Stem cell transplantation from haploidentical donor (haplo-SCT) is a potential therapeutic option for patients lacking an HLA-identical donor. However, GvHD and failure of immune reconstitution severely limit the outcome of this approach. T-cell depletion (TCD) is effective in preventing OvHD, but further delays immune reconstitution and results in a high incidence of disease relapse. We previously showed that the infusion of donor lymphocytes (DLI) expressing the herpes simplex virus thymidine kinase (Tk) to patients with disease relapse results in GvL (10/15 pt) and GvHD (4/15 pt) efficiently controlled by ganciclovir (GCV) (3β pt). Therefore, we designed a clinical protocol for programmed Tk-DLI for immune reconstitution and relapse prevention in haplo-SCT. 5 pt with acute leukemia who underwent haplo-SCT in the presence of disease received escalating doses of Tk-DLI 42 days post SCT beginning at SxlOVkg up to 108/kg. In addition, 2 pt at high risk for relapse after TCD HLA-identical SCT received 10'/kg Tk-DLI. Infused lymphocytes were 100% CD3+, 13-50% CD4+. Circulating transduced cells were documented in 6/7 pt (from less than 0.01 to 100% of CD3+ cells). 1/5 haplo pt reached 50 CD3+/H1 by day 30, increasing steadily thereafter. 1/2 pt receiving a SCT from the HLA identical donor reached 100 CD3+/-4il by day 30. In this patient, an anti-cytomegalovirus (CMV) effect was detected resulting in the clearance of the anü'genenüa. 5/7 pt maintained the complete remission for over 3 months after the infusion. 1 pt relapsed in the absence of Tk ceil engraftment. No acute GvHD was observed in this initial series of patients. However, 4/7 patients had to be treated with GCV to control CMV infection. This resulted in the rapid elimination of Tk cells. Three patients received a second Tk-DLI after GCV discontinuation. T-cell engraftment was documented in all pt, with a kinetic comparable to the first infusion. A pt who relapsed after GCV-elimination of transduced cells received 107/kg Tk-DLI and remained in stable disease. One patient received unmodified lymphocytes during GCV treatment and died of GvHD. In conclusion, Tk-DLI represents a promising tool for preventing disease relapse and promoting immune reconstitution after haplo-SCT. However, the concomitant need for utilization of GCV early post-transplantation severely limits the impact of this technology. To circumvent this limitation, a new suicide system based on the death domain of FAS is under investigation.
|Issue number||11 PART I|
|Publication status||Published - 2000|
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