Childhood aggressive gliomas are rare brain tumors with very poor prognosis. Due to the tumor's location and infiltrative nature, surgical removal is not always possible, and even when resection is performed and combined with chemo- and/or radiotherapy, tumor cells frequently persist, eventually giving rise to tumor recurrence. A promising strategy to eradicate persisting tumor cells is vaccination with dendritic cells (DC). DC are immune cells that play an important role in organizing the body's defense against cancer. The goal of DC vaccination is to activate these natural anti-tumor defense mechanisms to delay or prevent tumor progression or recurrence. Previous clinical studies have demonstrated that DC vaccination is well-tolerated, safe and capable of eliciting tumorspecific immunity. A clinical study including 10 pediatric patients (aged ≥ 12 months and \< 18 years at the time of signing the informed consent) with brain (stem) tumors is initiated at the Antwerp University Hospital to investigate intradermal vaccination with WT1 mRNA-loaded autologous monocyte-derived DCs, either combined with first-line chemoradiation treatment or administered as adjuvant therapy following previous therapies. The general objective of this phase I/II clinical study is (1) to demonstrate that WT1-targeted DC vaccine production and administration in pediatric patients with HGG and DIPG, either combined with first-line chemoradiation treatment or administered as adjuvant therapy following previous therapies, is feasible and safe, (2) to study vaccine-induced immune responses, (3) to document patients' quality of life and clinical outcome for comparison with current patients' outcome allowing indication of the added value.
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.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
10
1. Leukocyte apheresis (before chemoradiation): for dendritic cell (DC) vaccine production. 2. 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. 3. 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. 4. 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.
1. 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. 2. Induction immunotherapy: intradermal vaccination with autologous WT1 mRNA-loaded DCs weekly (-1 day, +2 days) for 3 weeks, starting ≥ 4 weeks after apheresis. 3. Booster immunotherapy: 6 DC booster vaccinations administered at regular intervals (+- 4 weeks), starting ≥ 3 weeks after the last induction vaccine. 4. (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.
Unitversity Hospital Antwerp
Edegem, Belgium
Feasibility of leukapheresis in pediatric patients with HGG and DIPG
Proportion of patients in the intention-to-treat (ITT) population that had successful leukapheresis
Time frame: Vaccine production and quality testing (i.e. from leukapheresis until 4 weeks after)
Feasibility of WT1-targeted DC vaccine production
Proportion of patients in the ITT population that had successful vaccine production (i.e. production of 9 or more vaccine doses meeting quality control requirements)
Time frame: Vaccine production and quality testing (i.e. from leukapheresis until 4 weeks after)
Feasibility of DC vaccine administration in pediatric patients with HGG and DIPG (administration of 1st vaccine)
Proportion of efficacy evaluable patients (i.e. having received at least 1 vaccine + no major protocol violation) in the intention-to-treat (ITT) population
Time frame: At the administration of the 1st vaccine (i.e. +- 2 months after leukapheresis)
Feasibility of DC vaccine administration in pediatric patients with HGG and DIPG according to the study treatment schedule
Proportion of patients in the ITT population who completed the study treatment (i.e. from leukapheresis until administration of the 9th vaccine)
Time frame: Study treatment scheme (i.e. from leukapheresis to administration of the 9th vaccine, +- 34 weeks)
Safety of DC vaccine administration in pediatric patients with HGG and DIPG: Related (Severe) Adverse Events ((S)AEs)
Proportion of patients of the safety population that experienced (S)AEs possibly, probably or definitely related to DC vaccination
Time frame: over the entire study duration (i.e. from inclusion to end of follow-up, which lasts until 90 days after the last DC vaccine, or 24 months after inclusion, whichever occurs later)
Safety of DC vaccine administration in pediatric patients with HGG and DIPG: total (S)AEs (number)
Number of (S)AEs in the safety population (i.e. having received at least 1 DC vaccine)
Time frame: over the entire study duration (i.e. from inclusion to end of follow-up, which lasts until 90 days after the last DC vaccine, or 24 months after inclusion, whichever occurs later)
Safety of DC vaccine administration in pediatric patients with HGG and DIPG: total (S)AEs (grade)
Grade of (S)AEs in the safety population
Time frame: over the entire study duration (i.e. from inclusion to end of follow-up, which lasts until 90 days after the last DC vaccine, or 24 months after inclusion, whichever occurs later)
Indicators of clinical efficacy: Best overall response (BOR)
BOR will be determined per patient as the best response designation over the study, based on radiologic RANO criteria. The response categories are: complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD).
Time frame: over the entire study duration (i.e. from inclusion to end of follow-up, which lasts until 90 days after the last DC vaccine, or 24 months after inclusion, whichever occurs later).
Indicators of clinical efficacy: Progression-free survival (PFS)
PFS is defined as the time (in months) between diagnosis/study entry and the date of progression (recurrence in the case of total resection) or death due to any cause, whichever occurs first.
Time frame: over the entire study duration (i.e. from inclusion to end of follow-up, which lasts until 90 days after the last DC vaccine, or 24 months after inclusion, whichever occurs later). PFS may be updated after study completion.
Indicators of clinical efficacy: Overall survival (OS)
OS is defined as the time (in months) between diagnosis/study entry and death due to any cause.
Time frame: over the entire study duration (i.e. from inclusion to end of follow-up, which lasts until 90 days after the last DC vaccine, or 24 months after inclusion, whichever occurs later). OS may be updated after study completion.
Immunogenicity of vaccination with WT1-targeted DC in pediatric patients with HGG and DIPG: occurrence of WT1-specfic CD8+ T cells
Occurrence of WT1-specific CD8+ T cells as assessed by tetramer staining (% positive cells)
Time frame: On the day of the 1st (about 2 months after leukapheresis), 4th (about 3 months after leukapheresis) and 7th DC vaccine (about 6 months after leukapheresis)
Immunogenicity of vaccination with WT1-targeted DC in pediatric patients with HGG and DIPG: occurrence of WT1-specfic CD8+ T cells
Occurrence of WT1-specific CD8+ T cells as assessed by TCR sequencing
Time frame: On the day of the 1st (about 2 months after leukapheresis), 4th (about 3 months after leukapheresis) and 7th DC vaccine (about 6 months after leukapheresis)
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Immunogenicity of vaccination with WT1-targeted DC in pediatric patients with HGG and DIPG: Functional WT1-specific T cell responses
Functional WT1-specific T cell responses as assessed by multiparametric flow cytometry following antigen-specific stimulation (% positive cells)
Time frame: On the day of the 1st (about 2 months after leukapheresis), 4th (about 3 months after leukapheresis) and 7th DC vaccine (about 6 months after leukapheresis)
Evaluation of changes in quality of life: How patients experience different phases of the study treatment schedule
PedsQL Generic core scale and PedsQL Cancer Module. Higher scores indicate better health-related quality of life/lower problems.
Time frame: over the entire study duration (i.e. from inclusion to end of follow-up, which lasts until 90 days after the last DC vaccine, or 24 months after inclusion, whichever occurs later)
Evaluation of changes in quality of life: How patient- and proxy-reported disease-related symptoms evolve over time during the study
PedsQL Cancer Module. Higher scores indicate lower problems.
Time frame: over the entire study duration (i.e. from inclusion to end of follow-up, which lasts until 90 days after the last DC vaccine, or 24 months after inclusion, whichever occurs later)
Evaluation of changes in quality of life: How patient- and proxy-reported general quality of life evolves over time during the study
PedsQL Generic core scale. Higher scores indicate better health-related quality of life.
Time frame: over the entire study duration (i.e. from inclusion to end of follow-up, which lasts until 90 days after the last DC vaccine, or 24 months after inclusion, whichever occurs later)