An emerging strategy in the treatment of various neoplasms involves the stimulation of an immune response against the malignant cells. Among the new treatments currently being investigated for malignant cancers, immunotherapy is theoretically very appealing, because it offers the potential for high tumor-specific toxicity.14,19,28,31 However, there is concern about the applicability of immunologically based therapies to central nervous system (CNS) tumors. One aspect of this is that the CNS is immunologically privileged; it is devoid of lymphoid reactivity and normal immune surveillance.26 Although this may be true in healthy brain tissue, many recent studies have documented that T lymphocytes and major histocompatibility complex (MHC) antigens are easily detectable in the CNS during illness and disease (such as multiple sclerosis, encephalitis, or tumor).12,18 Furthermore, it has been observed in several different laboratories that effective anti—CNS tumor immune responses can be generated using cytokine-modified tumor cell vaccines.15,21,30 Therefore, the possibility that the immune system can mediate interactions with lesions in the CNS (such as brain tumors) presents excellent opportunities to investigate immunological modes of therapy.
Recent advances in the understanding of antigen presentation, antigen recognition requirements, and T-cell activation have centered around dendritic cells as a novel form of immunotherapy for the treatment of cancer.2,5,16,17,22–24,32–34,39,40 Dendritic cells are the most potent “professional” antigen-presenting cells in the body. Research evidence indicates that, although tumors may contain immunogenic antigens, tumor cells themselves are poor antigen-presenting cells. Therefore, professional antigen-presenting cells may be needed to internalize, process, and/or present tumor antigens to T cells efficiently.11,20
Dendritic cells are derived from proliferating bone marrow precursor populations. Investigators have recently discovered that large numbers of functional dendritic cells can be isolated from bone marrow precursor cells in vitro with the support of certain cytokines. Granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-4 (IL-4) induce progenitor cell differentiation into dendritic cells, whereas tumor necrosis factor—α inhibits granulopoiesis and maintains the viability of dendritic cells in culture.17,41 In mouse models and in clinical trials, these cytokine-stimulated dendritic cells have been successfully pulsed ex vivo with tumor antigens for use as antitumor vaccines against cancers outside the CNS.5,16,22,25,33,39,40 In the present study we report the use of dendritic cell immunotherapy for the treatment of brain tumors within the CNS.2,23
We thank Dr. William H. McBride for his assistance with the flow cytometry analysis and Dr. James S. Economou for his invaluable advice.
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This work was supported in part by an American Brain Tumor Association Fellowship, an American Cancer Society Grant, and the Ray and Estell Spehar Fellowship awarded to Dr. Liau.