Clinical Trial Finder

Inclusion Criteria:

• - Diagnosis of.

• - High grade glioma (WHO grade III or IV), histologically verified.

• - Diffuse Intrinsic Pontine Glioma, verified by radiologic criteria (magnetic resonance imaging (MRI)) or by histology.

A biopsy is not required but recommended.

• - Aged ≥ 12 months and < 18 years at the time of signing the informed consent.

• - Body weight ≥ 10 kg.

• - Lansky score (for patients < 16 years) or Karnofsky score (for patients ≥ 16 years) of ≥ 50.

• - Reasonable life expectancy ≥ 8 weeks, as estimated by the treating physician.

• - Adequate hematological blood values and sufficient recovery from treatment-related toxicities (> grade 1) following previous anti-glioma treatments, as judged by the treating physician.

• - Written informed consent of parents or legal guardian.

Written informed consent of patients aged 12 years or older (written informed consent of patients younger than 12 years is optional).

• - Willing and able to comply with the protocol, as judged by the treating physician.

• - Female patients of child bearing potential must have a negative serum or urine pregnancy test at the time of screening.

Female patients of child bearing potential and male patients must agree to use effective contraception before, during and for at least hundred days after the last study treatment administration. Female subjects who are breastfeeding should discontinue nursing prior to the first dose of study treatment and until at least hundred days after the last study treatment administration.

Exclusion Criteria:

• - Use of any investigational agents ≤ 4 weeks before the planned day of leukapheresis.

• - Concomitant malignancy or history of another malignancy (unless the Investigator rationalizes otherwise) - Known concomitant presence of any active immunosuppressive disease (e.g. HIV) or any active autoimmune condition, except for vitiligo.

• - Any pre-existing contra-indication for contrast-enhanced MRI.

• - Pregnant or breastfeeding.

- Any other condition, either physical or psychological, or reasonable suspicion thereof on clinical or special investigation, which contraindicates the use of the vaccine, or may negatively affect patient compliance, or may place the patient at higher risk of potential treatment complications

1. Overview of the study treatment scheme. 1.1 Newly diagnosed HGG and DIPG patients (stratum A) Patients will be screened and registered in the study following diagnosis, which is based on either histological confirmation or radiographic criteria. Maximal safe resection prior to study entry is strongly recommended, but not required. Eligible patients will undergo leukapheresis prior to temozolomide-based chemoradiation and subsequent chemo-immunotherapy with maintenance temozolomide and autologous WT1 mRNA-loaded DC vaccination. Chemoradiation with subsequent maintenance temozolomide is considered best available treatment and therefore not considered investigational. The investigational treatment, i.e. adjuvant DC vaccination, is administered in 2 phases:

• - an induction phase, consisting of 3 weekly (-1 day, +2 days) DC vaccines, which is initiated after chemoradiation, but before maintenance temozolomide therapy, and.

• - a booster phase, consisting of 6 4-weekly (±3 days) DC vaccines, which are administered during temozolomide maintenance cycles.

1.2 Non-treatment naïve HGG and DIPG patients (stratum B) Patients who have undergone previous anti-glioma treatments can be included in the study, provided they are eligible according to the in- and exclusion criteria. The decision to start, continue or re-initiate conventional anti-glioma treatment, including radio- and/or chemotherapy, and, if applicable, the treatment dose and scheme, are at the Investigator's discretion. The backbone DC immunotherapy scheme for the induction and booster phase will be maintained with minor modifications:

• - during the induction phase, 3 DC vaccines will be administered on a weekly (-1 day, +2 days) basis.

• - during the booster phase, 6 DC vaccines will be administered at regular intervals.

It is recommended that the time between subsequent vaccinations is no longer than 4 weeks. 1.3 Continuation of DC vaccination. While the study treatment schedule consists of 9 DC vaccinations (i.e. 3 induction and 6 booster vaccines), continuation of DC vaccination after the booster phase is allowed, on the conditions that

• (1) the Investigator judges that the participant's clinical situation justifies additional vaccinations, (2) consent for continuation of DC vaccination of the parents/guardian and the participant (if aged 12 years or older) has been obtained, and (3) residual vaccine aliquots are available.

2. Response assessment. Disease evolution will be assessed radiologically according to the Response Assessment in Neuro-Oncology (RANO) criteria. In addition, blood samples will be collected for immunomonitoring purposes on the day of the first, fourth and seventh DC vaccine. Tumor resection or biopsy specimens, if available, will be used for local immunological and biomarker analysis. At regular time points throughout the study scheme, parents and participants will be asked to fill out questionnaires on general and disease-specific quality-of-life, as well as on executive function. 3. Follow-up. Patients will be followed-up until 90 days after administration of the final DC vaccine or 24 months after study entry, whichever occurs later.

Arms

Experimental: Stratum A (newly diagnosed)

Dendritic cell vaccination plus temozolomide-based chemoradiotherapy

Experimental: Stratum B (prior treatment)

Dendritic cell vaccination plus optional conventional anti-glioma treatment (in line with standard-of-care practice, at the investigator's discretion)

Interventions

Biological: - Dendritic cell vaccination + temozolomide-based chemoradiation

Leukocyte apheresis (before chemoradiation): for dendritic cell (DC) vaccine production. Chemoradiation (1st part standard treatment, initiated as soon as the patient's hematological blood values are adequate after apheresis, but no later than 6 weeks after surgery or confirmed diagnosis): 1.8 Gy once daily 5 days/week for 6 weeks with 90 mg/m² temozolomide daily from the first until the last day of radiotherapy. Induction immunotherapy: intradermal vaccination with autologous Wilms' tumor-1 (WT1) mRNA-loaded DCs weekly (-1 day, +2 days) for 3 weeks, starting ≥ 1 week after radiotherapy. Chemo-immunotherapy: 150-200 mg/m²/d temozolomide days 1-5 every 28 days +/- 3 days (max. 6 months, 2nd part standart treatment) starting ≥3 days after the third vaccine of the induction immunotherapy + DC vaccination on day 21±3 days of every 28-day cycle.

Biological: - Dendritic cell vaccination +- conventional next-line treatment

Leukocyte apheresis (upon recovery of hematological blood values following previous anti-glioma treatments and ≥ 4 weeks after the last dose of any investigational agent): for DC vaccine production. Induction immunotherapy: intradermal vaccination with autologous WT1 mRNA-loaded DCs weekly (-1 day, +2 days) for 3 weeks, starting ≥ 4 weeks after apheresis. Booster immunotherapy: 6 DC booster vaccinations administered at regular intervals (+- 4 weeks), starting ≥ 3 weeks after the last induction vaccine. (Optional) Concomitant conventional anti-glioma treatment: The decision to continue or re-initiate conventional anti-glioma treatment, and, if applicable, its dose and scheme, are at the Investigator's discretion and will depend on the patient's previous treatment scheme and condition.