**11. Interferons**

Existent evidence, shows that recombinant interferon-α (INF-α) is a biologic agent able to inhibit DNA synthesis, it binds to the interferon-a/b receptor and is involved in cell resistance to viral infection [64]. In 1991 in vitro studies also reported that interferon-alpha inhibits tumor cells growth [158].

In 1997 Kaba et al., reported a minor reduction of tumor size in one patient and a stable disease that lasted up to 14 months in four of six patients with recurrent unresectable meningioma who received INF-α 2b [159]. Other study in 2001, reported a stable disease that lasted up to eight years in nine of twelve patients treated with INF-α [160]. In 2008 Chamberlain and Glantz, reported in a phase II study that 26 of 35 patients that received treatment with INF-α demonstrated stable disease after the first 3 cycles and that 9 patients developed progressive disease. Additionally, a PFS rate was 54% at 6 months and 31% at 12 months were reported, median time to tumor progression was 7 months and median survival was 8 months. Furthermore, no patient demonstrated neuroradiographic complete or partial response, fatigue, anemia and leukopenia were the most common toxicities but overall, the drug was safe. A limitation form this study is that it was conducted only in patients with refractory grade I meningiomas [161]. Currently, these options are used as therapy for recurrent meningiomas or progression following surgery and radiation. It is also used for meningiomas that no respond to standard treatment options. Nevertheless, evidence that supports the use of interferons for meningiomas is poor.

### **12. Oncolytic virus**

Oncolytic viruses are biologic anti-tumor agents that selectively kill tumor cells leaving non tumoral cells intact [63]. A lot of oncolytic viruses have been investigated in different clinical trials, however no clinical trials have been conducted in meningiomas [162].

There are a few preclinical trials conducted in meningioma models. In 2005 Grill et al. evaluated the efficacy of conditionally replicating adenovirus (Ad) for oncolysis of meningiomas of 12 patients. Four different Ads were constructed and tested on meningioma cells and spheroids: Ad with an E1ACR2 deletion (Ad.d24), Ad with complete E1 region (Ad.E1+), Ad encoding the luciferase marker gene (Ad.Luc) and Ad encoding the luciferase gene in the E3 region (Ad.E1Luc). They demonstrated replication of adenovirus and oncolysis in primary cell cultures of meningioma cells at high dose (greater than 50 plaque-forming units per cell). Additionally, they also reported that at a lower dose (5 plaque-forming units per cell), Ad.d24 kills meningioma cells more efficiently than Ad.E1+ in benign, atypical, and malignant meningiomas [163].

Herpes virus it has a large dsDNA with more than 30 kb making the virus encoding for nonessential genes, this feature allows for genetic manipulation. Additionally, herpesviruses have a good safety profile, because they replicate in the nucleus without causing insertional mutagenesis [164].

In 1992, Market et al. added thymidine kinase-negative herpes simplex-I mutant virus, d/sptk, to meningioma cell cultures. They reported an antineoplastic effect against the malignant meningioma and significant tumor regressions [165]. In the study from Yazaki et al., reported that mutant herpes simplex virus (termed G207)

can replicate and kill cells from human malignant meningiomas in cell culture. They also reported tumor growth reduction in nude mice harboring human malignant meningioma [166]. Additionally, it is reported that efficacy of oncolytic herpes simplex viruses (HSV) as single agent is unsatisfactory; so in 2006 Liu et al. demonstrated that oncolytic HSV encoding dnFGFR enhances antitumor efficacy [167]. In 2016 Nigim et al., reported that G47∆, an oncolytic HSV derived from G207, was able to replicate and kill several human primary meningioma cultures in vitro. They also reported that this treatment prolonged survival, with 20% of mice surviving more than160 days. Furthermore, a lack of signs of encephalitic associated with G47∆ treatment was reported [168]. In 2018, they also reported that the mechanism of action of oHSV enables killing NF2 intact and mutant meningiomas and meningiomas that harbor other mutations [63].

Several studies have demonstrated the ability of oncolytic viruses to recruit T cells and induce immune responses against virus and tumor. Furthermore, some studies have demonstrated that oncolytic viruses combined with other cancer therapies, create synergistic effects in brain cancer treatment. Although many questions remain to be answered to fully exploit the therapeutic potential of oncolytic viruses against meningiomas [169].
