Immunotherapy With Autologous Tumor Lysate-Loaded Dendritic Cells In Patients With Newly Diagnosed Glioblastoma Multiforme

Background and significance. The therapeutic program will include radical surgical resection of the tumor, followed by radiotherapy (fractionated local field irradiation in daily fractions of 2 Gy given 5 days per week, Monday through Friday for 6 weeks, for a total of 60 Gy) plus temozolomide (TMZ) chemotherapy (75 mg per square meter of body-surface area per day, 7 days per week from the first to the last day of radiotherapy). After a 4-week break, up to 6 cycles of maintenance TMZ (mTMZ) will be administered according to the standard 5-day (oral intake) schedule every 28 days. TMZ dose will be 150 mg per square meter for the first cycle and will be increased to 200 mg per square meter beginning with the second cycle, so long as there is no hematologic toxic effect. Immunotherapy will follow radiochemotherapy and will comprise 4 vaccinations every second week (injections I, II, III, IV), 2 further monthly vaccinations (injections V, VI) and a final vaccination (injection VII) 2 months after the sixth one. Injections I, V, VI and VII will contain 10 million tumor lysate-loaded DC, while the others will be of 5 million cells only. In correspondence to the third vaccine injection (week 13), mTMZ will start. On the basis of the patient clinical status, further vaccine boosts will be considered as appropriate addition at the standard vaccination cycle.

Inclusion criteria

• Age ≥18 years and ≤70 years.
• Postoperative Karnofsky Performance Status ≥70.
• First diagnosis of GBM (World Health Organization [WHO] grade IV astrocytoma).
• Diagnosis confirmed by the reference histopathology.
• Residual tumor volume after resection <10 cc, confirmed by postoperative MRI assessment
• Total or subtotal resection of tumor mass, confirmed by assessment of the neurosurgeon and by postoperative radiological assessment.
• Amount of non-necrotic tissue for lysate preparation and DC loading ≥1 gr, stored at -80°C.
• Corticosteroids daily dose ≤4 mg during the 2 days prior to leukapheresis.
• Clinical indication for radiochemotherapy according to the Stupp protocol (Stupp et al., 2005).
• Life expectancy > 3 months.
• Informed consent

Exclusion criteria

• Pregnancy.
• Participation in other clinical trials with experimental drugs simultaneously or within 1 month before this trial entry.
• Presence of acute infection requiring active treatment.
• Mandatory treatment with corticosteroids or salicylates in anti-inflammatory dose.
• Presence of sub-ependymal diffusion of the tumor.
• Presence of multi-focal GBM lesions.
• Haematology: leukocytes < 3,000/μl, lymphocytes < 500/μl, neutrophils < 1,000/μl, hemoglobin <9 g/100 ml, thrombocytes < 100,000/μl one or two days prior to leukapheresis.
• Documented immune deficiency.
• Documented autoimmune disease.
• Positive serology for HIV, HBs antigen, HCV, TPHA.
• Allergies to any component of the DC vaccine.
• Known intolerance to TMZ.
• Other active malignancy.