The progressively exhausted T cell response to a poorly immunogenic model of HCC can be partially rescued by immune checkpoint blockade and is heavily suppressed by T cell responses to oncolytic virotherapy.

Currently, the benefits of Immune Checkpoint Blockade (ICB) for Hepatocellular carcinoma (HCC) are restricted to a subset of patients. We hypothesized that co-treatment with the inflammatory oncolytic virus (OV) Vesicular Stomatitis Virus (VSV-IFNβ) would reprogram the highly immunosuppressive Tumor Microenvironment (TME) to enhance ICB. However, VSV-IFNβ inhibited the efficacy of ICB.

Exploiting viral infection/vaccination to focus high-affinity T cell populations into tumors using oncolytic viro-immunotherapy.

Immune tolerance restricts the number of T cells with significant affinity for self-tumor-associated antigens (TAAs), thereby limiting successful cancer immunotherapy through an inability to generate populations of high-affinity anti-tumor T cells. In contrast, viral infection/vaccination primes and expands high-affinity effector and memory T cells against viral antigens. We show here that it is possible to exploit population-wide preexisting, anti-viral memory recall responses against SARS-CoV-2 antigens to focus a high-affinity, immunodominant T cell response into tumors by oncolytic virus (OV)-mediated or chimeric antigen receptor (CAR)-mediated delivery of viral antigens that are not themselves related to TAAs.

Repeat Systemic Delivery of Cross-Neutralization Resistant Synthetic Vesiculoviruses Immunomodulates the Tumor Microenvironment.

The clinical efficacy of systemic oncolytic virotherapy (OV) is constrained by the rapid development of neutralizing antibodies (nAbs), which prevent repeat systemic administration, a critical barrier to sustained anti-tumor immunity. Vesiculoviruses offer potent oncolytic and immunogenic potential. However, leveraging their serological diversity for repeat dosing remains unexplored.

Oncolytic immunovirotherapy: finding the tumor antigen needle in the antiviral haystack.

Immunovirotherapy integrates the oncolytic capabilities of viruses with the modulation of the host immune system to establish robust tumor-specific immune responses. Oncolytic viruses (OVs) are natural or engineered viruses that specifically replicate in and lyse tumor cells, triggering inflammation which recruits immune effector cells to the site of infection. These conditions theoretically synergize with immune checkpoint blockade (ICB), which aids in establishing and maintaining tumor-infiltrating CD8 T cells.

Immunodominant antiviral T cell responses outcompete immuno-subdominant antitumor responses to reduce the efficacy of oncolytic viroimmunotherapy.

The paradigm in the field of oncolytic virotherapy proposes that tumor cell killing by an oncolytic virus (OV) culminates in the priming of antitumor CD8 T cells. However, this ignores the impact a highly immunodominant antiviral response against the OV has on the antitumor response which has been weakened by mechanisms of central tolerance. Here, we show that inflammatory Vesicular Stomatitis Virus (VSV) failed to prime an adoptively transferred, or pre-existing, population of tumor-reactive T cells.

Cancer Immunotherapy Using AIRE Conditioning of the Tumor Epitopeome.

T cell immune tolerance is established in part through the activity of the Auto-immune Regulator (AIRE) transcription factor in the medullary Thymic Epithelial Cells (mTEC) of the thymus. AIRE induces expression of SELF peripheral tissue-specific antigens for presentation to naïve T cells to promote activation/deletion of potentially autoreactive T cells. We show, for the first time to our knowledge, that tumors mimic the role of AIRE in mTEC to evade immune rejection.

APOBEC3B expression in 293T viral producer cells drives mutations in chimeric antigen receptors and reduces CAR T cell efficacy.

Chimeric antigen receptor (CAR) T cells are a clinically approved therapy for blood cancers. To produce clinical-grade CAR T cells, a retroviral or lentiviral vector is used to deliver the CAR and associated genes to patient T cells. Apolipoprotein B editing enzyme, catalytic polypeptide 3 (APOBEC3) enzymes are known to be upregulated after transfection and retroviral infection and to deaminate cytidine to uracil in nucleic acids, resulting in cytidine-to-thymine mutations in DNA.

Smoldering oncolysis by foamy virus carrying CD19 as a CAR target escapes CAR T detection by genomic modification.

Chimeric antigen receptor (CAR) T cells have had limited success against solid tumors. Here, we used an oncolytic foamy virus (oFV) to display a model CAR target antigen (CD19) on tumors in combination with anti-CD19 CAR T cells. We generated oFV-Δ and oFV- vectors to test the efficiency and stability of viral/CD19 spread.

Chimerization of the Anti-Viral CD8 T Cell Response with A Broad Anti-Tumor T Cell Response Reverses Inhibition of Checkpoint Blockade Therapy by Oncolytic Virotherapy.

Although immune checkpoint inhibition (ICI) has produced profound survival benefits in a broad variety of tumors, a proportion of patients do not respond. Treatment failure is in part due to immune suppressive tumor microenvironments (TME), which is particularly true of hepatocellular carcinoma (HCC). Since oncolytic viruses (OV) can generate a highly immune-infiltrated, inflammatory TME, we developed a vesicular stomatitis virus expressing interferon-ß (VSV-IFNß) as a viro-immunotherapy against HCC.

Trap and ambush therapy using sequential primary and tumor escape-selective oncolytic viruses.

In multiple models of oncolytic virotherapy, it is common to see an early anti-tumor response followed by recurrence. We have previously shown that frontline treatment with oncolytic VSV-IFN-β induces APOBEC proteins, promoting the selection of specific mutations that allow tumor escape. Of these mutations in B16 melanoma escape (ESC) cells, a C-T point mutation in the cold shock domain-containing E1 () gene was present at the highest frequency, which could be used to ambush ESC cells by vaccination with the mutant CSDE1 expressed within the virus.

Medication affordability discussions with older adults in primary care.

Introduction: Cost is a major barrier to medication accessibility. While a minority of adults experience problems affording their medications, older adults are particularly vulnerable due to increased polypharmacy and fixed incomes.Clinicians can help reduce cost-related non-adherence and improve medication affordability; however, opportunities to improve affordability are often missed due to failure of the patient or clinician to discuss the issue.

The FusX TALE Base Editor (FusXTBE) for Rapid Mitochondrial DNA Programming of Human Cells and Zebrafish Disease Models .

Functional analyses of mitochondria have been hampered by few effective approaches to manipulate mitochondrial DNA (mtDNA) and a lack of existing animal models. Recently a TALE-derived base editor was shown to induce C-to-T (or G-to-A) sequence changes in mtDNA. We report here the FusX TALE Base Editor (FusXTBE) to facilitate broad-based access to TALE mitochondrial base editing technology.

Fluoroquinolone Antibiotics Exhibit Low Antiviral Activity against SARS-CoV-2 and MERS-CoV.

Repurposing FDA-approved drugs that treat respiratory infections caused by coronaviruses, such as SARS-CoV-2 and MERS-CoV, could quickly provide much needed antiviral therapies. In the current study, the potency and cellular toxicity of four fluoroquinolones (enoxacin, ciprofloxacin, levofloxacin, and moxifloxacin) were assessed in Vero cells and A549 cells engineered to overexpress ACE2, the SARS-CoV-2 entry receptor. All four fluoroquinolones suppressed SARS-CoV-2 replication at high micromolar concentrations in both cell types, with enoxacin demonstrating the lowest effective concentration 50 value (EC) of 126.

Characterization of flavivirus infection in salivary gland cultures from male Ixodes scapularis ticks.

Infected Ixodes scapularis (black-legged tick) transmit a host of serious pathogens via their bites, including Borrelia burgdorferi, Babesia microti, and tick-borne flaviviruses (TBFVs), such as Powassan virus (POWV). Although the role of female I. scapularis ticks in disease transmission is well characterized, the role of male ticks is poorly understood.