This research study is a Phase I clinical trial, which tests the safety of an investigational drug and also tries to define the appropriate dose of the investigational drug as a possible treatment for this diagnosis. "Investigational" means that the intervention is being studied.

The FDA (the U.S. Food and Drug Administration) has not approved rQNestin34.5v.2 as a treatment for any disease. This is the first time that rQnestin34.5v.2 will be given to humans.

The research drug, rQNestin34.5v.2, is made from the herpes simplex virus type 1 (HSV1). The large majority of humans already have regular HSV1 in their nervous system. Normally, this virus can cause cold sores in areas like the lips, fingers and genitals in humans by making copies of itself in normal healthy cells. In some cases, HSV1 can cause severe infection of the brain and liver and/or death. However, scientists have removed or changed parts of the rQNestin virus being used on this study so it can only make copies of itself in glioma cells and not normal healthy cells.

If it is effective, the rQNestin34.5v.2 drug will spread to a glioma cell, kill it, and then make a copy of itself and spread again. This should be repeated over and over until all glioma cells are reached. If rQNestin34.5v.2 moves into a normal brain cell, it should not grow and make copies, and therefore should not spread to other normal brain cells.

The purpose of this research study is to test if rQnestin34.5v.2 is safe to use in humans, and if it is effective in treating malignant glioma. This study is also looking for the highest dose of rQNestin34.5v.2 that can be given safely to people with malignant brain tumors.

Inclusion Criteria:

• At the time of surgery, frozen biopsy confirmation of high grade or malignant glioma by neuropathologist. To be confirmed at time of surgery, after registration in OnCore.
• Participants must have prior diagnosis of glioma (astrocytoma, malignant astrocytoma, oligodendroglioma, anaplastic oligodendroglioma, mixed oligo-astrocytoma), exclusive of ependymoma, ganglioglioma, pylocytic/pylomyxoid astrocytoma as confirmed by a neuropathologist or by a previous local pathology report.
• Prior history of external beam radiotherapy ≥ 5,000 cGy delivered to the tumor at least 4 weeks prior to QACT registration;
• Prior history of temozolomide chemotherapy provided concurrent to external beam radiotherapy and after as per current standard of care. At least 8 weeks must have passed from the last dose of temozolomide and first dose of cyclophosphamide and/or rQNestin34.5v.2;
• If participant was treated with bevacizumab, at least 4 weeks must elapse before treatment with either agent (Cyclophosphamide or rQNestin34.5v.2);
• Recurrent lesion must be ≥ 1.0 cm in diameter as determined by MRI;
• Normal hematological, renal and liver function as defined below: Leukocytes ≥3,000/mcL; Absolute lymphocyte count > 800/ mcL; Absolute neutrophil count ≥1,500/mcL; platelets ≥100,000/mcL; PT or PTT <1.5 x institutional upper limit; Hemoglobin >10.0 g/dL; Total serum bilirubin within normal institutional limits; AST(SGOT)/ALT(SGPT) ≤2.5 × institutional upper limit of normal; Serum creatinine within normal institutional limits OR Creatinine clearance ≥60 mL/min/1.73 m2 for participants with creatinine levels above institutional normal;
• Karnofsky Performance Score ≥70.
• Age≥ 18 years;
• Ability to understand and the willingness to sign a written informed consent document;
• The effects of rQNestin34.5v.2 and cyclophosphamide on the developing human fetus are unknown. For this reason and because cytotoxic & immunomodulating agents as well as other therapeutic agents used in this trial are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation including 3 months following the study. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study and for the duration of study participation including 3 months following the study. Women of child-bearing potential must have a negative serum pregnancy test within 48 hours of study registration.
• Steroid regimen stable or decreasing for at least 7 days prior to inoculation;
• Ability to undergo MRI scanning with contrast;
• Subjects with any recurrence (first, second, third, etc recurrence) will be able to be enrolled.

Exclusion Criteria:

Participants who exhibit any of the following conditions prior to initiating study treatment will not be eligible for this study:

• Participants with significant renal or liver disease
• Participants with progressive systemic malignancy.
• Known chronic infections with HIV, hepatitis B or C; participants with a history of resolved Hepatitis A may be included in the trial.
• Participants with active viral, bacterial or fungal infection requiring concurrent antiviral or antibiotics.
• Subjects with active HSV1 infection on current valacyclovir, acyclovir or ganciclovir therapy must be off treatment with any of these agents at least 7 days prior to surgery.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to cyclophosphamide (only for arm B).
• Active, known, or suspected immunosuppressive disorders, such as acquired or congenital immune deficiency syndromes and autoimmune diseases
• Unacceptable anesthesia risk
• Serious cardiopulmonary medical condition
• Pregnant or lactating females
• Recurrent glioma where injection in either arm A or B of the biologic agent would require access and/or considerable spillage into the ventricular system.
• Prior participant in another protocol using an investigational agent or device within 6 weeks of the first dose of rQNestin34.5v.2.
• Known HIV seropositivity.
• Concurrent therapy with drugs active against HSV (acyclovir, valaciclovir, penciclovir, famciclovir, ganciclovir, foscarnet, cidofovir). Participants must be off treatment with these agents for at least 7 days prior to surgery.
• Active oral or genital herpes lesions.
• Participants who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier.
• Participants who are receiving any other investigational agents.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• Participants with tumor ≤ 1 cm proximity to the ventricles will be excluded. This criterion is only applicable for the initial 6 subjects enrolled to study. After 6 subjects have been successfully enrolled, participants with tumor ≤ 1 cm proximity to the ventricles will be allowed to enroll however the study agent (rQNestin34.5v.2) may not be injected in any area that is within 1 cm of the ventricle regardless of where the tumor is located.