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Antitumor Activity and Surface Phenotypes of Human Glioma-infiltrating Lymphocytes after in Vitro Expansion in the Presence of Interleukin 2¹

Department of Neurosurgery [Y. S., T. A., H. A.] and Laboratory of Pathology, Cancer Institute [M. H., H. K.], Hokkaido University School of Medicine, North-15, West-7, Kita-ku, Sapporo 060, Japan, and Neurosurgical Service, Centre Hospitalier Universitaire Vaudois, CH-1011 Lausanne, Switzerland [Y. S., M. C. K., N. T.]

The present study describes a method for in vitro expansion and characterization of antitumor-reactive lymphoid cells isolated from human malignant astrocytomas. Glioma-infiltrating lymphocytes were separated from 24 glioma specimens and cultured in medium containing interleukin 2 (50 to 2000 units/ml). Within 20 to 42 days after the initiation of culture, 20 of 24 cultures of glioma-derived lymphocytes expanded with a substantial increase in cell numbers, of at least 5 x 10⁸ cells up to 5 x 10⁹, with a simulaneous elimination of contaminating autologous glioma cells. The expanding glioma-derived lymphocytes consisted of 90 ± 8% (SD) CD3+ T-cells including both CD4+ and CD8+ subpopulations. CD16 was expressed on 4 ± 5% of the cells and three cultures studied exhibited 14% ± 1 of Leu-19-positive cells. After 4 to 8 weeks of proliferation, interleukin 2 receptor expression decreased from 36 ± 28% to less than 10% and the lymphocytes ceased to grow in all cultures. Glioma-derived effector lymphocytes could lyse almost all the autologous tumor targets as well as allogeneic glioma cells. The cytotoxic activity of long-term cultured peripheral blood lymphocytes obtained from the same patients appeared to be similar to that of glioma-derived lymphocytes in killing autologous tumor cells. In summary, gliomaderived lymphocytes expanded in bulk culture with high concentrations of interleukin 2 (2000 units/ml) consisted predominantly of T-lymphoblasts with the ability to kill autologous glioma cells. The tumor-infiltrating lymphocytes could be expanded to sufficient numbers for possible use in the adoptive immunotherapy of malignant gliomas.

¹ This work was supported in part by Grants-in-Aid for Cancer Research from the Japanese Ministry of Health and Welfare and by a grant from the Preuss Foundation.

² To whom requests for reprints should be addressed. Present address: Neurosurgical Service, Centre Hospitalier Universitaire Vaudois, CH-1011 Lausanne, Switzerland.

Received 9/13/88. Revised 12/13/88. Accepted 12/20/88.