Adenovirus Type 6: Subtle Structural Distinctions from Adenovirus Type 5 Result in Essential Differences in Properties and Perspectives for Gene Therapy

Adenovirus vectors are the most frequently used agents for gene therapy, including oncolytic therapy and vaccine development. It’s hard to overestimate the value of adenoviruses during the COVID-19 pandemic as to date four out of four approved viral vector-based SARS-CoV-2 vaccines are developed on adenovirus platform. The vast majority of adenoviral vectors are based on the most studied human adenovirus type 5 (HAdV-C5), however, its immunogenicity often hampers the clinical translation of HAdV-C5 vectors. The search of less seroprevalent adenovirus types led to another species C adenovirus, Adenovirus type 6 (HAdV-C6). HAdV-C6 possesses high oncolytic efficacy against multiple cancer types and remarkable ability to induce the immune response towards carrying antigens. Being genetically very close to HAdV-C5, HAdV-C6 differs from HAdV-C5 in structure of the most abundant capsid protein, hexon. This leads to the ability of HAdV-C6 to evade the uptake by Kupffer cells as well as to distinct opsonization by immunoglobulins and other blood proteins, influencing the overall biodistribution of HAdV-C6 after systemic administration. This review describes the structural features of HAdV-C6, its interaction with liver cells and blood factors, summarizes the previous experiences using HAdV-C6, and provides the rationale behind the use of HAdV-C6 for vaccine and anticancer drugs developments.

Selective modulation of cell surface proteins during vaccinia infection: implications for immune evasion strategies

The interaction between immune cells and virus-infected targets involves multiple plasma membrane (PM) proteins. A systematic study of PM protein modulation by vaccinia virus (VACV), the paradigm of host regulation, has the potential to reveal not only novel viral immune evasion mechanisms, but also novel factors critical in host immunity. Here, >1000 PM proteins were quantified throughout VACV infection, revealing selective downregulation of known T and NK cell ligands including HLA-C, downregulation of cytokine receptors including IFNAR2, IL-6ST and IL-10RB, and rapid inhibition of expression of certain protocadherins and ephrins, candidate activating immune ligands. Downregulation of most PM proteins occurred via a proteasome-independent mechanism. Upregulated proteins included a decoy receptor for TRAIL. Twenty VACV-encoded PM proteins were identified, of which five were not recognised previously as such. Collectively, this dataset constitutes a valuable resource for future studies on antiviral immunity, host-pathogen interaction, poxvirus biology, vector-based vaccine design and oncolytic therapy.

Trends in end-of- life (EOL) systemic oncologic treatment in contemporary clinical practice: Insights from real-world data.

253 Background: Among patients with cancer, receipt of systemic oncolytic therapy near the end-of-life (EOL) does not improve outcomes and worsens patient and caregiver experience. Accordingly, the ASCO/NQF measure, Proportion Receiving Chemotherapy in the Last 14 Days of Life, was published in 2012. Over the last decade there has been exponential growth in high cost targeted and immune therapies which may be perceived as less toxic than traditional chemotherapy. In this study, we identified rates and types of EOL systemic therapy in today’s real-world practice; these can serve as benchmarks for cancer care organizations to drive improvement efforts. Methods: Using data from the nationwide Flatiron Health electronic health record (EHR)-derived de-identified database we included patients who died during 2015 through 2019, were diagnosed after 2011, and who had documented cancer treatment. We identified the use of aggressive EOL systemic treatment (including, chemotherapy, immunotherapy, and combinations thereof) at both 30 days and 14 days prior to death. We estimated standardized EOL rates using mixed-level logistic regression models adjusting for patient and practice-level factors. Year-specific adjusted rates were estimated in annualized stratified analysis. Results: We included 57,127 patients, 38% of whom had documentation of having received any type of systemic cancer treatment within 30 days of death (SD: 5%; range: 25% - 56%), and 17% within 14 days of death (SD: 3%; range: 10% - 30%). Chemotherapy alone was the most common EOL treatment received (18% at 30 days, 8% at 14 days), followed by immunotherapy (± other treatment) (11% at 30 days, 4% at 14 days). Overall rates of EOL treatment did not change over the study period: treatment within 30 days (39% in 2015 to 37% in 2019) and within 14 days (17% in 2015 to 17% in 2019) of death. However, the rates of chemotherapy alone within 30 days of death decreased from 24% to 14%, and within 14 days, from 10% to 6% during the study period. In comparison, rates for immunotherapy with chemotherapy (0%-6% for 30 days, 0% -2% for 14 days), and immunotherapy alone or with other treatment types (4%-13% for 30 days, 1%-4% for 14 days) increased over time for both 30 and 14 days. Conclusions: End of life systemic cancer treatment rates have not substantively changed over time despite national efforts and expert guidance. While rates of traditional chemotherapy have decreased, rates of costly immunotherapy and targeted therapy have increased, which has been associated with higher total cost of care and overall healthcare utilization. Future work should examine the drivers of end-of-life care in the era of immune-oncology.

Impact of an Oncology Clinical Pharmacist on Patient Engagement in Self-Administered Oral Oncolytic Therapy: Case Study of Venetoclax in Acute Myeloid Leukemia Patients

Oncology clinical pharmacists are uniquely positioned to make interventions to increase patient activation and engagement. To accomplish this goal, pharmacists can target health system-related, provider-related, and patient-related factors to help enhance patient-centered care and drive behavioral health changes. Interventions that pharmacists must tackle include educating team members and patients on the medication acquisition process, communicating urgency of treatment, optimizing workflows, facilitating guideline recommendations, preventing, and managing treatment toxicities, and promoting patient self-advocacy through education and shared decision-making. As crucial members of the healthcare team, oncology clinical pharmacists can simplify highly complex treatment regimens to facilitate and optimize patients’ ownership of their care. This review will focus on the example of venetoclax treatment in acute myeloid leukemia to demonstrate the impact that pharmacists provide that leads to behavioral change of patients and clinicians.

Update on Senecavirus A research: Epidemiology of infection, evolution of the virus and its oncolytic activity

Senecavirus A (SVA), formerly known as Seneca valley virus (SVV) (20), is a critical pathogen causing vesicular lesions in pigs and acute death of newborn piglets, resulting in very large economic losses in the pig industry. The aim of this paper was to present the current knowledge about the epidemiology and evolution of Senecavirus A, as well as the role of the virus in oncolytic therapy. From 1988 to 2005, a number of virus isolates were sporadically recovered from pigs in various regions of the United States, but without a detailed description of the clinical signs. After 2014, a sudden increase in SVA outbreaks appeared outside the United States and Canada, and SVA infection was reported in more regions of the United States, in Brazil, China, Colombia, Thailand and Vietnam with extensive distribution. After the expansion of the SVA area, complete and partial SVA genomic sequences were determined from SVA strains in most of these regions. Therefore, advances were also possible in the molecular epidemiology of the virus. A certain genetic distance has been determined between SVA strains isolated in various countries and at different times, suggesting a constant and rapid evolvement of SVA. It was shown that a combination of evolutionary processes, such as multiple mutations at variable sites and purifying selection, drove the genetic diversity and evolution of SVA. Evolutionary changes that accumulated in the SVA genome over the years may have contributed to the increased incidence of the disease. SVA is the first oncolytic picornavirus to be tested in humans and to penetrate solid tumours through the vascular system, unlike many other oncolytic viruses. SVA has a potential cytolytic activity and high selectivity for tumour cell lines with neuroendocrine properties versus adult normal cells

Improving direct pharmacist counseling rates for oral oncolytic medications at an outpatient oncology clinic

Background Due to the increasing prevalence of oral oncolytic utilization for patients with malignancy, implementation of strategies for increased monitoring and patient safety have become a necessity. Our focus was on the American Society of Clinical Oncology’s Quality Oncology Practice Initiative (QOPI) standards of care, standard 2.3, and its requirement for patient counseling prior to first administration of oral oncolytic therapy. Objective To assess the implementation of a workflow improvement strategy to determine its effect on the number of patients reached for pharmacist counseling prior to first dose of oral oncolytic medications. Methods In this quasi-experimental quality improvement study, we formed a multidisciplinary group to develop and implement a workflow improvement process. This process was focused on a redistribution of workflow and the implementation of new technology within EPIC Beacon. Results A total of 86 patients were identified as eligible for counseling (38 pre-intervention, 48 post-intervention). There was a statistically significant increase in number of eligible patients counseled in the post-intervention period as compared to the pre-intervention period (100% vs. 86.84%; 95% CI = –0.212, –0.205; P = 0.017). There were no significant differences observed in the number of patients counseled in-person or patients counseled prior first dose. Conclusion Our intervention showed a 100% rate of counsel in the post-intervention period. Further work needs to be done to improve the number of these patients we reach prior to them taking their first dose of medication, as well as the number of patients we are able to counsel face-to-face.

Tolerability of Highly Protein Bound Targeted Oral Oncolytic Drugs in Patients With Hypoalbuminemia: A Retrospective Analysis

Background: Hypoalbuminemia is commonly observed in cancer patients. Given the pharmacokinetic interactions between serum proteins and protein bound medications, administration of highly protein bound targeted oral oncolytic drugs may result in elevated unbound drug levels and decreased tolerability in those with hypoalbuminemia. Objective: To describe the impact of hypoalbuminemia on oral oncolytic drug tolerability. Methods: A retrospective study was conducted of adult patients receiving treatment with targeted oral oncolytic drugs with ≥95% protein binding. The primary end point of this study was to compare time to discontinuation resulting from documented toxicity in those with and without hypoalbuminemia. Results: The study included 143 patients receiving 16 targeted oral oncolytic drugs (42% with hypoalbuminemia, 58% without hypoalbuminemia). Adverse events were common, with similar incidence among patients with and without hypoalbuminemia (73% vs 76%, respectively; P = 0.727). Median time to therapy discontinuation resulting from documented toxicity was significantly shorter in those with hypoalbuminemia (22 months vs not reached; P = 0.003). Cox regression demonstrated that hypoalbuminemia was the only significant risk factor for shorter time to discontinuation resulting from documented adverse effects (hazard ratio = 3.0; 95% CI = 1.15-8.0; P = 0.025). Conclusion and Relevance: This represents the first report of the impact of hypoalbuminemia on tolerability of highly protein bound oral oncolytic drugs, demonstrating that patients with hypoalbuminemia may be at increased risk for early discontinuation resulting from toxicity. Given the importance of maintaining dose intensity in patients receiving oncolytic therapy, albumin levels should be monitored throughout treatment and supportive care maximized in those developing hypoalbuminemia.