Cellular and cytokine responses of the human central nervous system to intracranial administration of tumor necrosis factor α for the treatment of malignant gliomas

Abstract

To elucidate the role of tumor necrosis factor alpha (TNF alpha) as a biological response modifier, we studied cellular and cytokine responses of the central nervous system to TNF alpha administered intracranially in a phase I clinical trial for patients with malignant gliomas. Six patients received injections of TNF alpha (1.25 x 10(3)-10 x 10(3) U/injection) into the tumor cavities, and regional fluids (RF) and lumbar cerebrospinal fluids (CF) were serially sampled before and after the injections. Recruitment of neutrophils occurred, mostly peaking 8 h after TNF alpha injection, and fewer numbers of CD4+ T cells and monocytes/macrophages migrated, subsequently peaking at 24 h. The CF leukocytosis persisted for 48 h and was associated with an increased level of neutrophil chemotactic activity in the CF. This neutrophil chemotactic activity was attributed to interleukin-8 (IL-8) by HPLC. The level of IL-6 activity in the CF and RF consistently increased; beginning 2 h after TNF alpha injection and reaching the maximum between 8 h and 12 h. It returned to the basal level within 48 h. IL-1 beta was detected in the CF of three patients, its level peaking at 8 h. Prostaglandin E2 also increased after injection of TNF alpha, peaking between 4 h and 12 h and then gradually decreasing. Transforming growth factor beta was found in all cases tested and one patient showed a significant change after TNF alpha injection. IL-2 activity, interferon alpha (INF alpha) activity, IFN beta, and granulocyte/macrophage-colony-stimulating factor were not detected in the CF or RF. In conclusion, TNF alpha is biologically effective in inducing migration of immune cells and generating multiple cytokine responses in the human central nervous system.

Adenovirus‐mediated Gene Transduction of IkB or IkB Plus Bax Gene Drastically Enhances Tumor Necrosis Factor (TNF)‐induced Apoptosis in Human Gliomas

“…In addition to the direct cytotoxic effect, TNF administration exerts immunological effects which would greatly augment the in vivo antitumoral effect. TNF treatment induces immune cell migration, 1,2) generates multiple cytokine responses, 3,5) and makes glioma cells susceptible to natural killer cell-mediated lysis. 48) These immunological responses would induce an in vivo bystander effect of Adv-IκBdN infection in the presence of TNF.…”

“…3) However, TNF does not exhibit a direct cytotoxic effect on most glioma cell lines. [4][5][6] Instead, TNF promotes the growth of U-373 glioma cells.…”

Treatment of intracranial gliomas in immunocompetent mice using herpes simplex viruses that express murine interleukins

“…4 Gliomas are poor antigen presenting cells in vivo with low expression of MHC class I and II antigens. 5 They also secrete several immunosuppressive molecules such as TGF-␤2 and prostaglandin E 2 . 6 Thus, a major goal of immunotherapy is to stimulate recognition of tumor cells by the host's immune system and to activate tumor antigen-specific cellular immunity.…”

Human glioblastoma cells produce 77 amino acid interleukin-8 (IL-877)

“…Furthermore, some human neoplastic cell lines, including lung giant cell carcinoma LU65C cells [17,18] and thyroid carcinoma KHM-5M cells [19], can produce IL-8. Recently, we demonstrated that human glioblastoma cells produce IL-8 in vitro and that IL-8 is detected in cerebrospinal fluid of patients bearing cerebral glioblastoma or bacterial meningitis [20,21].…”