GMCI, Nivolumab, and Radiation Therapy in Treating Patients With Newly Diagnosed High-Grade Gliomas

Inclusion Criteria:

* Patients must have operable brain tumor presumed to be high grade glioma (HGG) based on clinical and radiologic evaluation, where a gross total surgical resection of the contrast-enhancing area is intended; pathologic confirmation of HGG must be made at the time of surgery prior to AdV-tk injection, if not previously determined
* Patients must have a Karnofsky performance status \>= 70% (i.e. the patient must be able to care for himself/herself with occasional help from others)
* Absolute neutrophil count \>= 1,500/uL
* Platelets \>= 100,000/uL
* Hemoglobin \>= 9 g/dL
* Total bilirubin =\< 1.5 x institutional upper limit of normal (ULN), (except for patients with known Gilbert's syndrome who must have normal direct bilirubin)
* Aspartate aminotransferase (AST) serum glutamic-oxaloacetic transaminase (SGOT)/alanine aminotransaminase (ALT) serum glutamate pyruvate transaminase (SGPT) =\< 3.0 x institutional ULN
* Creatinine =\< institutional ULN
* Calculated creatinine clearance \>= 40 ml/min (use a modified Cockcroft-Gault equation)
* Activated partial thromboplastin time/partial thromboplastin time (APTT/PTT) =\< 1.5 x institutional ULN
* Patients must be able to provide written informed consent
* Patients must have magnetic resonance imaging (MRI) within 14 days of starting treatment; patients must be able to tolerate MRI
* Women of childbearing potential must agree to have a negative serum pregnancy test within 24 hours prior to treatment start; women of childbearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study treatment, and through at least 5 months after the last dose of study drug; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately; sexually active men of reproductive potential who are partners of women with reproductive potential must also agree to use adequate contraception prior to the study, for the duration of study participation, and through at least 7 months after the last dose of study drug; adequate methods of effective birth control include sexual abstinence (men, women); vasectomy; or a condom with spermicide (men) in combination with barrier methods, hormonal birth control or intrauterine device (IUD) (women)
* Patients must have no concurrent malignancy except curatively treated basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix, breast, or bladder; patients with prior malignancies must be disease-free for \>= two years; patients with low-risk prostate cancer on active surveillance are eligible
* Patients must be able to swallow oral medications
* Patients must not have received prior radiation therapy, chemotherapy, immunotherapy or therapy with biologic agent (including immunotoxins, immunoconjugates, antisense, peptide receptor antagonists, interferons, interleukins, tumor infiltrating lymphocyte \[TIL\], lymphokine-activated killer \[LAK\] or gene therapy), or hormonal therapy for their brain tumor; glucocorticoid therapy is allowed

Exclusion Criteria:

* Patients receiving any other investigational agents are ineligible
* Patients with a history of hypersensitivity or allergic reactions attributed to compounds of similar chemical or biologic composition to valacyclovir, acyclovir, or temozolomide are ineligible; the valacyclovir and temozolomide package inserts can be referenced for more information
* Patients with a history of severe hypersensitivity reaction to any monoclonal antibody are ineligible
* Patients who require therapy with systemic immunosuppressive drugs except corticosteroids are ineligible
* Patients with a history of active autoimmune disease requiring treatment in the past 2 years are ineligible
* Patients with uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, active liver disease or active hepatitis, or psychiatric illness/social situations that would limit compliance with study requirements, are ineligible
* Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with these agents through 1 week after receiving the last dose of study drugs
* Patients who are known to be human immunodeficiency virus (HIV) positive are ineligible