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Blood, 15 November 2004, Vol. 104, No. 10, pp. 3408-3409.
CORRESPONDENCE To the editor:Evidence for increased risk of secondary graft failure after in vivo depletion of suicide gene-modified T lymphocytes transplanted in conjunction with CD34+-enriched blood stem cellsSuicide gene transfer into donor T lymphocytes is a promising strategy to avoid severe graft-versus-host disease (GvHD) after allogeneic stem cell transplantation (SCT).1,2 We conducted a phase 1/2 study3 combining infusion of CD34-enriched peripheral blood stem cells (PBSCs) with suicide gene-modified (SGM) donor T lymphocytes. Before our study was put on hold (after the leukemia cases in France4), 3 patients had been treated (Table 1).
T lymphocytes were transduced5 with the retroviral vector Mo3TIN,6 selected with G418,2 cryopreserved, and safety-tested in a good manufacturing practice (GMP) facility (European Institute for Research and Development of Transplantation Strategies [EUFETS]). CD34 cells were enriched using the Miltenyi Clini-MACS (Miltenyi, Bergisch Gladbach, Germany) (Table 1). Following myeloablative conditioning, each patient received more than 4 x 106 CD34+/kg and approximately 5 x 106/kg body weight (BW) SGM donor T lymphocytes. The latter were immediately detectable in peripheral blood (PB) by quantitative polymerase chain reaction5 (Table 1; Figure 1). Transplantation was well tolerated without acute toxicity; all patients engrafted quickly (Table 1).
Patient 2, with stable numbers of SGM T cells for more than 3 months, is alive and well more than 2.5 years after transplantation (Table 1). Patient 1 early on showed a strong increase of SGM cell counts (Figure 1), without GvHD. Thereafter, PB was cleared of SGM T lymphocytes within a few days. This patient received a second dose of SGM T cells (day 65), which vanished within 2 days (Figure 1), strongly indicative of their immune rejection. Indeed, MLR7 data (not shown) confirmed anti-SGM reactivity of this patient's peripheral blood lymphocytes, possibly related to a herpes simplex virus (HSV) reactivation during transplantation. Patient 3 showed a similar early sharp rise in SGM T cells (Figure 1) associated with acute skin GvHD grade II. Treatment with ganciclovir led to complete resolution of GvHD and rapid disappearance of SGM donor T cells. Most important, patients 1 and 3 developed secondary graft failure (Table 1). Late graft failure may occur in more than 10% of T-cell-depleted hematopoietic SCTs,8 the amount of CD3+ cells in the transplant being most critical. In our study, numbers of "contaminating" T cells in the CD34+ grafts (Table 1) were far below the suggested threshold of 2 x 105/kg,8 but 5 x 106 SGM T cells/kg was added. Obviously, complete loss of these SGM T lymphocytes about 3 weeks after transplantation in both patients (Figure 1) led to a situation comparable to full T-cell depletion. This, probably in concert with other factors (HLA mismatch + busulphan conditioning for CML, patient 1; slightly reduced busulphan dose, patient 38), may have facilitated autologous T-cell recovery, as indicated by T-cell chimerism data from patient 3 (not shown). In conclusion, we confirmed earlier reports1,2 that the use of SGM T lymphocytes may allow control of acute GvHD. At the same time, we made the troubling observation that early total in vivo depletion of SGM donor T cells may be associated with an increased risk of transplant rejection. This suggests that minimum numbers of donor CD3+ cells are required after transplantation, not only to facilitate engraftment8 but also to prevent late rejection. To preclude the rejection risk associated with HSV-tk-mediated depletion of donor T cells, add-back of limited numbers of nonmodified T lymphocytes (eg, 2 x 105 CD3+/kg) to the CD34-enriched PBSCs8 may be a valuable approach.
Correspondence: Boris Fehse, Bone Marrow Transplantation, University Hospital Hamburg-Eppendorf, D-20251 Hamburg, Germany; e-mail: fehse{at}uke.uni-hamburg.de
One of the authors (K.K.) is employed by a company (EUFETS) whose (potential) products may be related to the present work.
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