Autologous Dendritic Cells, Metronomic Cyclophosphamide and Checkpoint Blockade in Children With Relapsed HGG

Inclusion Criteria:

1. Diagnosis of relapsed high-grade malignant glioma confirmed by central neuropathological and neuroradiological review (last magnetic resonance imaging diagnosis not older than 4 weeks) - including glioblastoma multiforme (WHO IV), anaplastic astrocytoma World Health Organization (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) relapsed after first-line therapy.
2. Patients aged 3 years and older but under 21 years at time of relapse diagnosis
3. Written informed consent of the patient (mandatory from 14 years of age) or the parents (mandatory till 18 years of age).
4. Prospect of resection of relapse tumour by neurosurgery (total, subtotal or partial)

Exclusion Criteria:

1. Known hypersensitivity or contraindication to cyclophosphamide
2. Known hypersensitivity or contraindications to Nivolumab or Ipilimumab.
3. Other malignancies, either simultaneous or within the last 2 years
4. Active, known or suspected autoimmune disease. Participants with type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll.
5. Pregnancy and / or lactation
6. Patients who are sexually active refusing to use effective contraception (oral contraception, intrauterine devices, barrier method of contraception in conjunction with spermicidal jelly or surgical sterile)
7. Current or recent (within 4 weeks prior to start of trial treatment) treatment with another investigational drug or participation in another investigational trial
8. Severe concomitant diseases (e.g. immune deficiency syndrome)
9. Severe psychological disease or neurological damage without possibility to communicate
10. Clinical signs of intracranial pressure
11. Intracerebral hemorrhage, gliomatosis
12. No severe blood count abnormalities: leukocytes \< 2.000/µl, Hb \<10 g/dl, thrombocytes \< 100.000/µl
13. No severe liver enzyme elevation (\> 2-3x fold of normal)
14. Ongoing reirradiation or chemotherapy (within the last 4 weeks) (irradiation of formerly non-involved fields is allowed, but not part of this study)
15. Estimated life expectancy of less than 2 months
16. Preexisting severe cardiac disease
17. Presence of unresectable spinal metastases
18. Karnofsky index \< 50%
19. Active infection within the last 2 weeks
20. Previous infection with Human Immunodeficiency, Hepatitis C, Human T-Lymphocyte 1/2, Hepatitis B Virus, Lues, protozoan parasites, or other chronic bacterial infections.
21. With regard to prevention of variant Creutzfeldt-Jakob disease the following patients have to be excluded.
22. Patients receiving systemic immunosuppressive or immunoactivating substances.