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Lymphokine-activated Killer Function following Autologous Bone Marrow Transplantation for Refractory Hematological Malignancies¹

Department of Medicine, Division of Medical Oncology, University of Washington School of Medicine, Seattle, Washington 98195 [C. M. H., J. A. T., T. C., C. G. L., A. F.], and the Fred Hutchinson Cancer Research Center, Seattle, Washington 98104 [C. D. B., A. F.]

Disease recurrence remains the major factor which limits the success of autologous bone marrow transplantation (ABMT) for refractory hematological malignancies. The administration of interleukin 2 (IL2) with or without ex vivo generated lymphokine-activated killer (LAK) cells represents a potential approach to eradicating residual disease after AMBT. However, since LAK precursor activity is radiosensitive, high dose chemoradiotherapy may abrogate LAK function and preclude clinical responsiveness to IL2 after ABMT. Furthermore, since lymphocyte subsets which mediate LAK activity may recover at different rates after ABMT, LAK cells may be phenotypically and/or functionally altered after ABMT. To determine whether IL2 responsive LAK precursor cells are present in the circulation after ABMT, peripheral blood mononuclear cells (PBMC) from 21 patients with acute leukemia or lymphoma were tested for IL2-inducible LAK activity 17–83 days after ABMT. Cells were cultured with IL2 (1000–2000 units/ml) for 4 or 5 days and then tested for cytolytic activity and/or cell phenotype. LAK activity against the Daudi cell line was detected in every PBMC sample from every patient at every time point tested. The Raji cell line and a fresh allogeneic ovarian carcinoma were also lysed by LAK cells generated after ABMT. In the subgroup of patients transplanted for non-Hodgkin's lymphoma, LAK precursor activity appeared comparable to that of healthy controls. Culture with IL2 resulted in increased mean IL2 receptor expression in lymphocytes from patients after ABMT (3.1–9.9%) and from healthy controls (3.1–12.0%). After culture with IL2, the percentage of cells bearing the natural killer cell-associated Leu-19 determinant was significantly higher in patient PBMC than in normal control PBMC (28.3 versus 8.7%). Positive and negative cell selection by fluorescence sorting after culture with IL2 revealed that most of the LAK activity after ABMT was mediated by the Leu-19⁺ cells. Although CD5⁺ T-cells were devoid of LAK activity, a subset LAK effectors was CD8⁺. Thus, LAK activity is rapidly reconstituted after ABMT and is mediated by cells phenotypically similar to those in normal controls. These results support the feasibility of IL2 ± LAK as consolidative immunotherapy after ABMT.

¹ This work was supported in part by Grant CA18029 awarded by the National Cancer Institute, Department of Health and Human Services, and the U.S.-Spain Joint Commission for Scientific and Technological Cooperation, CCA-8510/019.

² To whom requests for reprints should be addressed, at the Department of Medicine, Division of Medical Oncology RK-25, University of Washington School of Medicine, Seattle, WA 98195.

Received 3/20/89. Revised 7/ 7/89. Accepted 7/18/89.

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