promoting PD-L1 expression in both injected and non-injected tumors. Many studies in preclinical models suggest that the timing of anti-PD-1 administration influences the therapeutic success of the combination therapy (anti-PD-1 + OV).

Pathogenetic Features and Current Management of Glioblastoma.

Glioblastoma (GBM) is the most common form of primary malignant brain tumor with a devastatingly poor prognosis. The disease does not discriminate, affecting adults and children of both sexes, and has an average overall survival of 12-15 months, despite advances in diagnosis and rigorous treatment with chemotherapy, radiation therapy, and surgical resection. In addition, most survivors will eventually experience tumor recurrence that only imparts survival of a few months.

The Current State of Oncolytic Herpes Simplex Virus for Glioblastoma Treatment.

Glioblastoma (GBM) is a lethal primary malignant brain tumor with no current effective treatments. The recent emergence of immuno-virotherapy and FDA approval of T-VEC have generated a great expectation towards oncolytic herpes simplex viruses (oHSVs) as a promising treatment option for GBM. Since the generation and testing of the first genetically engineered oHSV in glioma in the early 1990s, oHSV-based therapies have shown a long way of great progress in terms of anti-GBM efficacy and safety, both preclinically and clinically.

Antibody-drug conjugates: an evolving approach for melanoma treatment.

Melanoma continues to be an aggressive and deadly form of skin cancer while therapeutic options are continuously developing in an effort to provide long-term solutions for patients. Immunotherapeutic strategies incorporating antibody-drug conjugates (ADCs) have seen varied levels of success across tumor types and represent a promising approach for melanoma. This review will explore the successes of FDA-approved ADCs to date compared to the ongoing efforts of melanoma-targeting ADCs.

Temozolomide antagonizes oncolytic immunovirotherapy in glioblastoma.

Background: Temozolomide (TMZ) chemotherapy is a current standard of care for glioblastoma (GBM), however it has only extended overall survival by a few months. Because it also modulates the immune system, both beneficially and negatively, understanding how TMZ interacts with immunotherapeutics is important. Oncolytic herpes simplex virus (oHSV) is a new class of cancer therapeutic with both cytotoxic and immunostimulatory activities.

Oncolytic Herpes Simplex Virus Encoding IL12 Controls Triple-Negative Breast Cancer Growth and Metastasis.

Triple-negative breast cancer (TNBC) is a difficult-to-treat disease with high rates of local recurrence, distant metastasis, and poor overall survival with existing therapies. Thus, there is an unmet medical need to develop new treatment regimen(s) for TNBC patients. An oncolytic herpes simplex virus encoding a master anti-tumor cytokine, interleukin 12, (designated G47Δ-mIL12) selectively kills cancer cells while inducing anti-tumor immunity.

Oncolytic Virus Encoding a Master Pro-Inflammatory Cytokine Interleukin 12 in Cancer Immunotherapy.

Oncolytic viruses (OVs) are genetically modified or naturally occurring viruses, which preferentially replicate in and kill cancer cells while sparing healthy cells, and induce anti-tumor immunity. OV-induced tumor immunity can be enhanced through viral expression of anti-tumor cytokines such as interleukin 12 (IL-12). IL-12 is a potent anti-cancer agent that promotes T-helper 1 (Th1) differentiation, facilitates T-cell-mediated killing of cancer cells, and inhibits tumor angiogenesis.

Immunohistochemistry for Tumor-Infiltrating Immune Cells After Oncolytic Virotherapy.

Immunohistochemistry (IHC) is an integral laboratory staining technique, which is used for the detection of immune cells in mouse/human tissues or tumors. Oncolytic herpes simplex virus (oHSV) treatment or virotherapy of solid tumors results in antitumor immune responses and infiltration of a variety of immune cells into the tumor. Here, we describe a step-by-step chromogen/substrate-based single- and dual-color IHC protocol to stain immune cells in formalin-fixed, paraffin-embedded mouse glioblastoma (GBM) brain tumor sections after oHSV virotherapy.

Multi-parametric flow cytometry staining procedure for analyzing tumor-infiltrating immune cells following oncolytic herpes simplex virus immunotherapy in intracranial glioblastoma.

Multi-color flow cytometry is a standard laboratory protocol, which is regularly used to analyze tumor-infiltrating immune cell subsets. Oncolytic herpes simplex virus has shown promise in treating various types of cancers, including deadly glioblastoma. Intracranial/intratumoral treatment with oncolytic herpes simplex virus expressing interleukin 12, .

Triple combination immunotherapy with GVAX, anti-PD-1 monoclonal antibody, and agonist anti-OX40 monoclonal antibody is highly effective against murine intracranial glioma.

Single-agent immunotherapy, including with immune checkpoint inhibition with anti-PD-1 antibody, has not extended survival in patients with malignant glioma. However, PD-1 inhibition may still play a role in combination immunotherapy with multiple agents. In this study, we evaluated anti-PD-1 antibody treatment in combination with multiple approaches, including vaccination and agonist anti-OX40 immunotherapy, as well as triple combination immunotherapy with each of the above agents in a murine glioma model.

Oncolytic herpes simplex virus immunovirotherapy in combination with immune checkpoint blockade to treat glioblastoma.

Oncolytic viruses, such as oncolytic herpes simplex virus (oHSV), are a new class of cancer therapeutic, which selectively replicate and kill cancer cells, while inducing an inflammatory microenvironment, immunovirotherapy. Recently, an oHSV (talimogene laherparepvec) has been approved for the treatment of advanced melanoma. Glioblastoma (GBM) is an almost always lethal primary tumor in the brain that is highly immunosuppressive, and posited to contain GBM stem-like cells (GSCs).