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Elimination of Established Liver Metastases by Human Interleukin 2-activated Natural Killer Cells after Locoregional or Systemic Adoptive Transfer¹

Departments of Pathology [K. O., N. L. V., P. B., R. B. H., T. L. W.], Medicine [R. B. H.], and Cell Biology and Physiology [S. W.], University of Pittsburgh School of Medicine, and Pittsburgh Cancer Institute [K. O., U. N., N. L. V., S. W., P. B., R. B. H., T. L. W.], Pittsburgh, Pennsylvania 15213, and Department of Anatomy and Cell Biology, University of Goteborg, Goteborg, Sweden [U. N.]

An in vivo model of liver metastasis induced by human gastric carcinoma was established in nude mice and used for locoregional or systemic immunotherapy with a subset of human A-natural killer (NK) cells defined previously. A single intrasplenic (i.s.) delivery of A-NK cells (1 x 10⁷) and interleukin 2 (IL-2; 60,000 international units, twice a day for 5 days, i.p.) to animals with 3-day established liver metastases, but not IL-2 alone, resulted in rapid (within 24 h) elimination of the majority of metastases and significantly improved survival. A single i.s. or i.v. transfer of these effector cells and IL-2 significantly prolonged survival of the mice with 3-day established metastases (P < 0.03 and P < 0.02, respectively) compared with untreated mice. Using ⁵¹Cr-labeled A-NK cells, it was determined that, at best, 75% of 1 x 10⁷ cells delivered i.s., and up to 50% of those delivered i.v. were found in the liver 30 min-4 h later. Using image analysis with Di-O dye-labeled A-NK cells, 60–100% of A-NK cells delivered i.s. or i.v. were detected in the liver 24 h later. By light microscopy, 3-day liver metastases were mostly intravascular, but some had already begun to spread into liver tissue. When rhodamine- or Di-O dye-labeled A-NK cells were injected i.s. or i.v. to study their distribution in the liver, they were detectable by confocal fluorescence microscopy in tumor-free tissue and in association with tumor cells 12–24 h after transfer. No evidence for selective localization of A-NK cells to liver metastases was obtained; many A-NK cells were randomly distributed in tissue and not associated with visible metastases. However, confocal fluorescence and electron microscopy showed some A-NK cells to be in cell-to-cell contact with tumor cells, both in the blood vessels and liver tissue. These results indicate that a majority of human A-NK cells transferred i.s. or i.v. to mice with liver metastases have the capacity to migrate to the liver and to enter liver tissue and tumor metastases in vivo. The presence of these effector cells even in a modest number in the liver leads to elimination of most, but not all, metastases and to significantly prolonged survival of animals treated with A-NK cells and IL-2.

¹ This work was supported in part by American Cancer Society Grants IM-696 (T. L. W.) and IM-713 (N. L. V.), NIH Grant RO1-CA63513 (T. L. W.), Danish Cancer Society Grant 90-086 (P. B.), Swedish Cancer Society Grant 1000 (U. N.), and the Pathology, Education, and Research Foundation (Pittsburgh, PA).

² To whom requests for reprints should be addressed, at Pittsburgh Cancer Institute. W1041 Biomedical Science Tower, 211 Lothrop Street, Pittsburgh, PA 15213. Phone: (412) 624-0096; Fax: (412) 624-0264.

Received 8/31/95. Accepted 2/ 1/96.

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