Dendritic Cell Therapy of High‐Grade Gliomas

Abstract

The prognosis of patients with malignant glioma is poor in spite of multimodal treatment approaches consisting of neurosurgery, radiochemotherapy and maintenance chemotherapy. Among innovative treatment strategies like targeted therapy, antiangiogenesis and gene therapy approaches, immunotherapy emerges as a meaningful and feasible treatment approach for inducing long-term survival in at least a subpopulation of these patients. Setting up immunotherapy for an inherent immunosuppressive tumor located in an immune-privileged environment requires integration of a lot of scientific input and knowledge of both tumor immunology and neuro-oncology. The field of immunotherapy is moving into the direction of active specific immunotherapy using autologous dendritic cells (DCs) as vehicle for immunization. In the translational research program of the authors, the whole cascade from bench to bed to bench of active specific immunotherapy for malignant glioma is covered, including proof of principle experiments to demonstrate immunogenicity of patient-derived mature DCs loaded with autologous tumor lysate, preclinical in vivo experiments in a murine orthotopic glioma model, early phase I/II clinical trials for relapsing patients, a phase II trial for patients with newly diagnosed glioblastoma (GBM) for whom immunotherapy is integrated in the current multimodal treatment, and laboratory analyses of patient samples. The strategies and results of this program are discussed in the light of the internationally available scientific literature in this fast-moving field of basic science and translational clinical research.

Immunogenic versus tolerogenic phagocytosis during anticancer therapy: mechanisms and clinical translation

“…Chemotherapeutic ICD inducers cannot be integrated in clinical cell-based vaccination protocols owing to their residual amounts being capable of exerting side effects or toxicity. 107 This is one of the primary reasons why clinical anticancer vaccines (whole-tumour-cell or DC vaccines) utilize physicochemical cancer cell death inducers. 108 However, while some physicochemical strategies can induce ICD (e.g., radiotherapy, PDT) yet certain others cannot (e.g., freeze/thawing-based necrosis).…”

Stable antigen‐specific T‐cell hyporesponsiveness induced by tolerogenic dendritic cells from multiple sclerosis patients

“…In the design of an antigen-specific cellular therapy, antigen loading of APC is of important relevance. Current cancer treatments undergoing investigation include DCs loaded with tumor lysates [42] and genetically engineered DC vaccines expressing relevant tumour antigens [43]. Another approach for toleranceinducing therapies is the use of apoptotic cells as a "pool of antigens," which has the potential to induce a tolerogenic profile in DCs [44,45].…”

Current Studies of Immunotherapy on Glioblastoma

“…The principle behind a dendritic cell vaccine involves activating dendritic cells removed from a patient with antigens that are tumor-specific, then re-introducing them to the patient. Antigens that have been favored for vaccine production are usually whole tumor-cell antigens, and are isolated in a variety of ways, including acid elution of membrane proteins, various lysates, gamma-irradiation, and isolation of protein from paraffin-embedded samples [48]. Over the last decade there have been a variety of clinical trials demonstrating the efficacy of various dendritic cell vaccines.…”