DC vaccination with anti-CD25 treatment leads to long-term immunity against experimental glioma

Abstract

We studied the feasibility, efficacy, and mechanisms of dendritic cell (DC) immunotherapy against murine malignant glioma in the experimental GL261 intracranial (IC) tumor model. When administered prophylactically, mature DCs (DCm) ex vivo loaded with GL261 RNA (DCm-GL261-RNA) protected half of the vaccinated mice against IC glioma, whereas treatment with mock-loaded DCm or DCm loaded with irrelevant antigens did not result in tumor protection. In DCm-GL261-RNA-vaccinated mice, a tumor-specific cellular immune response was observed ex vivo in the spleen and tumordraining lymph node cells. Specificity was also shown in vivo on the level of tumor challenge. Depletion of CD8 DC vaccination with anti-CD25 treatment leads to long-term immunity against experimental gliomaWim Maes, Georgina Galicia Rosas, Bert Verbinnen, Louis Boon, Steven De Vleeschouwer, Jan L. Ceuppens, and Stefaan W. Van Gool Clinical Immunology, Department of Experimental Medicine (W.M., G.G.R., B.V., S.D.V., J.L.C., S.W.V.G.), Experimental Neurosurgery and Neuroanatomy (S.D.V.), and Pediatric Hemato-Oncology, Department of Child and Woman (S.W.V.G.), Katholieke Universiteit Leuven, University Hospital Gasthuisberg, Leuven, Belgium; Bioceros BV, Utrecht, The Netherlands (L.B.) Received October 23, 2008; accepted December 24, 2008. Address correspondence to Stefaan W. Van Gool, University Hospital Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium (Stefaan .VanGool@uz.kuleuven.be).clearly demonstrate the effectiveness of DC vaccination for the induction of long-lasting immunological protection against IC glioma. They also show the beneficial effect of Treg depletion in this kind of glioma immunotherapy, even combined with DC vaccination. NeuroOncology 11, 529-542, 2009 (Posted to Neuro-Oncology [serial online], Doc. D08-00292, March 31, 2009 DOI: 10.1215 DOI: 10. /15228517-2009 Keywords: anti-CD8, anti-CD25, DC immunotherapy, glioma, regulatory T-cells E scape from immunosurveillance is nowadays considered one of the hallmarks of malignant cell growth, and several mechanisms leading to immune suppression or immune escape have been described. 1 On the other hand, it is generally accepted that a patient's immune system can be instructed to recognize and attack several types of malignant lesions more efficiently.2,3 Hence, immunotherapy based on immunization with tumor antigen (Ag)-loaded dendritic cells (DCs) as professional Ag-presenting cells (APCs) represents a promising strategy in the multimodal treatment for different types of cancer, 4,5 including malignant glioma. [6][7][8][9][10][11][12][13][14][15] Immunotherapeutic approaches for malignant glioma are currently under investigation by our group [14][15][16] and others. 17,18 Results of in vitro experiments 19,20 and animal studies, 21 together with pilot data from clinical trials, [14][15][16] are very promising, although it is still too early to draw definitive conclusions. Orthotopic rodent glioma models are highly useful to address fundamental questions regarding the bala...

Preclinical efficacy of immune-checkpoint monotherapy does not recapitulate corresponding biomarkers-based clinical predictions in glioblastoma

“…To generate intra-brain GBM, the mice were intra-axially injected with 5£10 5 GL261 cells as described previously. 47 In brief, mice were anesthetized, set in a stereotactic frame (Kopf Instruments) and injected (in sterile circumstances) with the GL261 cells at 2 mm lateral and 2 mm posterior from the bregma, and at 3 mm underneath the dura mater. After intrabrain inoculation, the mice were monitored 2-3 times per week and clinical symptoms were noted with a neurologic-deficit grading scale modified from an experimental autoimmune encephalomyelitis model, described in the past.…”

In Vitro Generation of Murine Dendritic Cells for Cancer Immunotherapy: An Optimized Protocol

“…Murine DC were produced based on existing protocols (16)(17)(18). The mice were euthanized by cervical dislocation.…”

Radiation Immune Modulation Therapy of Glioma

“…Thus immunotherapeutic strategies for treating metastatic CNS tumors must fight against Treg (Sugihara, et al 2009). In an experimental GL261 intracranial tumor model, it was shown that depletion of CD25(+) regulatory T-cells (Treg) using anti-CD25 antibodies enhance the efficacy of DC immunotherapy (Maes, et al 2009). Infiltration of myeloid suppressor cells (MSC) is another factor inhibiting the function of the CD8(+) T cells, which results in tumour progression (Graf, et al 2005).…”