Pediatr Blood Cancer 2010;54:519–525 Adjuvant Dendritic Cell-Based Tumour Vaccination for Children With Malignant Brain Tumours Hilko Ardon, MD, 1,2 * Steven De Vleeschouwer, MD, PhD, 1,2 Frank Van Calenbergh, MD, 1 Laurence Claes, PhD, 3 Christof M. Kramm, MD, 4 Stefan Rutkowski, MD, 5 Johannes E.A. Wolff, MD, 6 and Stefaan W. Van Gool, MD, PhD 2,7 INTRODUCTION The prognosis of high grade malignant paediatric brain tumours remains unsatisfactory in spite of surgical resection, external beam radiotherapy and chemotherapy. There is a clear need for well- tolerated treatments that are tumour-specific and able to kill not only all residual tumour cells that infiltrate in the adjacent areas of the brain [1], but also the recently described radio- and chemoresistant CD133þ cancer stem cells, particularly in case of malignant glioma [2–4]. The development of immune therapy and its integration in the current therapeutic concepts to induce tumour control remains a potentially promising approach for further testing. We are exploring the feasibility and clinical benefits of dendritic cell (DC)-based tumour vaccination for paediatric and adult malignant brain tumours. A significant experience with this treatment approach for malignant glioma has been gained in the adult population during the last years in patients with relapsed tumours, and in patients with newly diagnosed tumours [5–9]. Tumour vaccination has been shown to be feasible, well tolerated and possibly beneficial for patients with minimal residual tumour burden. Here we focus on our experience with DC vaccination to treat children (18 years or younger) with relapsed malignant brain tumours. METHODS Patient Population 45 children (18 males and 27 females) were vaccinated after Ethics Committee approval and informed consent by the parents. We treated 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. Histology at relapse was confirmed by central review in 37 patients. In the remaining patients, at least two independent pathological reviews in university hospitals were performed. All three ATRT diagnoses were performed by reference pathologists, and were based on typical immunohistochemical appearance. Patients’ characteristics are described in Supplemental Table I [10]. In In all patients, except for one patient with primary metastasised ATRT, vaccination was performed as second or third stage treatment. All patients had already had surgery and were off corticosteroids at the time of leukapheresis/blood sampling and during vaccination. Assessment of Extent of Tumour Resection Before Vaccination Total resection was defined by the neurosurgical report and the absence of any residual tumour mass on postoperative MRI (T1 weighted spin-echo images before and after gadolinium enhancement) within 72 hr after surgery. Any resection leaving a measurable tumour <2 cm 3 was considered subtotal. Background. A large experience with dendritic cell (DC)-based vaccination for malignant brain tumours has been gained in adults. Here we focus on the results obtained in children with relapsed malignant brain tumours. Procedure. In total 45 children were vaccinated: 33 high grade glioma (HGG), 5 medulloblastoma (MB)/ primitive neuro-ectodermal tumour (PNET), 4 ependymoma and 3 atypical teratoid-rhabdoid tumour (ATRT). Autologous, monocyte- derived DC were generated and loaded with tumour lysate, which was used as source of tumour-associated antigens. Results. In 38 patients peripheral blood mononuclear cells (PBMC) were obtained from leukapheresis and in 7 patients from fresh blood samples. 7 HGG patients are still alive with median follow-up (FU) of 35.7 months (range: 12.1–85.6). Median overall survival (OS) was 13.5 months (range: 1.4–85.6). All patients with MB/PNET died (median OS 5.7 months; range 4.3–51.2). One patient with ependymoma is still alive at 22.3 months FU. The other three patients died at, respectively, 7.7, 30.1 and 31.5 months. Two patients with ATRT are still alive at, respectively, 34.1 and 52.6 months FU. The third patient died at 50.5 months. No severe adverse events were noticed. Conclusions. In this exploratory study, HGG and ATRT seem to respond more favourably to vaccination than MB/PNET and ependymoma. Although preliminary, our results are promising and support further testing of DC-based immunother- apy in new treatment protocols for HGG and ATRT. Pediatr Blood Cancer 2010;54:519–525. ß 2009 Wiley-Liss, Inc. Key words: brain tumours; dendritic cell vaccination; immunotherapy ß 2009 Wiley-Liss, Inc. DOI 10.1002/pbc.22319 Published online 22 October 2009 in Wiley InterScience (www.interscience.wiley.com) —————— Additional Supporting Information may be found in the online version of this article. 1 Department of Neurosurgery, University Hospital Gasthuisberg, Leuven, Belgium; 2 Laboratory of Experimental Immunology, University Hospital Gasthuisberg, Leuven, Belgium; 3 Department of Psychology, Catholic University of Leuven, Leuven, Belgium; 4 Department of Paediatric Oncology, Haematology and Immunology, University Children’s Hospital, Halle, Germany; 5 Department of Paediatric Haematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; 6 Department of Paediatric Oncology, MD Anderson Cancer Center, Houston, Texas; 7 Department of Paediatrics, University Hospital Gasthuisberg, Leuven, Belgium Grant sponsor: Olivia Hendrickx Research Fund; Grant sponsor: The Herman Memorial Research Fund; Grant sponsor: IWT-Flanders; Grant sponsor: The Belgian Foundation Against Cancer. *Correspondence to: Hilko Ardon, Department of Neurosurgery, University Hospital Leuven, Herestraat 49, 3000 Leuven, Belgium. E-mail: hilko.ardon@uz.kuleuven.be Received 16 February 2009; Accepted 4 September 2009