Cytokine Responses to Intraventricular Injection of Interleukin 2 into Patients with Leptomeningeal Carcinomatosis: Rapid Induction of Tumor Necrosis Factor a, Interleukin 10, Interleukin 6, -Interferon, and Soluble Interleukin 2 Receptor (Mr 55,000 Protein)

Interleukin 2 (IL-2) is a potent immunostimulant that causes the release of secondary cytokines and the production of lymphokine-acti-vated killer cells. We investigated the cellular and cytokine responses to injection of recombinant human IL-2 into the human cerebrospinal fluid of 11 patients with metastatic tumors involving the spinal or cerebral leptomeninges. After initial intraventricular IL-2 administration (1.25 x 10s to 2 x 106 Cetus units/injection), cerebrospinal fluid samples were collected at intervals from 0 to 24 h. Enzyme-linked immunosorbent assay results indicated that IL-2 levels gradually decreased during the first 24 h, with an average f” between 4 and 8 h. Induction of tumor necrosis factor a, interleukin 1/9, interleukin 6,γ-interferon, and interleukin 2 receptor (p55) was also assessed by enzyme-linked immunosorbent assay. Tumor necrosis factor a and interleukin 6 levels peaked at 2 to 4 h and 4 to 6 h, with concentrations between 71 to 1,714 pg/ml and 942 to 10,500 pg/ml, respectively. Interleukin 1/9, γ-interferon, and soluble IL-2 receptor peaked later, during 6 to 12 h; the levels achieved were 234 pg/ml, 25 NIH units/ml, and 207 units/ml, respectively. All cytokine concentrations returned to near baseline between 12 and 24 h; however, the soluble IL-2 receptor levels remained elevated. Additional observations included a rapid influx of neutrophilic leukocytes, followed by a prolonged presence of lymphocytes. These data indicate a broad and complex potential of the immune response in the central nervous system, as well as further define the cytokine cascade in response to IL-2 alone.