Dendritic Cell Immunotherapy Against Cancer Stem Cells in Glioblastoma Patients Receiving Standard Therapy

Study Overview
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Brief Summary
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Open, randomized study of a trivalent dendritic cell therapy compared to standard therapy in primary treated patients with IDH wild-type, MGMT-promotor methylated glioblastoma. The IMP is dendritic cells transfected with mRNA of survivin, hTERT og autologous tumor stem cells derived from tumorspheres.

Detailed Description
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Autologous leukapheresis for enrichment of PBMCs is performed after enrollment of the patient into the trial. Ex vivo generated DCs will be frozen and stored in the vapour phase of liquid nitrogen. At first surgery, tumor biopsies will be cultured under sphere-forming conditions under ex vivo conditions for enrichment of glioblastoma stem cells. mRNA will purified and amplified from these autologous tumor stem cells. At specified intervals patients randomized to the vaccine group will receive intradermal injections of DCs transfected with mRNA from autologous tumor stem cells, survivin and hTERT. Injections will be given as three separate injections at three separate sites. Vaccination will be continued for as long as there are vaccines available.

Official Title
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Open Label Randomized Phase II/III Trial of Dendritic Cell Immunotherapy Against Cancer Stem Cells in Glioblastoma Patients Receiving Standard Therapy (DEN-STEM)

Conditions
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Glioblastoma

Intervention / Treatment
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* Biological: Dendritic cell immunization
* Drug: Adjuvant temozolomide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: All of the following conditions must apply: Must be at least 18 years and less than 70 years of age. Must be ambulatory with a ECOG performance status 0 or 1 Must have histologically confirmed glioblastoma IDH wild-type, with unmethylated MGMT-gene promotor, and a candidate for combined radiation therapy and chemotherapy (Stupps Regimen). Must have accessible volume and quality of tumor tissue for vaccine production (proliferation of cells and extraction of tumor mRNA) at first surgery. Must have postoperative MRI after surgery with contrast enhancing tumor remnant of less than 1 cm3 or less than 10% of original tumor volume. Normal organ function defined by laboratory values as following: ANC > 1.5 x 109/L; platelets >100 x109/L, Hb >9g/dL (> 5.6 mmol/L). Creatinine < 140 µmol/L (1.6 mg/dL); if borderline, the creatinine clearance >40 mL/min, Bilirubin < 20% above the upper limit of normal, ASAT and ALAT < 2.5 the upper limit of normal. Albumin >2.5 g/L. Serology indicating contagious HIV, HBV, HCV and Treponema pallidum must be negative. Signed informed consent and expected cooperation of the patients for the treatment and follow up must be obtained and documented according to ICH GCP, and national/local regulations. Exclusion Criteria: Tumor in a localization where a modest increase in size due to reactive oedema may have a large impact on the patient's neurological condition, i.e. brain stem. History of prior malignancy other than glioblastoma, with the exception of curatively treated basal cell or squamous cell carcinoma of the skin and ca. cervicis stage IB. Active infection requiring antibiotic therapy. Significant cardiac or other medical illness that would limit activity or survival, such as severe congestive heart failure, unstable angina, or serious cardiac arrhythmia. Prior splenectomy. Glucocorticoid treatment not possible to terminate due to autoimmune disease or increased intracranial pressure. Adverse reactions to vaccines such as asthma, anaphylaxis or other serious reactions. History of immunodeficiency or autoimmune disease such as rheumatoid arthritis, systemic lupus erythematosus, scleroderma, polymyositis-dermatomyositis, juvenile onset insulin dependent diabetes, or a vasculitic syndrome. Chemotherapy or other potentially immune-suppressive therapy outside protocol that has been administered within the last 4 weeks prior to vaccination. Positive pregnancy test in women of childbearing potential (within 7 days before the first vaccination). Women of childbearing potential and sexually active male participants must use reliable methods of contraception during the whole treatment period and 3 months after the last trial drug dose. Reliable methods of contraception are defined in section . Any reason why, in the opinion of the investigator, the patient should not participate.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Open label, randomized
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: DC immunization<br>Leukapheresis before start of radiotherapy. Immunization with DCs starting first week after finalizing radiotherapy (2Gy x 30) and concomitant temozolomide. | Biological: Dendritic cell immunization<br>* Intradermal injection<br>|
| Active Comparator: Standard therapy<br>Radiotherapy (2 Gy x30) with concomitant and adjuvant temozolomide. | Drug: Adjuvant temozolomide<br>* After a 4-week break, patients were then to receive up to six cycles of adjuvant temozolomide according to the standard 5-day schedule every 28 days at 150 mg per square meter for the first cycle and thereafter increase to 200 mg per square meter beginning with the second cycle.<br>* Other names: Standard therapy;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression free survival | Defined as time from first surgery to first certain progress of contrast enhancing tumor or clinical progression, according to the Response Assessment in Neuro-Oncology (RANO) criteria. | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival | Survival from the time of diagnosis. | 2 years from inclusion | 
| Patient reported quality of life, overall | Evaluated by EORTC Quality of Life Questionaire (QLQ-C30), a questionnaire developed to assess the quality of life of cancer patients. Scale 30 to 120 points, where higher is worse. | 2 years from inclusion | 
| Patient reported quality of life, brain specific | Evaluated by EORTC Quality of Life Questionaire, Brain module (QLQ-BN20). The brain cancer module is meant for use among brain cancer patients varying in disease stage and treatment modality. Scale 20 to 80 points, where higher is worse. It should always be complemented by the QLQ-C30. | 2 years from inclusion | 
| Immunological response, skin | Evaluated by delayed type hypersensitivity reaction in skin. | 2 years from inclusion | 
| Immunological response, cellular | Evaluated by lymphocyte clonal analysis. | 2 years from inclusion | 
| Adverse events | Classified according to Common Terminology Criteria for Adverse Events (CTCAE). | 2 years from inclusion |