Adjuvant Dendritic Cell-Based Tumour Vaccination for Children With Malignant Brain Tumours

Progression free survival

Progression free survival

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Summary

The study focuses on the results obtained in children with relapsed malignant brain tumours. the results primarily are promising and support further testing of DC-based immunotherapy in new treatment protocols for high grade glioma and Atypical Teratoid Rhabdoid Tumor.

Patients characteristics

33 patients with high grade glioma (HGG) (23 glioblastoma multiforme (GBM), 5 anaplastic astrocytoma (AA), 2 recurrent malignant pleomorphic xanthoastrocytoma (PXA), 1 oligo-astrocytoma (OA) grade III, 1 diffuse intrinsic pontine glioma (DIPG) and 1 anaplastic ganglioglioma), 5 patients with MB/PNET, 4 patients with ependymoma and 3 patients with ATRT.

Methodology

Preparation of vaccine
Fresh peripheral blood mononuclear cells were isolated. Adherent cells were cultured in the presence of 20 ng/ml rIL-4 and 1000 U/ml recombinant granulocyte macrophage–colony stimulating factor. After 7 days of culture immature DCs were loaded with 30 μg proteins per million DCs. Maturation was induced with 120 g/ml recombinant tumor necrosis factor–, 120 ng/ml rIL-1, and 20 g/ml PGE2 . After 24 hours, the cells were harvested and injected intradermally.

Treatment

Autologous DC loaded with tumour lysate were injected intradermally in the upper arms according to a predefined vaccination schedule as defined in the HGG-IMMUNO-2003 cohort comparison study.
In cohort A, DC vaccinations were given at weeks 1 and 3 and then further each 4 weeks. In cohort B, 5 DC vaccinations were given at a 2-week interval and then further each 4 weeks. In cohort C, 4 weekly DC vaccinations were given, followed by monthly boosts with intradermal injections of autologous tumour lysate, without DC. In cohort D, the same vaccination schedule as in cohort C was used, but DC maturation was altered. The ex vivo DC maturation after loading was induced with IL-1b and TNF-a instead of the classical cytokine cocktail (IL- 1b, TNF-a, PGE2). These early mature DC were injected intradermally and further in vivo DC maturation was induced with topical imiquimod (Aldara1). Imiquimod was administered locally one night before and two nights after injection of the vaccine.
Vaccine administration
Vaccination was performed by intradermal (i.d.) injection of 0.25–11.9 million (median 2.8×106) DC per lymph node region in the upper third of the arms (left and right). Boost vaccinations (cohorts C and D) were given with tumour lysate with a median of 1,500 mg (range: 220 – 3,125) proteins per vaccine injected in two syringes each containing a final volume of 400 ml.

Results

Clinical outcomes
There were six long-term survivors (OS >24 months) in the group of relapsed HGG patients (3 GBM). Four of them are still alive at last FU, at 85.6, 59.2, 35.7 and 47.7 months, respectively. Five of the long-term survivors did not receive concomitant chemotherapy to the immunotherapy. Three of the come from cohort A (#1 and #2 GBM), one from cohort B (#32) and one from cohort C (#26). The long-term surviving (GBM) patient (#13) that did receive concomitant chemotherapy (temozolomide) was vaccinated according to the protocol of cohort C.
In the subgroup of relapsed anaplastic astrocytoma (AA) patients, three patients underwent a total resection of the tumour and in two patients the resection was subtotal. Patient #28 is still free of progression at last FU at 13.0 months. The other two patients with a total resection (#24 and #26) had PFS of, respectively, 4.4 and 32.6 months.
One of the two patients with a recurrent malignant PXA (#30) is still alive at last FU at 12.1 months. The other patient (#29) died at 79.1 months FU. Tumour resection was, respectively, subtotal and total. PFS was, respectively, 1.9 and 65.7 months.
The patient with a DIPG (#31, a radiological diagnosis) was first treated with radiotherapy and chemotherapy according to the HIT- GBM-D protocol. Temozolomide was given for a metastatic lesion in the right temporal lobe. PFS and OS in this patient were 1.6 and 7.0 months, respectively.
In the patient with an anaplastic ganglioglioma (#32) tumour resection was subtotal and PFS was 24.4 months. This patient is still alive at 47.7 months FU. The patient with an anaplastic OA (#33) underwent a subtotal resection of the tumour and died at 4.6 months FU. Tumour progression was noticed in this patient at 2.4 months.
Feasibility and Toxicity
Only mild adverse events were noticed. Fatigue was seen in eight patients, headache in five patients, postvaccination fever in three patients, general itching in three patients, vomitus in two patients and flu- like symptoms in one patient. Temporary, vaccine- induced redness with or without itching and swelling at the injection sites was the rule in all patients.

Conclusion

Immunotherapy with autologous DC loaded with tumour lysate for children of all ages with a recurrent malignant brain tumour is feasible without major adverse events, even in young children. HGG seem to respond more favorably to vaccination and—for ATRT— the addition of immunotherapy to radio- and chemotherapy might be beneficial. Although preliminary, and derived from a heterogeneous patient group, this results on DC-based vaccination support testing of the integration of this innovative immunotherapy approach in new treatment protocols for HGG and ATRT.

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Scientific article publishing date 10/22/2009

Immucura identifier BSC21_296EN

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