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Background. The median survival for adults with glioblastoma multiforme (GBM) is 12 months, despite surgery, radiation, and chemotherapy. Regimens using interleukin-2 (IL-2) plus lymphokine-activated killer (LAK) cells have been beneficial against systemic cancers, albeit with significant toxicity. Methods. Nineteen adults with recurrent malignant glioma (5 GBMs, and 4 anaplastic astrocytomas (AA)), Karnofsky performance status 60 or greater, were treated with intracavitary autologous LAK cells plus IL-2 after reoperation. Lymphokine-activated killer cells and IL-2 were given on day 1, and IL-2 alone was given 5 times during a 2-week cycle. This cycle was repeated at 2 weeks to constitute one 6-week course of therapy. Each two-cycle course of treatment was repeated at 3-month intervals for patients with stable disease or response to therapy. At the conclusion of immunotherapy, all patients were offered chemotherapy, generally carmustine or procarbazine, including responders. Corticosteroids were strictly limited during immunotherapy. Sequential reservoir aspirates were obtained for microbiologic and cytologic analyses. Results. The maximal tolerated dose for a 12-dose course of therapy was 1.2 million international units (MIU) per dose. Dose-limiting, cumulative IL-2-related central nervous system (CNS) toxicity was observed at 2.4 MIU per dose. Three responses were confirmed by computed tomography scan during therapy: one complete response (CR) (1 AA), and two partial responses (PR) (2 GBM); as well as a significant increase in GBM survival. One additional CR (GBM) was observed at 17 months. The median survival for immunotherapy patients with GBM was 53 weeks after reoperation (N = 15) (mean, 87.9 [+ or -] 21.4 weeks, standard error for the mean), with 8 of 15 surviving more than 1 year (53%). The median survival for 18 contemporary patients with GBM reoperated and treated with chemotherapy was 25.5 weeks (mean, 27.4 [+ or -] 3.7 weeks), with 1/18 alive at 1 year (>6%). Six of the 15 patients with GBM had additional surgery or biopsy, and chemotherapy after immunotherapy. The contribution of subsequent chemotherapy to survival cannot be discounted. Conclusions. Lymphokine-activated killer cells and IL-2 can be administered safely within the CNS resulting in improved long term survival in patients with recurrent glioblastoma. Increased survival was associated with significant biologic changes characterized by a regional eosinophilia, and extensive lymphocytic infiltration. A prospective randomized clinical trial is warranted. Cancer 1995; 76:840-52. Key words: interleukin-2, lymphokine-activated killer cells, glioma, glioblastoma, astrocytoma, brain, immunotherapy, eosinophil, survival, biologic response modifiers.

Classification of high grade astrocytomas of children into genetic subtypes similar to the adult remains to be defined. Here we report an extensive characterization of 29 high grade pediatric astrocytomas, 7 WHO grade III and 22 WHO grade IV, for genetic alterations frequently observed in high grade adult astrocytomas occurring in either the p53/MDM2/p14ARFor Rb/CDK4/p16INK4atumor suppressor pathways. In addition, we have assessed the contribution of EGFR overexpression and amplification and LOH for chromosome 10, two genetic alterations commonly associated with the development of de novoadult glioblastoma for their roles in the development of de novoastrocytomas of childhood. Our results suggest two major differences in the genetic pathway(s) leading to the formation of de novohigh grade astrocytomas in children compared with those of the adult. Our findings show preferential inactivation of the p53 tumor suppressor pathway in > 95% of pediatric astrocytomas versusinactivation of the Rb tumor suppressor pathway in < 25% of the same tumors. In addition, de novohigh grade pediatric astrocytomas lack amplification of the EGFR gene compared with EGFR amplification in one‐third of adult glioblastomas. Since drug treatments and gene therapy strategies exploit specific genetic alterations in tumor cells, our findings have important implications for the future development of treatments for high grade pediatric astrocytomas.