Vascular Biogenics Ltd (VBLT)

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This is a MUST read.

Amazing article about the future of VB-111.

VB-111 represents one such modality that is being actively investigated in high-grade gliomas. As evidenced above, VB-111 can be combined safely with other antiangiogenic therapies. It is intriguing to consider the combination of VB-111 with standard cytotoxic agents, or even with the combination of immunotherapy. In the rapidly evolving field of oncology, the latter combination may prove to be the more likely scenario that may be examined in future clinical trials. Thus, the onus will be to demonstrate that unleashing a host immune response against highly vascular malignancies can be safely done in the setting of TNFa-mediated endothelial cell apoptosis; a consideration especially important in the setting of those patients who develop fevers while receiving VB-111 compared to those that do not. With respect to the latter group of patient, a possible hypothesis to consider is whether immunotherapy may improve response rates in this population.

Overall, VB-111 represents an important step forward to using genetically engineered biotherapy for the treatment of high-grade gliomas. Its safety, efficacy, and comparative benefit warrant further exploration in large clinical trials.


FULL article: http://www.tandfonline.com/doi/full/10.1080/21678707.2016.1235971

Abstract

Introduction: High grade gliomas continue to represent a group of cancers that are difficult to control with current cytotoxics and antiangiogenics. With tumor angiogenesis representing a critical mechanism, there is an unmet need for novel types of treatment that can hone in on this important pathway of tumorigenesis.

Areas covered: Virotherapy is a promising modality of cancer treatment that is defined by genetic manipulation of a virus to preferentially target neoplastic cells. VB-111 (ofranergene obadenovec) is a genetically modified adenovirus that is designed to selectively target tumor-associated endothelial cells. Utilizing PubMed and MEDLINE® databases, we identified key preclinical and clinical data pertaining to VB-111. We then reviewed ClinicalTrials.gov to determine the status of ongoing research.

Expert opinion: Demonstrating safety and showing signs of efficacy in early phase clinical trials, VB-111 is being studied in combination with and without bevacizumab in a large phase 3 trial for recurrent glioblastoma. Given the data, VB-111 is a unique viral-mediated, antiangiogenic approach that has significant potential to make an impact in the field of oncology and neuro-oncology. We agree with the continued study of this agent in expanded and randomized cohorts to determine if VB-111 can indeed impact survival in glioblastoma.

KEYWORDS: VB-111, virotherapy, angiogenesis, adenovirus, glioblastoma, glioma
1. Introduction

The treatment of gliomas has been a vexing discipline in the field of oncology. With a broad array of subtypes and pathogenic mechanisms that are not yet fully understood, currently approved regimens for the management of gliomas have had limited success. Gliomas are subdivided into histologic categories based on glial tissues of origin, as well as microscopic features connoting low- and high-grade characteristics. With respect to the topic at hand and for the purposes of this review, we will focus on high-grade gliomas given the urgent need for improved modalities of treatment.

High-grade gliomas are histologically defined by a propensity for neovascularization, degrees of anaplasia, areas of necrosis, and a relatively high growth index compared to their lower grade counterparts. Although various glial cell types can exhibit these features, the most common and most malignant of these are glioblastoma (GBM). With an annual incidence of less then 2% of all diagnosed malignancies, GBM still represents a disproportionately high rate of disease-specific morbidity relative to more common malignancies (i.e. breast, colon, and lung) [1 Ostrom QT, Gittleman H, Fulop J, et al. CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2008–2012. Neuro Oncol. 2015 Oct;17(Suppl 4):iv1–iv62.
[CrossRef], [PubMed], [Web of Science ®]

The current standard of care (SOC) was introduced by Stupp et al. in 2005 as a combination regimen that included surgery, radiotherapy, and concurrent temozolomide, followed by six cycles of adjuvant single-agent monthly temozolomide. This approach yielded a superior 1- and 5-year median overall survival (OS) advantage compared to radiation and subsequent chemotherapy (27% vs. 11% and 10% vs. 0%; hazard ratio [HR] 0.63, 95% CI 0.53–0.75, respectively) [2 Stupp R, Mason WP, van den Bent MJ, et al. European Organisation for research and Treatment of Cancer Brain Tumor and Radiotherapy Groups; National Cancer Institute of Canada Clinical Trials Group. N Engl J Med. 2005 Mar 10;352(10):987–996.
[CrossRef], [PubMed], [Web of Science ®]
]. It has been the SOC for newly diagnosed patients for over a decade.

In the setting of recurrent disease, there are few options. Given that high-grade gliomas are highly vascularized tumors, bevacizumab (BEV) represents the backbone of most second-line therapy for recurrent disease. BEV is a humanized IgG1 monoclonal antibody that targets vascular endothelial growth factor (VEGF) and prevents its interaction with the VEGF receptor on the malignant cell surface [3 Glade-Bender J, Kandel JJ, Yamashiro DJ. VEGF blocking therapy in the treatment of cancer. Expert Opin Biol Ther. 2003 Apr;3(2):263–276.
[Taylor & Francis Online], [Web of Science ®]
]. Thereby, it is postulated that BEV normalizes tumor vascular supply and may improve cytotoxic chemotherapeutic delivery, with the added potential benefit of decreasing the propensity of tumors to form new vasculature [3 Glade-Bender J, Kandel JJ, Yamashiro DJ. VEGF blocking therapy in the treatment of cancer. Expert Opin Biol Ther. 2003 Apr;3(2):263–276.
[Taylor & Francis Online], [Web of Science ®]
]. The initial approval of BEV was based on its clinical response rate in patients with recurrent GBM, as well as its impact on quality of life and patient reliance on glucocorticoids for symptom control [4 Kreisl TN, Kim L, Moore K, et al. Phase II trial of single-agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma. J Clin Oncol. 2009;27(5):740.
[CrossRef], [PubMed], [Web of Science ®]
]. Friedman et al. went on to demonstrate that antiangiogenic therapy can be safely combined with conventional cytotoxic chemotherapy in the setting of recurrent GBM. Although the combination arm had slightly more toxicity compared to patients who received BEV alone, the group receiving BEV and irinotecan demonstrated a trend toward improved progression-free survival (PFS); however, there was no OS difference between the two groups [5 Friedman HS, Prados MD, Wen PY, et al. Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol. 2009 Oct 1;27(28):4733–4740.
[CrossRef], [PubMed], [Web of Science ®]
].

Synergizing BEV in combination with cytotoxic therapy has been studied but has yet to be optimized in the setting of high-grade glioma. Late phase clinical trial data from EORTC 26101 compared the addition of BEV to lomustine versus lomustine alone in 437 patients who had a first recurrence of disease after SOC therapy. With approximately two-thirds of patients in the combination arm, the investigators concluded that OS was not superior to lomustine alone (HR 0.95, CI 0.74–1.21, p = 0.65) [6 Wick A, Brandes AA, Gorlia T, et al. Phase III trial exploring the combination of bevacizumab and lomustine in patients with first recurrence of glioblastoma: the EORTC 26101 trial. Neuro Oncol. 2015;17(suppl 5):v1.
[CrossRef], [PubMed], [Web of Science ®]
]. In addition to BEV, small-molecule inhibitors of the VEGF pathway have also been investigated; however, none has shown significant improvement in OS to warrant approval within recurrent GBM [7 Batchelor TT, Mulholland P, Neyns B, et al. Phase III randomized trial comparing the efficacy of cediranib as monotherapy, and in combination with lomustine, versus lomustine alone in patients with recurrent glioblastoma. J Clin Oncol. 2013;31(26):3212.
[CrossRef], [PubMed], [Web of Science ®]

With its wide spread adoption in multiple cancer types, angiogenesis inhibition via VEGF blockage (both monoclonals and small molecules) has yielded clinically significant complications in a subset of patients, such as hypertension, proteinuria, thromboembolic events, and cardio- and cerebro-vascular events [8 Economopoulou P, Kotsakis A, Kapiris I, et al. Cancer therapy and cardiovascular risk: focus on bevacizumab. Cancer Manag Res. 2015 Jun;3(7):133–143.
[CrossRef]
]. There is also mounting evidence that anti-VEGF therapy with BEV may contribute to a more invasive phenotype in recurrent GBM [9 de Groot JF, Fuller G, Kumar AJ, et al. Tumor invasion after treatment of glioblastoma with bevacizumab: radiographic and pathologic correlation in humans and mice. Neuro Oncol. 2010 Jan;12(3):233–242.
[CrossRef], [PubMed], [Web of Science ®]
,10 Delay M, Jahangiri A, Carbonell WS, et al. Microarray analysis verifies two distinct phenotypes of glioblastomas resistant to antiangiogenic therapy. Clin Cancer Res. 2012 May 15;18(10):2930–2942.
[CrossRef], [PubMed], [Web of Science ®]
].

As evidenced above, there is an urgent need to improve upon the treatment of GBM. Virotherapy is one such modality that is being explored as a novel means of treatment. The impact of viral infections on cancer has been anecdotally observed as far back as the 1890s; however, its practical application has been limited in scope and practice until recently [11 Dock G. The influence of complicating disease upon leukemia. Am J Med Sci. 1904;127:563–592.
[CrossRef]
]. In general, the application of viruses to the treatment of cancer relies on either a direct oncolytic effect or an indirect means of stimulating the immune system against a malignancy by way of genetically modifying viruses to selectively target neoplastic cells. An example of this is talimogene laherparepvec (T-VEC), which was recently approved in the setting of advanced melanoma. T-VEC is a genetically modified herpes simplex virus 1 with attenuated virulence for non-tumor cells and an enhanced replicative capacity in tumor cells [12 Liu BL, Robinson M, Han ZQ, et al. ICP34.5 deleted herpes simplex virus with enhanced, immune stimulating, and anti-tumour properties. Gene Ther. 2003 Feb;10(4):292–303.
[CrossRef], [PubMed], [Web of Science ®]
]. T-VEC is injected intralesionally. Infection leads to viral replication within the cell and subsequent oncolysis. Additionally, the consequent expression of virally encoded stimulates an innate immune response against granulocyte-macrophage colony-stimulating factor (GM-CSF) the infected cell [12 Liu BL, Robinson M, Han ZQ, et al. ICP34.5 deleted herpes simplex virus with enhanced, immune stimulating, and anti-tumour properties. Gene Ther. 2003 Feb;10(4):292–303.
[CrossRef], [PubMed], [Web of Science ®]
,13 Andtback RH, Kaufman HL, Collichio F, et al. Talimogene laherparepvec improves durable response rate in patients with advanced melanoma. J Clin Oncol. 2015 Sep 1;33(25):2780–2788.
[CrossRef], [PubMed], [Web of Science ®]
]. With median OS trending toward significance in a randomized phase 3 trial, intralesional T-VEC was approved by the FDA for the treatment of advanced melanoma after meeting its primary end point of a superior durable response rate compared to subcutaneous GM-CSF alone [13 Andtback RH, Kaufman HL, Collichio F, et al. Talimogene laherparepvec improves durable response rate in patients with advanced melanoma. J Clin Oncol. 2015 Sep 1;33(25):2780–2788.
[CrossRef], [PubMed], [Web of Science ®]
,14 U.S. Food and Drug Administration. 2015. [updated Oct 27; cited 2016 Jan 23]. Available from:
http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm469571.htm


2. VB-111: mechanism of action

Ofranergene obadenovec (VB-111) (Box 1) is genetically modified adenoviral construct that is being developed by VBL Therapeutics. Unlike the recently approved T-VEC, the unique anticancer properties of VB-111 stem from its propensity to target tumor vasculature without the need for viral replication and direct oncolysis. The backbone of VB-111 is a nonreplicating adenovirus type 5 (Ad-5) vector. What it lacks in typical virulence, it compensates with its ability to carry a proapoptotic human Fas-chimera transgene under the control of a modified murine pre-pro-endothelin 1 (PPE-1) promoter [15 Varda-Bloom N, Shaish A, Gonen A, et al. Tissue-specific gene therapy directed to tumor angiogenesis. Gene Ther. 2001 Jun;8(11):819–827.
[CrossRef], [PubMed], [Web of Science ®]
]. The integration of modified PPE-1 (termed PPE-1-3x) within the genome of infected angiogenic endothelial cells allows it to be preferentially expressed due to a unique regulatory element. Preclinical models demonstrated that normal blood vessels do not express this promotor sequence [16 Greenberger S, Shaish A, Varda-Bloom N, et al. Transcription-controlled gene therapy against tumor angiogenesis. J Clin Invest. 2004 Apr 1;113(7):10717–11024.
[CrossRef]
].

Box 1. Drug summary


CSVDisplay Table
As the promotor region is transcribed, the Fas-chimera transgene is thus expressed. The product is then incorporated as a transmembrane protein, with its extracellular domain possessing human tumor necrosis factor receptor 1 (TNFR1). Subsequently, the TNFR1 receptor interacts with tumor necrosis factor alpha (TNFa) leading to caspase-mediated apoptosis of angiogenic tumor endothelial cells (Figure 1) [17 Boldin MP, Mett IL, Varfolomeev EE, et al. Self-association of the “death domains” of the p55 tumor necrosis factor (TNF) receptor and Fas/APO1 prompts signaling for TNF and Fas/APO1 effects. J Bio Chem. 1995 Jan 6;270(1):387–391.
[CrossRef], [PubMed], [Web of Science ®]

Figure 1. Adenovirus type 5 interacting with cancer-related endothelial cell (1), with subsequent transcription of the Fas-chimera transgene (2), followed by the incorporation of the protein product at the cell surface (3). TNFR1 interacting with TNFa, leading to apoptosis of endothelial cells (4).TNFR1: tumor necrosis factor receptor 1; TNFa: tumor necrosis factor alpha. Source: VBL therapeutic public presentation. Obtained with permission from the company.

3. Preclinical data

Preclinical models assessing the efficacy of VB-111 in high-grade gliomas have demonstrated robust radiographic responses and an OS benefit. Gruslova et al. employed nude rat and mouse xenograft models with intracranially implanted U87MG or U251. Both cell lines were tagged with luciferase, allowing the investigators to use bioluminescence imaging to assess response. After tumors were established, the animals were injected with VB-111 or a control. Survival was in favor of those animals that were injected with VB-111 (log rank p < 0.05). This corresponded to a decrease in tumor volume over time. The antiangiogenic effect of VB-111 was also measured using CD31, a marker for neovascularization. CD31 levels were fivefold higher in the control group compared to the group that received VB-111 (p = 0.022). Additionally, magnetic resonance imaging demonstrated a difference in tumor enhancement between the two groups, with the control group exhibiting a greater relative degree of contrast enhancement throughout the bulk tumor compared to the VB-111 group, which had a propensity to enhance peripherally with centrally necrotic features [18 Gruslova A, Cavazos DA, Miller JR, et al. VB-111: a novel anti-vascular therapeutic for glioblastoma multiforme. J Neurooncol. 2015 Sep;124(3):365–372.
[CrossRef], [PubMed], [Web of Science ®]
].

4. Pharmacodynamics, pharmacokinetics, and metabolism

Data from an early phase clinical trial have provided important insights into the biological behavior of VB-111. In a study by Brenner et al., 33 patients were divided into 7 dosing cohorts, with the viral particle (VP) dose ranging from 1 × 10e10 (cohort 1) to 1 × 10e13 (cohort 7) [19 Brenner AJ, Cohen YC, Breitbart E, et al. Phase I dose-escalation study of VB-111, an antiangiogenic virotherapy, in patients with advanced solid tumors. Clin Cancer Res. 2013 Jul 15; 19(14):3996–4007.
[CrossRef], [PubMed], [Web of Science ®]
]. The purpose of the study was to assess various biochemical parameters, safety, and early signals of survival (clinical data discussed below). With respect to biochemical measurements (i.e. pharmacodynamics, pharmacokinetics, and metabolism), serum and urine levels of Ad-5 DNA and Fas-chimera transgene expression were analyzed prior to and after the intravenous administration of each dose using quantitative real-time PCR and reverse transcriptase plus PCR, respectively. All samples were negative for Ad-5 DNA expression prior to administration. After infusion, blood levels of Ad-5 DNA demonstrated a dose-dependent response, and subsequently dropped off by day 56 in all patients. Urine levels of Ad-5 DNA were transiently detectable only within the initial 24 h after infusion. Transgene expression in the blood was negative in all samples after each infusion, suggesting that normal vasculature was not being targeted. A single patient’s subcutaneous metastatic site from esophageal cancer was sampled on days 4 and 28 and revealed detectable levels of Fas-chimera transgene expression, suggesting infiltration by the virus of host tumor vasculature.

5. Clinical data

To date, there have been at least two published patient studies assessing the safety and tolerability of VB-111 in cancer. Although not powered for efficacy, these studies demonstrated encouraging signals of survival benefit that are being explored in expanded patient cohorts and at increasing numbers of institutions. As briefly touched on above, VB-111 was administered intravenously in patients with advanced solid tumors in an open-label phase 1, dose escalation study [19 Brenner AJ, Cohen YC, Breitbart E, et al. Phase I dose-escalation study of VB-111, an antiangiogenic virotherapy, in patients with advanced solid tumors. Clin Cancer Res. 2013 Jul 15; 19(14):3996–4007.
[CrossRef], [PubMed], [Web of Science ®]
]. With respect to safety, higher dosing cohorts (cohort 5 through cohort 7) demonstrated a propensity to elicit transient fevers, with rare grade 3–4 pyrexia being reported. Overall, all patients tolerated infusions and most adverse reactions were managed with conservative measures [19 Brenner AJ, Cohen YC, Breitbart E, et al. Phase I dose-escalation study of VB-111, an antiangiogenic virotherapy, in patients with advanced solid tumors. Clin Cancer Res. 2013 Jul 15; 19(14):3996–4007.
[CrossRef], [PubMed], [Web of Science ®]
]. As with most biotherapy, a maximum tolerated dose was not reached. Cytokine levels (i.e. interleukin-6) were monitored and did not suggest a predisposition for cytokine release syndrome [19 Brenner AJ, Cohen YC, Breitbart E, et al. Phase I dose-escalation study of VB-111, an antiangiogenic virotherapy, in patients with advanced solid tumors. Clin Cancer Res. 2013 Jul 15; 19(14):3996–4007.
[CrossRef], [PubMed], [Web of Science ®]
]. With respect to treatment response, patients in cohort 6 and cohort 7 demonstrated stable disease on days 28 and 56 more frequently compared to their counter parts in lower dosing cohorts. Median OS was significantly longer in cohort 7 when compared to all other cohorts (median OS not reached vs. 173 days, respectively; p = 0.0098) [19 Brenner AJ, Cohen YC, Breitbart E, et al. Phase I dose-escalation study of VB-111, an antiangiogenic virotherapy, in patients with advanced solid tumors. Clin Cancer Res. 2013 Jul 15; 19(14):3996–4007.
[CrossRef], [PubMed], [Web of Science ®]
].

In 2015, an early phase clinical trial was presented at the Society of Neuro-Oncology annual meeting, which highlighted the safety and efficacy of VB-111 in patients with recurrent GBM. In this phase 1/2, multicenter, dose-escalation study, VB-111 was administered intravenously to 62 patients at 1 × 10e12 VP and 1 × 10e13 VP, of which 46 received repeat doses of 1 × 10e13 VP administered every 2 months. Initially, VB-111 treatment was administered until further progression, thereafter it was discontinued and patients received BEV SOC (limited exposure cohort, n = 22). The protocol was then amended to allow further exposure to VB-111; thus, upon progression, BEV 10 mg/kg biweekly was added and combined with VB-111 bimonthly (continuous exposure cohort, n = 24) [20 Brenner A, Cohen Y, Vredenburgh J, et al. Phase 2 study of VB-111, an anti-cancer gene therapy, as monotherapy followed by combination of VB-111 with bevacizumab, in patients with recurrent glioblastoma [abstract]. In: 20th Annual Scientific Meeting and Education Day of the Society for Neuro-Oncology; 2015 Nov 19–22; San Antonio, TX. Neuro-Oncology 17: v45–v54, 2015.
].

The investigators demonstrated that there was a statistical improvement in OS among the continuous exposure cohort (16 months), compared to the limited exposure to VB-111 (8 months, p = 0.048). The study also revealed that the combination of BEV and VB-111 can be safely administered in the setting of progressive GBM [20 Brenner A, Cohen Y, Vredenburgh J, et al. Phase 2 study of VB-111, an anti-cancer gene therapy, as monotherapy followed by combination of VB-111 with bevacizumab, in patients with recurrent glioblastoma [abstract]. In: 20th Annual Scientific Meeting and Education Day of the Society for Neuro-Oncology; 2015 Nov 19–22; San Antonio, TX. Neuro-Oncology 17: v45–v54, 2015.
]. A large phase 3 trial is currently ongoing (discussed below).

6. Future directions

The use of VB-111 in the setting of high-grade glioma is currently being investigated in a phase 3, randomized, controlled, open-label, industry-sponsored clinical trial (NCT02511405). The study (also known as the GLOBE trial) is designed to assess VB-111 with or without the addition of BEV in patients with first or second progression of GBM. Within the experimental arm, VB-111 will be administered intravenously at a dose of 1 × 10e13 VP every 2 months along with BEV every 2 weeks. The control arm will only receive BEV. The primary outcome will be OS, with PFS and tumor response representing secondary end points [21 A phase 3, pivotal trial of VB-111 plus bevacizumab vs. bevacizumab in patients with recurrent glioblastoma (GLOBE). [updated 2016 Mar 16; cited 2016 Mar 23] Available from:
http://clinicaltrials.gov/ct2/show/NCTNCT02511405

7. Conclusion

VB-111 is a novel agent in a market that is dominated by FDA-approved small-molecule inhibitors and monoclonal antibodies targeting angiogenesis. The mechanism of action has been demonstrated to be safe and potentially effective in early phase clinical trials. Its development will hopefully lead the way to more vector-mediated genetic alteration of the neoplastic process via disruption of angiogenesis. Further clinical investigation of this exciting new means of targeting cancer is warranted.

8. Expert opinion

High-grade gliomas are characterized by a propensity to develop an intricate, yet disorganized array of blood vessels. These vascular networks potentiate growth of the tumor and have been the focus of several different modalities of treatment. Most notable of these agents is BEV, with its suggested efficacy being most evident in the recurrent setting; however, its impact on OS has been thrown into doubt. This lack of a survival benefit possibly stems from the intrinsically redundant nature of angiogenesis; in that, multiple pathways of blood vessel formation allow the tumor to escape a single agent that targets proliferation. Therefore, there is an unmet need to circumvent these mechanisms of escape and to fully take advantage of inhibiting angiogenesis in high-grade gliomas.

VB-111 represents a novel approach to tackling the issue of antiangiogenic escape mechanisms and potentially improving survival parameters in patients with high-grade gliomas. Using a genetically engineered viral construct, VB-111 is based on a nonreplicating adenovirus vector that preferentially targets tumor-associated endothelial cells. The viral payload it carries is a Fas-chimera transgene, which is regulated by a unique tissue-specific promotor region (PPE-1-3x). The activation of this promotor region is dependent on the elevated rate of angiogenesis intrinsic to high-grade gliomas. Upon transcription of the transgene, a chimeric receptor is expressed on the cell surface; of which, the extracellular domain is a human TNF receptor, and the transmembrane and intracellular domain is composed of Fas. The interaction of TNFa with the extracellular component leads to a Fas-dependent caspase-mediated apoptotic cascade. As demonstrated in preclinical animal models, this mechanism effectively starves the tumor of its blood supply and improves survival.

Early phase clinical data suggest that VB-111 is safe and can be well tolerated by patients with high-grade glioma. A maximum tolerated dose was not reached and the clinical behavior of the virus suggested that patients may derive the most benefit at higher doses. Additionally, results presented by Brenner et al. at the 2015 Society for Neuro-Oncology meeting suggested that the addition of BEV to continuous VB-111 therapy can be well tolerated and may provide a survival advantage. Thus, the GLOBE trial will help to further corroborate these findings in a large, randomized, phase 3 setting, where VB-111 is paired with or without BEV in patients with recurrent GBM.

Viral-mediated treatment of malignancies is an exciting field of research that may potentially circumvent many of the challenges posed by cancer’s intrinsic mechanisms of resistance to conventional therapy. VB-111 represents one such modality that is being actively investigated in high-grade gliomas. As evidenced above, VB-111 can be combined safely with other antiangiogenic therapies. It is intriguing to consider the combination of VB-111 with standard cytotoxic agents, or even with the combination of immunotherapy. In the rapidly evolving field of oncology, the latter combination may prove to be the more likely scenario that may be examined in future clinical trials. Thus, the onus will be to demonstrate that unleashing a host immune response against highly vascular malignancies can be safely done in the setting of TNFa-mediated endothelial cell apoptosis; a consideration especially important in the setting of those patients who develop fevers while receiving VB-111 compared to those that do not. With respect to the latter group of patient, a possible hypothesis to consider is whether immunotherapy may improve response rates in this population.

Overall, VB-111 represents an important step forward to using genetically engineered biotherapy for the treatment of high-grade gliomas. Its safety, efficacy, and comparative benefit warrant further exploration in large clinical trials.

Declaration of interest

VBL reviewed and agreed on the publication of this manuscript, also providing access to Figure 1 for the paper. KB Peters has acted on the advisory board for Novocure and Agios. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.