Vascular Biogenics (Israel)

5505 Background: Ofranergene obadenovec (ofra-vec, VB-111) is a nonreplicating adenoviral vector with a murine pro-endothelin 1 (PPE-1-3X) promoter and pro-apoptotic Fas-tumor necrosis factor receptor 1 (TNFR1) chimeric transgene thought to have a dual mechanism of action: vascular disruption and immune activation. Methods: This is a randomized, placebo-controlled, double-blind, multi-center randomized phase III trial (ClinicalTrials.gov identifier: NCT03398655) of ofranergene obadenovec combined with paclitaxel vs paclitaxel with placebo for the treatment of patients with recurrent platinum resistant ovarian cancer (PROC). Patients were randomly assigned 1:1 to receive IV VB-111 1x1013 viral particles (VPs) every 8 weeks with weekly IV paclitaxel 80 mg/m2 or placebo with paclitaxel until disease progression. The dual primary endpoints were overall survival (OS) and progression free survival (PFS) as assessed by Blinded Independent Central Review (BICR). Results: Between December 2017 and March 2022, 409 patients were randomized at 86 clinical sites in US, Israel, Spain, Poland and Japan. The median PFS was 5.29 months in the VB-111 arm and 5.36 months in the control arm; hazard ratio (HR) 1.03 (CI: 0.83-1.29, p = 0.7823), and median OS with was 13.37 months vs. 13.14 months HR 0.97 (CI: 0.75–1.27 p = 0.8440). Objective response rates (ORR) were similar in both arms: RECIST 1.1 ORR was 28.9% with VB-111 vs. 29.6% with control (CA-125 ORR 41.1% vs 49.4%). In both treatment arms response to CA-125 was a substantial prognostic factor for both PFS and OS. In the VB-111 arm, the HR in CA-125 responders compared to non-responders was for PFS HR 0.2428 (CI: 0.1642-0.3588), and for OS HR 0.3343 (CI: 0.2134-0.5238). Safety profile was consistent with the known safety profile of ofra-vec and was characterized by common transient flu like symptoms such as fever and chills. Conclusions: The addition of ofranergene obadenovec to paclitaxel did not improve PFS or OS. Clinical trial information: NCT03398655 .

TPS5606 Background: Ofranergene obadenovec (Ofra-vec, VB-111) is an anti-cancer gene based immune activator and targeted vascular disruptor. The dual mechanism of action triggers a broad antiangiogenic effect and induces of a tumor directed immune response. A phase II trial in patients with platinum resistant ovarian cancer (PROC) demonstrated that ofra-vec in combination with weekly paclitaxel was well tolerated and associated with a CA-125 Objective Response Rate (ORR) of 58%, a trend for improved survival and induction of an immunotherapeutic effect of tumor infiltration with CD-8 T cells. Based on these observations, a pivotal phase III study was initiated in collaboration with the GOG Foundation, Inc. Methods: Study NCT03398655 is an international, randomized, double-blind, placebo-controlled, phase III study. Eligible patients have recurrent PROC and may have been previously treated with up to 5 prior lines of therapy (but not >2 for PROC). Patient are randomized 1:1 to receive ofra-vec (1x1013 Viral Particles) with weekly paclitaxel (80mg/m2), or weekly paclitaxel with placebo. Randomization is stratified by number of prior treatment lines, prior antiangiogenic therapy and platinum refractory disease status. The dual primary endpoints are OS and PFS. A pre-planned interim analysis of CA-125 response (GCIG) performed by the DSMC met the pre-defined criteria showing that CA-125 ORR in the treatment arm was at least 10% higher than in the control arm. Study is enrolling in the US, EU, Japan and Israel, with 90% enrollment to date. Completion of accrual is anticipated in Q1 2022. Clinical trial information: NCT03398655.

Abstract We have previously shown that diffusion MR characteristics are a predictive imaging biomarker for survival benefit in recurrent glioblastoma treated with anti-VEGF therapy; however, contemporary clinical use of bevacizumab is often limited to patients with very large tumors and/or after multiple recurrences. We hypothesize that diffusion MR characteristics can be used to predict long-term survival benefit in these patients, which may be beneficial for clinical decision-making. The current study identified 83 recurrent glioblastoma patients from our institution who were treated with bevacizumab over the past 5 years with high quality anatomic and diffusion MRI data. Of these 83 patients, 35 had large contrast enhancing tumors (>20cc or >3.4cm diameter, group average). Additionally, we identified 37 recurrent glioblastoma patients from the bevacizumab treated control arm of a recent multicenter phase III trial (NCT02511405) with high quality data and large enhancing tumors for validation. Pre-treatment tumor volume was quantified using T1 subtraction maps and apparent diffusion coefficient (ADC) histogram analysis was used to phenotype patients as having high (> 1.24 um2/ms) or low (< 1.24 um2/ms) ADCL, the mean value of the lower peak using a double Gaussian mixed model. Median overall survival in patients with large volume recurrent glioblastoma was ~5.7 months. High ADCL was associated with significantly longer overall survival (OS) compared with low ADCL in both single center (P=0.0271, HR=0.486, mOS=5.5 vs. 2.8mo) and multicenter phase III data (P=0.0457, HR=0.507, mOS=7.9 vs. 5.7mo). Accounting for absolute tumor volume and age, both cohorts showed that ADCL was an independent prognostic factor for OS (Cox, P< 0.01). In summary, pre-treatment diffusion MR imaging is an independent predictive biomarker for OS in recurrent glioblastoma with a large tumor burden.

Consumer genomics databases have reached the scale of millions of individuals. Recently, law enforcement authorities have exploited some of these databases to identify suspects via distant familial relatives. Using genomic data of 1.28 million individuals tested with consumer genomics, we investigated the power of this technique. We project that about 60% of the searches for individuals of European descent will result in a third-cousin or closer match, which theoretically allows their identification using demographic identifiers. Moreover, the technique could implicate nearly any U.S. individual of European descent in the near future. We demonstrate that the technique can also identify research participants of a public sequencing project. On the basis of these results, we propose a potential mitigation strategy and policy implications for human subject research.

In this study, we reexamine the mental pain-suicidality link in adolescence, by focusing on mental pain tolerance as a critical factor in explaining youth suicidal behavior. In a series of three studies, participants completed measures of mental pain (tolerance and intensity), emotional regulation, depression, and suicidality. Study 1 included a nonclinical sample of 183 Israeli adolescents. Study 2 included a nonclinical sample of 139 Israeli adolescents, who completed additional measures of self-esteem, optimism, mindfulness, meaning in life, positive affectivity, and life satisfaction. Study 3 included suicidal psychiatric inpatients (N=24), nonsuicidal psychiatric inpatients (N=24), and nonclinical adolescents (N=24). In Study 1, mental pain tolerance was significantly associated with depression, suicidality, and emotion-regulation skills. In Study 2, mental pain tolerance was significantly associated with measures of psychological resources. In Study 3, we found that suicidal psychiatric inpatients reported significantly lower levels of mental pain tolerance than nonsuicidal psychiatric inpatients and nonclinical adolescents. No significant group difference was found in the reported intensity of mental pain. Findings imply that mental pain tolerance may be a better indicator for suicidal behavior during adolescence than reported pain intensity.

Family trees have vast applications in fields as diverse as genetics, anthropology, and economics. However, the collection of extended family trees is tedious and usually relies on resources with limited geographical scope and complex data usage restrictions. We collected 86 million profiles from publicly available online data shared by genealogy enthusiasts. After extensive cleaning and validation, we obtained population-scale family trees, including a single pedigree of 13 million individuals. We leveraged the data to partition the genetic architecture of human longevity and to provide insights into the geographical dispersion of families. We also report a simple digital procedure to overlay other data sets with our resource.

Rheumatoid arthritis (RA) is a symmetric inflammatory polyarthritis associated with high concentrations of pro-inflammatory, cytokines including tumor necrosis factor (TNF)-α. Adalimumab is a monoclonal antibody (mAb) that binds TNF-α, and is widely used to treat RA. Despite its proven clinical efficacy, adalimumab and other therapeutic mAbs have disadvantages, including the requirement for repeated bolus injections and the appearance of treatment limiting anti-drug antibodies. To address these issues, we have developed an innovative ex vivo gene therapy approach, termed transduced autologous restorative gene therapy (TARGT), to produce and secrete adalimumab for the treatment of RA. Helper-dependent (HD) adenovirus vector containing adalimumab light and heavy chain coding sequences was used to transduce microdermal tissues and cells of human and mouse origin ex vivo, rendering sustained secretion of active adalimumab. The genetically engineered tissues were subsequently implanted in a mouse model of RA. Transduced human microdermal tissues implanted in SCID mice demonstrated 49days of secretion of active adalimumab in the blood, at levels of tens of microgram per milliliter. In addition, transduced autologous dermal cells were implanted in the RA mouse model and demonstrated statistically significant amelioration in RA symptoms compared to naïve cell implantation and were similar to recombinant adalimumab bolus injections. The results of the present study report microdermal tissues engineered to secrete active adalimumab as a proof of concept for sustained secretion of antibody from the novel ex vivo gene therapy TARGT platform. This technology may now be applied to a range of antibodies for the therapy of other diseases.