Adjuvant Dendritic Cell Immunotherapy for Pediatric Patients With High-grade Glioma or Diffuse Intrinsic Pontine Glioma

NCT04911621 | Active Not Recruiting Phase 1 DMC

• 1 other identifier: CCRG19-002
• Study Type: interventional
• Target: 10
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

High Grade Glioma; Diffuse Intrinsic Pontine Glioma

Keywords

childhood glioma; dendritic cells; adjuvant therapy; immunotherapy; Wilms' tumor protein 1

Outcome Measures

Primary Outcomes (7)

• Feasibility of leukapheresis in pediatric patients with HGG and DIPG

  Proportion of patients in the intention-to-treat (ITT) population that had successful leukapheresis

  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)

  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

  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)

  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

  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)

  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

  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)

Secondary Outcomes (9)

• Indicators of clinical efficacy: Best overall response (BOR)

  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)

  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)

  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

  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

  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)

Other Outcomes (2)

• Biomarker identification

  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 executive function

  at baseline, upon completion of the study treatment scheme (i.e. after the 9th DC vaccine), at progression (if applicable) and 90 days after the final DC vaccine

Study Arms (2)

Stratum A (newly diagnosed)

EXPERIMENTAL

Dendritic cell vaccination plus temozolomide-based chemoradiotherapy

Biological: Dendritic cell vaccination + temozolomide-based chemoradiation

Stratum B (prior treatment)

EXPERIMENTAL

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

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

Interventions

Dendritic cell vaccination + temozolomide-based chemoradiation BIOLOGICAL

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.

Stratum A (newly diagnosed)

Dendritic cell vaccination +- conventional next-line treatment BIOLOGICAL

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.

Stratum B (prior treatment)

Eligibility Criteria

• Age: 12 Months - 17 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• University Hospital, Antwerp: lead
• Kom Op Tegen Kanker: collaborator
• Stichting Semmy: collaborator
• Olivia Hendrickx research Fund vzw: collaborator

Study Sites (1)

Unitversity Hospital Antwerp

Edegem, Belgium

Location

Related Publications (12)

• Van Tendeloo VF, Ponsaerts P, Lardon F, Nijs G, Lenjou M, Van Broeckhoven C, Van Bockstaele DR, Berneman ZN. Highly efficient gene delivery by mRNA electroporation in human hematopoietic cells: superiority to lipofection and passive pulsing of mRNA and to electroporation of plasmid cDNA for tumor antigen loading of dendritic cells. Blood. 2001 Jul 1;98(1):49-56. doi: 10.1182/blood.v98.1.49.

  PMID: 11418462 BACKGROUND

• Van Tendeloo VF, Van de Velde A, Van Driessche A, Cools N, Anguille S, Ladell K, Gostick E, Vermeulen K, Pieters K, Nijs G, Stein B, Smits EL, Schroyens WA, Gadisseur AP, Vrelust I, Jorens PG, Goossens H, de Vries IJ, Price DA, Oji Y, Oka Y, Sugiyama H, Berneman ZN. Induction of complete and molecular remissions in acute myeloid leukemia by Wilms' tumor 1 antigen-targeted dendritic cell vaccination. Proc Natl Acad Sci U S A. 2010 Aug 3;107(31):13824-9. doi: 10.1073/pnas.1008051107. Epub 2010 Jul 14.

  PMID: 20631300 BACKGROUND

• Benteyn D, Anguille S, Van Lint S, Heirman C, Van Nuffel AM, Corthals J, Ochsenreither S, Waelput W, Van Beneden K, Breckpot K, Van Tendeloo V, Thielemans K, Bonehill A. Design of an Optimized Wilms' Tumor 1 (WT1) mRNA Construct for Enhanced WT1 Expression and Improved Immunogenicity In Vitro and In Vivo. Mol Ther Nucleic Acids. 2013 Nov 19;2(11):e134. doi: 10.1038/mtna.2013.54.

  PMID: 24253259 BACKGROUND

• Van Driessche A, Berneman ZN, Van Tendeloo VF. Active specific immunotherapy targeting the Wilms' tumor protein 1 (WT1) for patients with hematological malignancies and solid tumors: lessons from early clinical trials. Oncologist. 2012;17(2):250-9. doi: 10.1634/theoncologist.2011-0240. Epub 2012 Jan 30.

  PMID: 22291091 BACKGROUND

• Anguille S, Smits EL, Bryant C, Van Acker HH, Goossens H, Lion E, Fromm PD, Hart DN, Van Tendeloo VF, Berneman ZN. Dendritic Cells as Pharmacological Tools for Cancer Immunotherapy. Pharmacol Rev. 2015 Oct;67(4):731-53. doi: 10.1124/pr.114.009456.

  PMID: 26240218 BACKGROUND

• Anguille S, Van de Velde AL, Smits EL, Van Tendeloo VF, Juliusson G, Cools N, Nijs G, Stein B, Lion E, Van Driessche A, Vandenbosch I, Verlinden A, Gadisseur AP, Schroyens WA, Muylle L, Vermeulen K, Maes MB, Deiteren K, Malfait R, Gostick E, Lammens M, Couttenye MM, Jorens P, Goossens H, Price DA, Ladell K, Oka Y, Fujiki F, Oji Y, Sugiyama H, Berneman ZN. Dendritic cell vaccination as postremission treatment to prevent or delay relapse in acute myeloid leukemia. Blood. 2017 Oct 12;130(15):1713-1721. doi: 10.1182/blood-2017-04-780155. Epub 2017 Aug 22.

  PMID: 28830889 BACKGROUND

• Z. Berneman, A. Van de Velde, S. Anguille, Y. Willemen, M. Huizing, P. Germonpré, K. Saevels, G. Nijs, N. Cools, A. Van Driessche, B. Stein, H. De Reu, W. Schroyens, A. Gadisseur, A. Verlinden, K. Vermeulen, M. Maes, M. Lammens, H. Goossens, M. Peeters, V. Van Tendeloo, E. Smits. Vaccination with Wilms' Tumor Antigen (WT1) mRNA-Electroporated Dendritic Cells as an Adjuvant Treatment in 60 Cancer Patients: Report of Clinical Effects and Increased Survival in Acute Myeloid Leukemia, Metastatic Breast Cancer, Glioblastoma and Mesothelioma. Cytotherapy 2016, 18(6), p. S13-14

  BACKGROUND

• Z. Berneman, S. Anguille, Y. Willemen, A. Van de Velde, P. Germonpré, M. Huizing, V. Van Tendeloo, K. Saevels, L. Rutsaert, K. Vermeulen, A. Snoeckx, B. Op de Beeck, N. Cools, G. Nijs, B. Stein, E. Lion, A. van Driessche, M. Peeters, E. Smits. Vaccination of cancer patients with dendritic cells electroporated with mRNA encoding the Wilms' Tumor protein (WT1): correlation of clinical effect and overall survival with T-cell response. Cytotherapy 2019, 21(5), p. S10.

  BACKGROUND

• de Bruijn S, Anguille S, Verlooy J, Smits EL, van Tendeloo VF, de Laere M, Norga K, Berneman ZN, Lion E. Dendritic Cell-Based and Other Vaccination Strategies for Pediatric Cancer. Cancers (Basel). 2019 Sep 19;11(9):1396. doi: 10.3390/cancers11091396.

  PMID: 31546858 BACKGROUND

• Benitez-Ribas D, Cabezon R, Florez-Grau G, Molero MC, Puerta P, Guillen A, Paco S, Carcaboso AM, Santa-Maria Lopez V, Cruz O, de Torres C, Salvador N, Juan M, Mora J, La Madrid AM. Immune Response Generated With the Administration of Autologous Dendritic Cells Pulsed With an Allogenic Tumoral Cell-Lines Lysate in Patients With Newly Diagnosed Diffuse Intrinsic Pontine Glioma. Front Oncol. 2018 Apr 26;8:127. doi: 10.3389/fonc.2018.00127. eCollection 2018.

  PMID: 29755954 BACKGROUND

• Lasky JL 3rd, Panosyan EH, Plant A, Davidson T, Yong WH, Prins RM, Liau LM, Moore TB. Autologous tumor lysate-pulsed dendritic cell immunotherapy for pediatric patients with newly diagnosed or recurrent high-grade gliomas. Anticancer Res. 2013 May;33(5):2047-56.

  PMID: 23645755 BACKGROUND

• Van Genechten T, De Laere M, Van den Bossche J, Stein B, De Rycke K, Deschepper C, Hazes K, Peeters R, Couttenye MM, Van De Walle K, Roelant E, Maes S, Vanden Bossche S, Dekeyzer S, Huizing M, Caluwaert K, Nijs G, Cools N, Verlooy J, Norga K, Verhulst S, Anguille S, Berneman Z, Lion E. Adjuvant Wilms' tumour 1-specific dendritic cell immunotherapy complementing conventional therapy for paediatric patients with high-grade glioma and diffuse intrinsic pontine glioma: protocol of a monocentric phase I/II clinical trial in Belgium. BMJ Open. 2024 Mar 18;14(3):e077613. doi: 10.1136/bmjopen-2023-077613.

  PMID: 38503417 DERIVED

Related Links

• Related Info

MeSH Terms

Conditions

Glioma; Diffuse Intrinsic Pontine Glioma

Condition Hierarchy (Ancestors)

Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Brain Stem Neoplasms; Infratentorial Neoplasms; Brain Neoplasms; Central Nervous System Neoplasms; Nervous System Neoplasms; Neoplasms by Site; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases

Study Officials

• Zwi N Berneman, MD, PhD

  Antwerp University Hospital, Division of Hematology and Center for Cell Therapy and Regenerative Medicine

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Both newly diagnosed patients and patients who previously underwent anti-glioma treatment are eligible for the study, provided they comply with all in- and exclusion criteria. The study hence consists of two strata, newly diagnosed patients are included in stratum A, while pre-treated patients are included in stratum B.

Study Record Dates

• First Submitted: April 30, 2021
• First Posted: June 3, 2021
• Study Start: September 10, 2021
• Primary Completion (Estimated): June 1, 2027
• Study Completion (Estimated): June 1, 2027
• Last Updated: May 8, 2024

Record last verified: 2024-05

Locations

BE (1)