**7. Glioma virus therapies**

The ReACT study is the randomized, Phase II trial of RINTEGA® in combination with bevacizumab (Avastin®) in patients with recurrent EGFRvIII-positive glioblastoma. In November 2015, Celldex Therapeutics reported long-term survival data in group 1 (bevaci‐ zumab-naive patients randomized to receive either RINTEGA or a control injection of KLH in a blinded fashion; all patients also received bevacizumab) at the Society for Neuro-Oncology Annual Meeting. At two years, the survival rate was 25% for patients in the RINTEGA arm versus 0% for patients in the control arm, with continuing advantage shown across multiple

The pathological angiogenesis of glioblastomas is a hallmark of the disease process, with multiple mechanisms hypothesized, including the transdifferentiation of tumor cells into endothelial cells, vascular mimicry, and vessel co-opting [27]. Tumor angiogenesis has been shown to be associated with the recruitment of hematopoietic and circulating precursor cells

The VEGF (vascular endothelial growth factor) pathway is highly expressed in glioma angiogenesis with overexpression of VEGF-A. There have been a multitude of factors identified to propagate and inhibit the VEGF pathway, including hypoxia inducible angio‐ genic factors, and endogenous factors like placenta growth factor. The anti-VEGF/VEGR compounds inhibit the proliferation of endothelial cells and neoangeogenesis, with a corre‐ sponding decrease in the permeability of the blood–brain barrier. Within 48 hours of anti-VEGF-A therapy with bevacizumab (Avastin®), there is decreased contrast enhancement, which may be misleading and hence to be read as a pseudoresponse. In contrast the T2/FLAIR progression is seen on serial radiological imaging, which has been postulated to be a nonan‐ giogenic invasive growth pattern and the likelihood of T2 progress predicting subsequent T1 and in turn tumor progression [14, 29]. Hence, our above discussion on RANO criteria will be called upon here to be borne in mind while analysing the imaging characteristics of patients

Bevacizumab (Avastin®) is the antibody to VEGF-A which has been utilized in Phase I, II and III trials to investigate its role in both newly diagnosed and recurrent glioblastoma. Of note, the AVAglio (Avastin® in Glioblastoma) study was undertaken in a for newly diagnosed glioblastoma patients in a randomized manner (bevacizumab versus placebo) with doubleblinding. Postsurgical resection, the patients were commenced on the Stupp protocol (concurrent radiotherapy 2 Gy 5 days a week and temozolomide 75 mg/kg) in combination with intravenous bevacizumab 10 mg/kg (or placebo) every fortnight. After a 28-day treat‐ ment break, the patients were commenced on a maintenance dose of temozolomide (150– 200 mg/kg) and fortnightly intravenous bevacizumab (10 mg/kg) or placebo for 6 weeks. This was followed by bevacizumab (10 mg/kg) every three weeks as monotherapy. The patients were assessed clinically at predetermined, regular time points. The results of the AVAglio study echoed those of the Phase III Radiation Therapy Oncology Group (RTOG-0825) with

endpoints [26].

274 Neurooncology - Newer Developments

[28].

**6. Anti-angiogenic treatments**

on antiangiogenic therapy.

Glioma virus therapies are broadly divided into two categories. Replication-deficient viral vectors to be used as delivery vehicles for therapeutic, antitumor genes. Second, are the replication-competent oncolytic viruses that target, infect, and replicate within the host glioma cell with the intent of destroying the tumor host cells with progeny particle release [36, 37]. The two viruses studied most widely are the adenovirus and herpes simplex (HSV-1) virus. There are double-stranded DNA viruses, whereby extensive modification may be carried out

in order for the virus vectors to carry the therapeutic genes under investigation [36]. While there are multiple Phase I and II clinical trials underway (clinicaltrials.gov), an impetus remains on the parallel to streamline the efficacy of these viruses to ensure the potency of the viral vectors without overtly impairing the host immune system response (may want to note that the mechanism of some of these virus such as the Duke polio virus may be by immune system induction). Convection enhanced delivery using continuous, positive pressure bulk flow of the therapeutic virus to the glioma may be undertaken to improve delivery [38, 39]. Specificity may be enhanced for viral entry into the glioma on modification of attachmentmediating surface proteins and chimeric capsids [25]. Of most interest, are the viral genes being engineered to be enhanced using hypoxia-responsive promoters in areas of low-hypoxia, a known glioma phenotype [37, 39].

Of note is the Toca511 trial, with an estimated completion date of November 2017. This is a multicenter, randomized, Open label Phase II/III study of Toca 511 and Toca FC versus standard of care. This comprises investigator's choice of single-agent chemotherapy (lomus‐ tine or temozolomide) or bevacizumab administered to patients with recurrent high-grade gliomas. Toca 511 (vocimagene amiretrorepvec) is an investigational injectable retroviral replicating vector (RRV) encoding a yeast-derived prodrug activator enzyme, cytosine deaminase (CD). Toca 511 selectively infects and spreads through the high-grade glioma cells, thereby delivering the CD gene and the tumor cells can then produce the CD enzyme.

Toca FC is an orally administered, extended-release version of prodrug 5-fluorocytosine (5- FC) which is absorbed and carried through the bloodstream. This crosses the blood–brain barrier and is then converted by the CD enzyme into the active 5-FU, at high concentrations within the glioma cells infected by Toca 511. 5-FU in turn causes tumor cell apoptosis and activation of the immune system by the release of tumor-associated antigens and viral proteins from the dying cells. We look forward to the results of this retroviral replicating vector against high-grade gliomas and the possible extrapolation to other solid cancers.
