Surgery and adjuvant dendritic cell-based tumour vaccination for patients with relapsed malignant glioma, a feasibility study

MRI scan

MRI scan

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Summary

DC loaded with proteins derived from autologous tumour homogenate is used for the treatment of patients with relapsed malignant glioma. As a result the approach may prolong survival of patients with malignant brain tumours without compromising their quality of life.

Patients characteristics

12 patients (seven female and five male) with relapsed malignant glioma with a median age of 32 years (range: 11 – 78 years). 7 patients with glioblastoma multiforme, 5 with anaplastic astrocytoma, 1 pilocytic astrocytoma, 1 with oligodendroglioma stage III and 1 with ODG stage IV and 1 with acute lymphatic leukemia.

Methodology

Preparation of autologous DC
In eight patients’ peripheral blood mononuclear cells (PBMC) were isolated from fresh blood samples. DC were differentiated out of the monocytes in the presence of 20 ng ml rIL-4 and 1000 U ml-1 rGM-CSF for 7 days. In the other patients, PBMC were obtained from leukapheresis, and kept frozen until use. For each vaccination, part of the PBMC was thawed, and adherent cells were differentiated to immature DC. Immature DC were loaded with 30 – 200 mg of tumor proteins per million DC, depending on the material available. For the loading procedure, 0.01% autologous plasma was used during the first 2 hours, 0.04% for the next 4 hours, and finally 0.28% for the last 20 hours. At time of loading, rTNF-a AG, rIL-1b and PGE2 were added in a final concentration of 120, 120 and 20 μg ml-1 respectively. After 24hours, mature loaded DC were resuspended in PBS with 0.5% human serum albumin (HSA) at a concentration of 2-6×106 mL. The syringes contained 1–2 million mature DC.

Treatment

Vaccination was performed by intradermal (i.d.) injection of 2 – 4 million DC per lymph node region in the upper third of the arms at weeks 1, 3, and further with an interval of 4 weeks. The patients were kept in the hospital for 2 hours after vaccination.

Results

Outcomes
The progression free survival (PFS) and overall survival (OS) at 36 months for the total group was 17% (median PFS 1⁄4 3 months; OS 1⁄4 10.5 months). In the six patients with residual tumor load after surgery and prior to vaccination, one stable disease (GBM) and one partial response of a metastatic lesion (GBM) were observed based on the volumetric analysis of the tumor. In the latter patient, the right temporal lesion, displaying a high grade malignant metabolic uptake ratio of 2.95 on methionine-PET, decreased in volume by 50% after the third vaccination. In two out of six patients (AA and PA) who had complete resection of their tumor, continuous complete remission was observed at the moment of writing the manuscript, with a follow-up of 36 and 35 months respectively. Patient 3 (pilocytic astrocytoma) had a transient contrast enhancement around the resection cavity after the fifth vaccine together with a transient increase of metabolic activity around the resection cavity, measured by methionine-PET.
Toxicity
No severe adverse events were noted, except for one patient. This patient suffered from peritumoral oedema that caused grade IV (NCI common toxicity criteria) neurological deficits and lethargy after vaccinations 2 – 5, but not after the first vaccination. Remarkably, the period of oedema appeared 30 hours after V2, 4 days after V3, and 9 days after V4, while the tumor volume calculated according to the formula AxBxC/2 (A, B and C are the largest diameters in axial, sagittal and coronal plane) remained stable. These symptoms were successfully controlled within 48h by administering steroids. The other 11 patients did not require corticosteroids during the vaccination period.

Conclusion

DC immunotherapy appears promising as an approach to successfully induce an antitumor immune response and long- lasting tumour control. This may prolong survival of patients with malignant brain tumours without compromising their quality of life.

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Scientific article publishing date 10/12/2004

Immucura identifier BSC21_294EN

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