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Activation and Growth of Murine Tumor-specific T-Cells Which Have in Vivo Activity with Bryostatin 1¹

Departments of Surgery [T. M. T., K. P. B., H. D. B.] and Microbiology and Immunology [T. H. I., C. W. M., H. D. B.], and The Massey Cancer Center, The Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia 23298, and The Cancer Research Institute, Arizona State University, Tempe, Arizona 85287 [G. R. P.]

We examined the ability of bryostatin 1 (Bryo), a novel protein kinase C activator, plus ionomycin (Io), a calcium ionophore, to activate T-cells with specific antitumor activity. Lymphocytes from the draining lymph nodes (DLN) of MCA-105 tumor-bearing host mice were stimulated with Bryo/Io, either fresh or after in vitro stimulation with autologous tumor, and then were incubated in interleukin-2 at 20 units/ml. Lymphocytes sensitized with tumor cells in vitro and then stimulated with Bryo/Io exhibited significant expansion (12-fold) after a total of 3 weeks in culture and moderate cytolytic activity (40% at an effector:tumor cell ratio of 80:1) and were exclusively CD8⁺ T-cells. DLN cells activated immediately with Bryo/Io, without tumor antigen sensitization in vitro, displayed marked growth (130-fold expansion) over 3 weeks in culture, had weak cytolytic activity (8% at an effector:tumor ratio of 80:1), and were a mixed population of CD8⁺ and CD4⁺ cells. Despite the differences in phenotypes and in cytotoxicity, both groups of DLN cells were highly effective in vivo against MCA-105 pulmonary metastases. Bryo/Io-activated DLN cells from MCA-105 tumor-bearing hosts had no therapeutic efficacy against B16 melanoma or MCA-203 sarcoma metastases. Lymph node cells from normal mice and non-draining lymph node cells from tumor-bearing hosts could be expanded with Bryo/Io to a degree similar to that of DLN cells but had no antitumor activity. Phenotypic analyses and in vitro and in vivo depletion studies demonstrate that CD8⁺ cells mediated tumor regression.

¹ Supported by Grant CA48075 from the National Cancer Institute. With thanks we acknowledge funds provided by the Arizona Disease Control Research Commission; the Outstanding Investigator Grant CA44344-01A1-02 awarded by the Division of Cancer Treatment, National Cancer Institute; National Cooperative Drug Discovery Group Grant AI25696-02-03 awarded by the National Institute of Allergy and Infectious Diseases, National Cancer Institute; the Fannie E. Rippel Foundation; the Robert B. Dalton Endowment Fund; Eleanor W. Libby; and the Donald Ware Waddell Foundation. T. H. I. is a recipient of a Medical Scholars Award from the A. D. Williams Foundation and a scholarship award from the Norfolk Foundation.

² To whom requests for reprints should be addressed, at Division of Surgical Oncology. Box 11, The Medical College of Virginia. Richmond. VA 23298.

Received 7/10/91. Accepted 11/ 1/91.

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