J Neurosurg 71:169-174, 1989 The effect of intravenous interleukin-2 on brain water content STEPHEN C. SARIS, M.D., NICHOLAS J. PATRONAS, M.D., STEVEN A. ROSENBERG, M.D., PH.D., JOSEPH T. ALEXANDER, M.D., JOSEPH FRANK, M.D., DOUGLAS J. SCHWARTZENTRUBER, M.D., JOSHUA T. RUBIN, M.D., DAVID BARBA, M.D., AND EDWARD a. OLDFIELD, M.D. Clinical Neurosurgery Section, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke," Department of Diagnostic Radiology, Clinical Center, and Surgical Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland," and Department of Radiology, Georgetown University, Washington, D.C. u,, Parenteral treatment with interleukin-2 (IL-2) is effective against certain advanced cancers outside the central nervous system. Prior to commencement of Phase II trials in patients with brain tumors, the neurologi- cal and neuroradiological features of 10 patients treated with intravenous administration of repeated doses of IL-2 were studied. Three patients had malignant gliomas, and seven patients had extracranial cancer without evidence of intracranial metastasis. All were treated with intravenous doses of 10 5 U/kg three times daily for up to 5 days. The patients with gliomas received cranial computerized axial tomography (CT) scans before IL-2 therapy was initiated and during the later stages of treatment. The patients with extracranial cancer under- went T2-weighted magnetic resonance (MR) imaging before and later during therapy. After two to 11 doses of IL-2, the patients with gliomas had marked neurological deterioration that was associated with a mild to marked increase in peritumoral edema and mass effect visible on CT scans. With cessation of treatment and appropriate supportive care, all returned to their pretreatment state. The patients with extracranial cancer were either neurologically unchanged or underwent minor transient changes in mental status (lethargy and confusion). In these patients, the MR signal intensity was quantified and compared in eight anatomic regions of interest. In six of the seven patients, there were increases in gray and white matter signal intensity consistent with increased cerebral water content. The percentage changes (means + standard error of the means) were 12.6% + 7.3% in the gray matter and 17.0% _+ 6.2% in the white matter. This study demonstrates that treatment with a high parenteral dose of IL-2 is not tolerated by patients with gliomas due to increased cerebral edema. In patients with extracranial cancer but no brain disease, parenteral IL-2 induces an increase in the cerebral water content of both gray and white matter. KEY WORDS 9 interleukin-2 9 immunotherapy 9 cerebral edema 9 blood-brain barrier 9 cancer 9 brain neoplasm S INCE an important advantage of immunotherapy is its potential for high tumor specificity, it has been investigated in various forms to determine antitumor activity in patients with brain tumors. How- ever, numerous efforts with adoptive agents such as autologous lymphocytes, alpha-interferon, and levami- sole have shown limited efficacy.10-1223 Recently, meth- ods have been developed to generate lymphokine-acti- vated killer (LAK) cells that destroy fresh autologous tumor cells but not normal cells by incubating human peripheral blood lymphocytes with the lymphokine in- terleukin-2 (IL-2)) 9 In vitro, LAK cells are cytotoxic against rodent and human gliomas, 5 and in vivo the administration of IL-2 alone or in conjunction with LAK cells prolongs survival in rodents with primary central nervous system (CNS) cancers. 2~'22 Adoptive immunotherapy is currently being evaluated for treat- ment of malignant brain tumors in several clinics, but has not yet been shown to have antitumor activity. The best route of administration of LAK cells and IL-2 for the treatment of brain tumors is unknown. The effectiveness of intratumoral administration of LAK cells and IL-2 might be limited by the absence of LAK cell migration 15 or IL-2 diffusion through brain parenchyma. To maintain optimum antitumor activity, LAK cells require continued exposure to IL-2 and, J. Neurosurg. / Volume 71/August, 1989 169