HIT-HGG Rez Immunovac

To evaluate the efficacy of combined treatment with metronomic oral cyclophosphamide, autologous pulsed dendritic cells from tumor lysate and dual checkpoint blockade as measured by 6-month overall survival (OS) after tumor resection in children and adolescents with recurrent high-grade malignant glioma.

Patients participating in the study will receive
- Cyclophosphamide 100 mg p.o. per day, divided into two doses perioperatively (1.5 mg/kg/d, max. 100 mg) until the day before vaccination.
- unstimulated leukapheresis 7-10 days after discontinuation of perioperative steroids
- 4 intradermal injections of 2-20x106 DCs into the skin prepared with imiquimod at weekly intervals, starting on day 9 after leukapheresis
- Tumor lysate boost injections intradermally 3 times a month and then every three months until the lysate reserves are depleted.
- Nivolumab 3 mg/kg plus ipilimumab 1 mg/kg, every 3 weeks for 4 doses, followed by nivolumab 6 mg/kg every 4 weeks (max. 480 mg).

• The diagnosis of recurrent high-grade malignant glioma was confirmed by central neuropathologic and neuroradiologic examination (last MRI diagnosis not older than 4 weeks) - including glioblastoma multiforme (WHO IV), anaplastic astrocytoma (WHO III), anaplastic oligodendroglioma (WHO III), anaplastic oligoastrocytoma (WHO III), anaplastic pilocytic astrocytoma (WHO III), anaplastic ganglioglioma (WHO III), anaplastic pleomorphic xanthoastrocytoma (analogous to WHO III), giant cell glioblastoma (WHO IV) and gliosarcoma (WHO IV) who have suffered a relapse after first-line therapy.
• Patients who were 3 years and older but under 21 years of age at the time of relapse diagnosis
• Diagnosis of relapse
• Written informed consent from the patient (mandatory from the age of 14) or the parents (mandatory up to the age of 18).
• Prospect of resection of the recurrent tumor by neurosurgery (total, subtotal or partial)

• Known hypersensitivity or contraindication to cyclophosphamide
• Known hypersensitivity or contraindication to nivolumab or ipilimumab
• Other malignancies, either concurrent or within the last 2 years
• Active, known or suspected autoimmune disease
• Participants with type I diabetes mellitus, hypothyroidism requiring hormone replacement only
• Hypothyroidism requiring hormone replacement only, skin conditions (such as vitiligo, psoriasis or alopecia) that do not require systemic treatment, or conditions that are unlikely to recur without an external trigger are eligible to participate.
• Pregnancy and / or lactation
• Sexually active patients who refuse to use effective (oral contraception, intrauterine devices, barrier methods in conjunction with contraceptive methods in conjunction with spermicidal gel or surgical infertility)
• Current or recent (within 4 weeks prior to the start of study treatment)
• Treatment with another investigational product or participation in another clinical trial
• Severe concomitant disease (e.g. immunodeficiency syndrome) Severe mental illness or neurological impairment without ability to communicate
• Clinical signs of intracranial pressure
• Intracerebral hemorrhage, gliomatosis, midline shift
• No severe blood count abnormalities: leukocytes below 2,000/µl, Hb below10 g/dl, platelets below 100,000/µl
• No serious increase in liver enzymes (more than 2-3 times the normal value)
• Ongoing re-irradiation or chemotherapy (within the last 4 weeks) (irradiation of previously unaffected fields is (irradiation of previously unaffected fields is permitted but not part of this study)
• Estimated life expectancy of less than 2 months
• Pre-existing severe heart disease
• Presence of inoperable spinal metastasesKarnofsky/Lansky index below 50%
• Active infection within the last 2 weeks
• Previous infection with HIV, HCV, HTLV1/2, HBV (if not more than 5 years ago and alpha-HBs above 100 U/ml), Lues, protozoan parasites or other chronic bacterial infections.
• With regard to the prevention of variant Creutzfeldt-Jakob disease (vCJD), the following patients must be excluded: Patients who have lived in the UK for more than 6 months between 1980 and 1996,
• Patients with a personal or family history of vCJD, recipients of GH or TSH of human origin, recipients of dura mater or corneal transplants.
• Patients receiving systemic immunosuppressive or immune-activating agents.