Multiple Treatment Cycles of Neural Stem Cell Delivered Oncolytic Adenovirus for the Treatment of Glioblastoma

Tumor tropic neural stem cells (NSCs) can improve the anti-tumor efficacy of oncovirotherapy agents by protecting them from rapid clearance by the immune system and delivering them to multiple distant tumor sites. We recently completed a first-in-human trial assessing the safety of a single intracerebral dose of NSC-delivered CRAd-Survivin-pk7 (NSC.CRAd-S-pk7) combined with radiation and chemotherapy in newly diagnosed high-grade glioma patients. The maximum feasible dose was determined to be 150 million NSC.CRAd-Sp-k7 (1.875 × 1011 viral particles). Higher doses were not assessed due to volume limitations for intracerebral administration and the inability to further concentrate the study agent. It is possible that therapeutic efficacy could be maximized by administering even higher doses. Here, we report IND-enabling studies in which an improvement in treatment efficacy is achieved in immunocompetent mice by administering multiple treatment cycles intracerebrally. The results imply that pre-existing immunity does not preclude therapeutic benefits attainable by administering multiple rounds of an oncolytic adenovirus directly into the brain.

12 Key pharmacokinetic and pharmacodynamic parameters that correlate with the anti-tumor activity of a bispecific PD-L1 conditional 4–1BB agonist

Background4-1BB is a costimulatory molecule that is predominantly expressed on activated CD8+ T cells and is induced upon T cell receptor mediated activation.1 Within the tumor microenvironment, 4-1BB-expressing T cells are enriched for anti-tumor reactivity 2; thus, 4-1BB agonism provides an opportunity for selective activation of anti-cancer immune effector cells. Early efforts to develop 4-1BB targeted agonists were limited by poor tolerability (Urelumab) or insufficient efficacy (Utomilumab). INBRX-105 is a bispecific antibody that aims to overcome these prior limitations through induction of 4-1BB agonism specifically at sites of PD-L1 expression. Preclinical models have defined pharmacokinetic (PK) and pharmacodynamic (PD) parameters that are correlated with maximal INBRX-105-specific immune responses and antitumor activity.MethodsINBRX-105 was generated by linking 2 humanized single-domain antibody binding domains targeting human PD-L1 and 4-1BB, fused to an effector-silenced human IgG1 constant domain (Fc). A bispecific, anti-mouse PD-L1x4-1BB surrogate molecule, INBRX-105-a, was engineered to match the function and target affinities of INBRX-105. This surrogate was tested for in vivo activity in non-tumor-bearing and MC-38 tumor-bearing animals, including measurements of serum exposure, PD-L1 receptor occupancy, immunophenotyping of peripheral blood and intra-tumoral immune cell populations.ResultsINBRX-105-a was shown to be an appropriate anti-mouse surrogate for INBRX-105 in a variety of in vitro assays. Comparable potencies of activity were demonstrated in a PD-L1 dependent 4-1BB reporter assay, as well as in cytokine induction through co-stimulation of primary T cells. In vivo, INBRX-105-a showed robust induction of mouse CD8+ T effector memory populations (CD8+ TEM) at dose levels that achieved ≥ 96 hours of PD-L1 receptor occupancy. A serum concentration of 800 ng/mL at 96 hours, achieved by a dose of 2 mg/kg in mice, was sufficient to provide the requisite occupancy for maximal pharmacodynamics. CD8+ TEM responses were dependent on 4-1BB agonism and were more efficiently induced by PD-L1 localization, as opposed to 4-1BB multivalent clustering alone. Optimal tumor responses, including complete responses and demonstration of immunological memory, were observed when maximal 4-1BB driven pharmacodynamics were paired with extended PD-1/PD-L1 pathway blockade, provided either by an orthogonal molecule or increased exposure of INBRX-105.ConclusionsPreclinical receptor occupancy and pharmacokinetic determinations have defined a dose of INBRX-105-like activity that induces maximal pharmacodynamics. Additional PD-1 checkpoint inhibition does not change the pharmacodynamic profile of INBRX-105-a, but does allow for optimal efficacy. INBRX-105 is currently being evaluated in patients with advanced solid tumors in a first-in-human trial (NCT03809624).Trial RegistrationINBRX-105 is currently being evaluated in patients with advanced solid tumors in a first-in-human trial (NCT03809624).ReferencesVinay DS, Kwon BS. 4-1BB (CD137), an inducible costimulatory receptor, as a specific target for cancer therapy. BMB Reports; 2014:47:122–129.Ye Q, Song D-G, Poussin M, et al. CD137 accurately identifies and enriches for naturally occurring tumor-reactive T cells in tumor. Clin Cancer Res; 2014:20:44–55.Ethics ApprovalThe care and use of all animals were reviewed and approved by Explora BioLabs’ IACUC # SP17-010-013 and conducted in accordance with AAALAC regulations.

Covid-19 Vaccination – A Saviour from Pandemic

BACKGROUND The world is hit by a global pandemic caused by severe acute respiratory syndrome coronavirus, a new genotype of the virus, which causes coronavirus disease, Covid19. The situation has challenged the entire scientific community nationally as well as internationally to fight back this deadly disease. Since its beginning in November 2019, it has disseminated throughout the human race, regardless of all the measures taken by healthcare sectors, governments, and world health organizations as well. Numerous investigations show that this virus uses air as a passage to commute and spread, the disease most commonly spreads through droplet infections and when comes in contact with the mucous membrane, enters the body. Entire medical staff along with scientists of various nations are working perpetually to develop successful vaccines and drugs to fight back this virus. Amongst various vaccines developing across the world, many of them are in their clinical trials and human trial phases and those which have succeeded in all the trial phases are getting delivered to citizens since December 2020. The present article aims to provide a review of the literature on the type of vaccinations that have been developed so far with their mechanism of action and their basic formulations. KEY WORDS Pandemic, SARS-CoV-2, Vaccine, Coronavirus, Antibody, Immunization, COVID-19

Epidemiology, virology, clinical features, diagnosis, and treatment of SARS-CoV-2 infection

Since December 2019, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has emerged and spread quickly worldwide. The disease is generally mild in adult people but in any with comorbidities may proceed to acute respiratory distress syndrome (ARDS), pneumonia, and multi-organ dysfunction. By performing molecular tests on respiratory secretions can diagnose the virus. Elevated C-reactive protein (CRP) and normal/low white cell counts are common laboratory diagnoses of COVID-19 while the tomographic chest scan is usually irregular for many infected people. Some patients progress to respiratory failure, pneumonia, and finally death by the end of the first week of illness because of the sharp rise in inflammatory cytokines such as IL7, IL2, GCSF, IL10, MIP1A, MCP1, IP10, and TNFα. Various approaches to the COVID- 19 are being performed by scientists. Use of chemical medical drugs that are effective for other viral infections. Among them, remdesivir was approved by FDA on 1th May 2020 because of its impact to treat patients. Also, several studies have revealed that many Chinese herbal remedies have a remarkable impact on the healing process when simultaneously were used along with pharmacological drugs. In the meantime, many efforts have been made to produce an effective vaccine, and so far, the Ad5-vectored COVID-19 vaccine has been successful and has entered phase 2 in the human trial. The current review focus on epidemiology, virology, clinical features, diagnosis, and available treatment of coronavirus that might assist researchers and clinicians in establishing action options for timely against this infection.

The tissue-engineered breast

The adipose tissue engineering paradigm of in vitro cell-seeded scaffolds subsequently implanted in vivo failed because of inadequate vascularization. Consequently, entirely in vivo models of tissue engineering are being trialled where angiogenic growth is stimulated in unison with expansion of implanted cells and matrices. In animals, impressive amounts of fat and fibroblastic tissue have been grown by matrix induction of preadipocytes or by redirecting a vascular pedicle with fat into a sealed chamber space and proof of principle shown in a human trial. The models are cumbersome limiting clinical translation and currently direct fat transfer by injection is simpler. Unlike true tissue engineering there is, however, no net gain of tissue and even when ‘successful’ it is debated whether the graft survives or is replaced by newly regenerated adipocytes. Research focuses on stem cell differentiation, cell survival, and matrix and biomechanical manipulations.

Percutaneous ultrasound gastrostomy (PUG): first prospective clinical trial

Graphical abstarct Purpose To report the results of the first-in-human trial evaluating the safety and efficacy of the percutaneous ultrasound gastrostomy (PUG) technique. Methods A prospective, industry-sponsored single-arm clinical trial of PUG insertion was performed in 25 adult patients under investigational device exemption (mean age 64 ± 15 years, 92% men, 80% inpatients, mean BMI 24.5 ± 2.7 kg/m2). A propensity score-matched retrospective cohort of 25 patients who received percutaneous radiologic gastrostomy (PRG) was generated as an institutional control (mean age 66 ± 14 years, 92% men, 80% inpatients, mean BMI 24.0 ± 2.7 kg/m2). Primary outcomes included successful insertion and 30-day procedure-related adverse events (AE’s). Secondary outcomes included procedural duration, sedation requirements, and hospital length of stay. Results All PUG procedures were successful, including 3/25 [12%] performed bedside within the ICU. There was no significant difference between PUG and PRG in rates of mild AE’s (3/25 [12%] for PUG and 7/25 [28%] for PRG, p = 0.16) or moderate AE’s (1/25 [4%] for PUG and 0/25 for PRG, p = 0.31). There were no severe AE’s or 30-day procedure-related mortality in either group. Procedural room time was longer for PUG (56.5 ± 14.1 min) than PRG (39.3 ± 15.0 min, p < 0.001). PUG procedure time was significantly shorter after a procedural enhancement, the incorporation of a Gauss meter to facilitate successful magnetic gastropexy. Length of stay for outpatients did not significantly differ (2.4 ± 0.5 days for PUG and 2.6 ± 1.0 days for PRG, p = 0.70). Conclusion PUG appears effective with a safety profile similar to PRG. Bedside point-of-care gastrostomy tube insertion using the PUG technique shows promise. Trial Registration Number: ClinicalTrials.gov ID NCT03575754. Graphical abstract