A Phase I/II Clinical Trial on the Per-operative Intratumoral Administration of Myeloid Dendritic Cells Plus Ipilimumab and Nivolumab, Followed by Repeated Intracavitary Plus Intravenous Administration of Nivolumab in Patients With Recurrent Glioblastoma.

1. Subjects must have signed and dated an approved written informed consent form in accordance with regulatory and institutional guidelines. This must be obtained before the performance of any protocol related procedures that are not part of normal subject care
2. Subjects must be willing and able to comply with scheduled visits, treatment schedule, laboratory tests, tumor biopsies, and other requirements of the study.
3. Histopathological diagnosis of glioblastoma (= WHO grade IV glioma of the central nervous system); both patients with "de novo" and "secondary" glioblastoma are eligible; patients who have histological proof of a lower-grade glioma (WHO grade I, II or III) and have evidence for transformation to WHO-grade IV glioma on imaging of the brain (gadolinium enhancement, areas of necrosis) are eligible for study participation;
4. Diagnosis of glioblastoma recurrence and/or progression following prior treatment with surgery consisting of a total or partial tumor resection, radiation therapy and temozolomide chemotherapy (recurrence/progression is defined as significant \[according to the investigators assessment\] growth and/or recurrence of the glioblastoma tumor mass on sequential MRI of the brain);
5. The following disease characteristics should be present:

   1. Presence of a measurable tumor lesion that is characterized by gadolinium enhancement on T1-MRI of the brain (with a longest diameter of \> 10 mm and a perpendicular diameter of \>5mm).
   2. No evidence of clinically relevant spontaneous intra-tumor hemorrhage on baseline MRI imaging or in the prior disease history
6. No ventriculo-peritoneal drain
7. No contraindication for evaluation by gadolinium enhanced MRI, FET-PET of the brain or whole-body contrast enhanced CT;
8. ECOG performance status score of 0, 1 or 2;
9. An interval of at least 4 months (: 16 weeks) after the end of postoperative radiation therapy for glioblastoma unless progression is confirmed on an MRI of the brain obtained \> 4 week after the first observation of progression; and with an interval of at least 4 weeks after the last administration of temozolomide;
10. Male or female, 18 years of age or older;
11. Resolution of all acute treatment related adverse effects of prior surgical procedures, radiotherapy and temozolomide to NCI CTCAEv4.0 grade 0 or 1 except for alopecia;
12. Adequate organ function as defined by the following criteria:

    1. Total serum bilirubin \< 1.5 x ULN (patients with Gilbert's disease exempt who should have bilirubin \< 2x ULN)
    2. AST and ALT \< 2.5 x upper limit of normal (ULN);
    3. Serum creatinine ≤1.5 x ULN or calculated creatinine clearance ≥60 mL/min
    4. Absolute neutrophil count (ANC) \> 1500/mm³ without growth factor support
    5. Platelets \> 75 000 cells/mm³
    6. Hemoglobin ≥9 g/dL (which may be obtained by transfusion or growth factor support)
    7. FT4 hormone levels within normal range
13. No prior treatment on a nivolumab and/or ipilimumab trial;
14. No prior treatment with an anti-CTLA-4 or anti-PD-1/-L1 targeted therapy
15. No gastrointestinal abnormalities including:

    1. Inability to take oral medication.
    2. Requirement for intravenous alimentation.
    3. Prior surgical procedures affecting absorption including gastric resection.
    4. Treatment for active peptic ulcer disease in the past 6 months.
    5. Malabsorption syndromes.
    6. Active gastrointestinal bleeding, unrelated to cancer, as evidenced by hematemesis, hematochezia or melena in the past 3 months without evidence of resolution documented by endoscopy or colonoscopy;
16. No evidence of pre-existing uncontrolled hypertension as documented by baseline blood pressure reading. The baseline systolic blood pressure reading must be ≤140 mm Hg, and the baseline diastolic blood pressure readings must be ≤90 mm Hg. If baseline blood pressure reading exceeds the inclusion values a second blood pressure reading (taken at least 1 hour apart) must be documented in order to confirm the absence of uncontrolled hypertension. Patients whose hypertension is controlled by antihypertensive therapies are eligible;
17. No concurrent treatment:

    1. In another therapeutic clinical trial;
    2. No requirement for permanent therapeutic anticoagulation therapy.
18. Subjects with active, known, or suspected autoimmune disease are not eligible. Subjects with type I diabetes mellitus, residual hypothyroidism due to autoimmune thyroiditis only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment are permitted to enroll.
19. Subjects requiring systemic treatment with either corticosteroids (\> 8 mg daily methylprednisolone equivalent) or other immunosuppressive medications within 14 days of study enrollment. Inhaled or topical steroids are permitted in the absence of active autoimmune disease.
20. Adequate venous access to undergo a leukapheresis procedure.
21. No active uncontrolled seizure disorder.
22. No myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure or any unstable arrhythmia, cerebrovascular accident or transient ischemic attack, within the 12 months prior to study drug administration. No current or recent (within 1 month) use of a thrombolytic agent or a thrombo-embolic event;
23. No known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness;
24. No serious uncontrolled medical disorder or active infection that would impair their ability to receive study treatment;
25. No history of a malignancy (other than glioma) except those treated with curative intent for skin cancer (other than melanoma) or in situ breast or cervical cancer or those treated with curative intent for any other cancer with no evidence of disease for 5 years;
26. No other severe acute or chronic medical or psychiatric condition, or laboratory abnormality that would impart, in the judgment of the investigator, excess risk associated with study participation or study drug administration, or which, in the judgment of the investigator, would make the patient inappropriate for entry into this study;
27. No dementia or significantly altered mental status that would prohibit the understanding or rendering of informed consent and compliance with the requirements of this protocol;
28. Women of childbearing potential must have a negative serum or urine pregnancy test within 3 days prior to treatment.; Female patients must be surgically sterile or be postmenopausal, or must agree to use effective contraception measures during the period of therapy which should be continued for 12 weeks after the last dose of nivolumab. All female patients with reproductive potential must have a negative pregnancy test (serum or urine) prior to enrollment. Male patients must be surgically sterile or must agree to use effective contraception during the period of therapy. The definition of effective contraception will be based on the judgment of the principal investigator or a designated associate; No pregnancy or breastfeeding; a) No contra-indication for neurosurgical resection of the glioblastoma recurrence.