This phase I/II trials evaluates the feasibility, safety and efficacy of an individualized
cancer vaccine, based on autologous, tumor-lysate loaded dendritic cells in children and
adolescents with relapsed high-grade gliomas. In addition, regulatory T cells are depleted by
a short cycle of metronomic cyclophosphamide upfront of the vaccine in order to facilitate
induction of immune responses.
Therapeutic DC vaccines are followed by four cycles of Nivo/Ipi double checkpoint blockade
and a Nivolumab monotherapy maintenance in order to optimize the induced T-cell response.
Relapsed high-grade gliomas (in the following addressed as high-grade gliomas = HGG) in
children and adolescents represent a very bad prognosis group for which a recommended
standard salvage therapy is currently not available.
Combination of Dendritic Cell (DC) vaccination, metronomic cyclophosphamide, and checkpoint
blockade will be investigated in the present trial as a new treatment strategy for these
patients: metronomic cyclophosphamide has been shown to significantly reduce numbers of
regulatory T cells (Treg) without inducing general leukopenia. DCs might induce
tumour-directed immune responses thereby facilitating long-term remissions. Efficacy of
primed T-cell responses by the vaccine will potentially be enhanced by the application of
checkpoint inhibitors Nivolumab (antiPD-L1) and Ipilimumab (antiCTLA4) in the post-vaccine
phase and during maintenance.
Cyclophosphamide is an established drug used as an anti-cancer or immunosuppressive substance
since decades, with extensive experience when used in low, non-myeloablative dosages. DCs
represent an innovative new strategy in cellular immunotherapy. DCs in cancer patients have
been used in a number of smaller studies, and in some of these trials, promising results
could be obtained. Several studies showed a trend towards a prolonged overall survival with a
few long-term survivors which is otherwise extremely rare in this high-risk population.
Results seemed to be more favourable in pediatric than in adult patients. Checkpoint
inhibitors (antiPD-L1 and/or antiCTLA4) have been shown to exhibit synergistic effects with
vaccines in preclinical models, and prelimnary data of several early stage trials have shown
promising results. Therefore, our study aims to improve the efficacy of a DC-based
therapeutic vaccine by optimizing the conditions upfront of the vaccine (Treg depletion) and
improving T-cell responses by checkpoint blockade after the vaccine in the effector phase.
In conclusion, this study will exploit the optimal efficacy of a therapeutic vaccine in
children and adolescents 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.
