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(Circulation. 1995;92:202-205.)
© 1995 American Heart Association, Inc.

Articles

Generation of Tumor-Specific T Lymphocytes for the Treatment of Posttransplant Lymphoma

J. Michael DiMaio, MD; Peter Van Trigt, MD; J. William Gaynor, MD; R. Duane Davis, MD; Eamonn Coveney, MD, FRCSI; Bryan M. Clary, MD; H. Kim Lyerly, MD

From the Departments of Surgery (J.M.DiM., P.V.T., J.W.G., R.D.D., E.C., B.M.C., H.K.L.) and Pathology (H.K.L.), Duke University Medical Center, Durham, NC.

Background The incidence of lymphoproliferative disease, including B-cell lymphomas (BCL) in patients who have undergone heart or combined heart-lung transplants, has been reported to be as high as 15%. The majority of these tumors contain Epstein-Barr virus (EBV) DNA and regress when immunosuppressive agents are discontinued. This tumor regression is thought to be secondary to cytotoxic T lymphocytes (CTL) reactive to EBV-infected cells whose function is impaired in patients receiving immunosuppressive agents. We hypothesize that EBV-CTL expanded in the absence of these agents may demonstrate an antitumor effect against an EBV-expressing human BCL in vitro and in vivo.

Methods and Results An EBV-expressing BCL from a heart transplant recipient was isolated and expanded in culture. EBV-CTL were generated by stimulation of peripheral blood leukocytes with irradiated autologous tumor cells in low-dose interleukin-2. Autologous BCL, HLA-mismatched BCL, lymphokine-activated killer target cell line (Daudi), and the natural killer target cell line (K562) were used in a standard 4-hour cytotoxicity assay using ⁵¹CrO₄ after 7, 14, and 28 days of stimulation. There was significant percent specific lysis of autologous BCL targets (78%) at an effector-to-target ratio as low as 20:1 as compared with control cells. EBV-CTL were then adoptively transferred into SCID mice (provided by Duke University Vivarium) that had been engrafted with autologous BCL 7 days before. There was a significant survival advantage to those mice engrafted with EBV-CTL as compared with control cells.

Conclusions The results indicate that ex vivo expansion of EBV-CTL in the absence of immunosuppressive agents results in a population that has significant antitumor activity. This strategy may be useful in the generation of EBV-CTL that might be effective antitumor agents in transplant recipients with EBV-associated lymphomas.

Key Words: lymphocytes • transplantation • cells • heart transplant • lymphoma • immunodeficiency