Immunotherapy for malignant glioma using human recombinant interleukin-2 and activated autologous lymphocytes

Abstract

Over the past few years, we and a number of other groups have conducted laboratory experiments and clinical trials of human recombinant interleukin-2 (rIL-2) alone or in combination with autologous 'activated' lymphocytes expressing in vitro tumoricidal activity in order to define toxicity and indicate its potential efficacy in patients with high-grade glioma. Because high rIL-2 concentrations can be attained with considerably less toxicity than with a systemic approach, all of the clinical trials, to date, have chosen a direct route; injecting lymphokine and cells into tumor tissue, the cystic cavity remaining after tumor excision, and/or neural parenchyma surrounding the site of tumor excision. While the rIL-2 therapies, as they have been applied in animal glioma models and patients, are safe, cerebral edema around the site of treatment has been a consistent finding. We have also seen, however, that steroid medications used by patients to control their cerebral edema may depress the anti-tumor activity of rIL-2 by depressing the capacity of lymphocytes to develop normal LAK activity. Although none of the immunotherapies involving rIL-2 have produced cures, the fact that sustained clinical responses have been reported, suggests that such therapies may slow a recurrence of tumor at the site of treatment. Efforts to improve outcome from rIL-2--based immunotherapies for malignant glioma are continuing with manipulation of rIL-2 dosing and scheduling and also with combinations of rIL-2 and other recombinant cytokines.

Changes in the Immunologic Phenotype of Human Malignant Glioma Cells after Passaging in Vitro

“…The need for new therapies has led investigators to study the specificity and efficacy of immune-mediated tumor destruction. While immunotherapeutic strategies against glioblastomas have been promising both in vitro (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13) and in animal models (14 -20), similar successes have not been realized in human clinical trials (17,(21)(22)(23)(24)(25)(26)(27)(28)(29)(30).…”

A phase 3 trial of local chemotherapy with biodegradable carmustine (BCNU) wafers (Gliadel wafers) in patients with primary malignant glioma

“…Their clinical effectiveness, however, has been limited because of the short half-life (about 20 min), the small fraction of the systemically administered dose reaching the tumor at an effective concentration, and their systemic toxicities. Other treatment modalities, including immunotherapy, immunoradiotherapy, and gene therapy, are under development but burdened with the problem of drug delivery across the blood-brain barrier Culver et al, 1992;Fontana et al, 1992;Jachimczak et al, 1993;Köppen et al, 1991;Kramm et al, 1995;Laske et al, 1997;Liebermann et al, 1995;Martuza, 1997;Merchant et al, 1990Merchant et al, , 1997Mesnil et al, 1996;Rainov, 2000;Ram et al, 1997;Reist et al, 1995;Riva et al, 1997;Wersall et al, 1997). In spite of the numerous therapies administered, the median survival of patients with high-grade gliomas is approximately one year (Brada and Yung, 2000;Hildebrand et al, 1997;Levin et al, 1997).…”

Alternative Therapies for Children with Brain Stem Gliomas: Immunotherapy and Gene Therapy

“…Jeffes et al [8] reported that 3 of 11 patients had a decrease in tumor size of 7 of 11 patients with recurrent high-grade glioma clinically improved after treatment with IL-2-stimulated killer cells. Merchant et al [9] treated 29 patients with brain tumors with intercavitary IL-2 LAK/treatment. Three of the 29 patients required a second surgical resection for uncontrollable cerebral ede ma and clinical deterioration.…”