Patients will be randomized to one of two treatment arms - Group I and Group II. Group I will receive nivolumab monotherapy until surgical resection, and Group II will receive nivolumab alone and with DC vaccine therapy until surgical resection. During surgical resection blood and tumor samples will be assessed and compared. Following surgery, both groups will continue to receive DC vaccines (total of 8) and nivolumab therapy until confirmed progression.

This two-arm randomized trial will evaluate the safety of nivolumab in combination with DC vaccinations for the treatment of bevacizumab-naïve subjects with first or second recurrent, resectable World Health Organization (WHO) Grade III and IV malignant gliomas (MGs). Up to 66 patients will be enrolled and treated with the goal of accruing 30 patients (15 per arm) that will receive nivolumab and at least 3 vaccines. After enrollment, leukapheresis will be done for generation of DC vaccines and immunologic monitoring. All subjects will undergo standard of care tetanus booster vaccination with 0.5 mL of Td (tetanus and diphtheria toxoids adsorbed) intramuscularly (I.M.) into the deltoid muscle to ensure adequate immunity to the tetanus antigen. Subjects will initially return every 2 weeks and receive approximately 3 infusions of nivolumab 3 mg/kg IV while the DC vaccines are being prepared from the initial leukapheresis and will then be randomized 1:1 to one of 2 arms (Group I: nivolumab only pre-surgery; Group II: nivolumab with DC vaccines pre-surgery). Patients who are unable to tolerate nivolumab will be withdrawn from the study and replaced. Patients whose DCs or Peripheral Blood Lymphocytes (PBLs) fail to meet release criteria will continue to receive nivolumab only and will not undergo repeat leukapheresis. For patients whose leukapheresis yields less than 4 vaccines, a repeat leukapheresis may be obtained a minimum of 2 weeks from the previous leukapheresis (and may be repeated as needed) if stable. Peripheral blood will be drawn for immune monitoring prior to treatment with the 4th cycle of nivolumab (first post-randomization infusion of nivolumab).

Group I Treatment Plan (Nivolumab Only Pre-Surgery) After randomization, patients in Group I will receive nivolumab 3 mg/kg IV every 2 weeks x approximately 8 weeks. The subject will then undergo surgical resection of tumor within approximately 1-3 weeks. Approximately 2-4 weeks later, leukapheresis is repeated for generation of DC vaccines and immunologic monitoring. Approximately 1 day to 2 weeks after leukapheresis, the subject will resume nivolumab 3mg/kg IV every two weeks with DC vaccine administration intradermally (i.d.) for a total of 3 vaccines. At the time of the third DC vaccine, patients will receive vaccine site pre-conditioning. A single dose of Td toxoid (1 flocculation unit (Lf) in 0.4 milliliters (mL) of saline) will be administered to a single side of the groin i.d. (as described above for all vaccine administrations 12-24 hours prior to the third DC vaccine, which is always given bilaterally at the groin site. At the vaccine #3 visit, prior to vaccine # 3 administration, erythema and induration measurements will be taken of pre-conditioning site. Group I subjects will then receive monthly DC vaccine administrations intradermally for 5 months or until progression (whichever comes first).Total vaccines to be administered will be 8 post-surgery unless subject is removed. Nivolumab will continue until progression. At the clinic visit following the last vaccine (#8), subjects will have peripheral blood drawn for immune monitoring prior to infusion of nivolumab.

Group II Treatment Plan (Nivolumab with DC Vaccines Pre-Surgery) After randomization, patients in Group II will receive the fourth cycle of nivolumab then receive nivolumab 3 mg/kg IV along with DC vaccines intradermally every 2 weeks x approximately 6 weeks for a total of 3 vaccines. At the time of the third DC vaccine, patients will receive vaccine site pre-conditioning. A single dose of Td toxoid (1 Lf in 0.4 mL of saline) will be administered to a single side of the groin i.d. 12-24 hours before the third DC vaccine, which is always given bilaterally at the groin site. At the vaccine #3 visit, prior to vaccine #3 administration, erythema and induration measurements will be taken of pre-conditioning site.The subject will then undergo surgical resection of tumor within approximately 1-3 weeks. Approximately 2-4 weeks later, leukapheresis is repeated for generation of DC vaccines and immunologic monitoring. Approximately 1 day to 2 weeks after leukapheresis, the subject will resume nivolumab 3mg/kg IV every two weeks. When DC vaccines have completed processing and are available for administration, monthly DC vaccine administrations as described above will be administered for 5 months or until progression (whichever comes first). Total vaccines to be administered will be 8 (3 pre- and 5 post-surgery) unless subject is removed. Nivolumab will continue until progression. At the clinic visit following the last vaccine (#8), subjects will have peripheral blood drawn for immune monitoring prior to infusion of nivolumab.

Inclusion Criteria:

• Age 18-80 years of age

• First or second recurrence of MG (WHO Grade III or IV glioma or astrocytoma) in surgically accessible areas with prior histologic diagnosis of MG

• Bevacizumab-naïve - no prior exposure to Bevacizumab

• Karnofsky Performance Status (KPS) of ≥ 70%

• Radiation Therapy (RT) with ≥ 45 Gray (Gy) tumor dose, completed ≥ 8 weeks prior to study entry

• Laboratory values must meet the following criteria:

  1. White Blood Count (WBC) ≥ 2000/microliters (uL)
  2. Neutrophils ≥ 1500/uL
  3. Platelets ≥ 100x103/uL
  4. Hemoglobin ≥ 9.0 g/dL
  5. Serum creatinine ≤ 1.5x the upper limit of normal (ULN) or creatinine clearance (CrCl)≥ 40 mL/min (using the Cockcroft-Gault formula) c. Female CrCl = (140 - age in years) x weight in kg x 0.85 /72 x serum creatinine in mg/dL d. Male CrCl = (140 - age in years) x weight in kg x 1.00/72 x serum creatinine in mg/dL
  6. Aspartate Aminotransferase (AST) ≤ 3x ULN
  7. Alanine Aminotransferase (ALT) ≤ 3x ULN
  8. Bilirubin≤ 1.5x ULN (except subjects with Gilbert Syndrome, who can have total bilirubin < 3.0 mg/dL)
  9. Subjects must have resting baseline O2 saturation by pulse oximetry of ≥ 92% at rest.

• Patients of child bearing potential or with partners of child-bearing potential must practice recommended contraceptive methods to prevent pregnancy during treatment and for 5 months after the last dose of nivolumab for women, 7 months after the last dose of nivolumab for men, and for 6 months after the last dose of bevacizumab for subjects receiving bevacizumab.

Exclusion Criteria:

• Contrast-enhancing tumor component crossing the midline, multi-focal tumor, or tumor dissemination (subependymal or leptomeningeal)
• Clinically significant increased intracranial pressure (e.g., impending herniation), uncontrolled seizures, or requirement for immediate palliative treatment
• Pregnant or need to breast feed during the study period (Negative human chorionic gonadotropin (β-HCG) test required), or unable to maintain use of contraception while on study and for 31 weeks after the last dose of nivolumab
• Active infection requiring treatment or an unexplained febrile (> 101.5o F) illness
• Known immunosuppressive disease, autoimmune disease or human immunodeficiency virus infection, Hepatitis B or Hepatitis C
• Known allergy or hypersensitivity to tetanus, or any other tetanus or diphtheria toxoid-containing vaccine, or any component of this vaccine (i.e., aluminum phosphate, formaldehyde)
• Known severe (Grade 3 or 4) infusion-related allergy or hypersensitivity to any monoclonal antibody
• Previous radiation therapy with anything other than standard radiation therapy (such as previous stereotactic radiosurgery) or previous treatment with an immune checkpoint inhibitor (i.e., nivolumab, pembrolizumab, ipilimumab)
• Unstable or severe intercurrent medical conditions such as severe heart (New York Association Class 3 or 4) or lung (FEV1 < 50%) disease, uncontrolled diabetes mellitus
• Corticosteroid use > 4 mg/day at time of consent
• Prior inguinal lymph node dissection.

12 months