Background: Severe viral infections are frequent and remain one of the most important cause of non-relapse mortality and morbidity in recipients of ab T cell-depleted grafts. In this analysis we have tested the hypothesis that adoptive transfer of low doses of memory T-cells is a safe way to improve immune response to common pathogens.
Methods: Fifty-one patients with non-malignant disorders received 1st ab T cell-depleted HSCT, median age was 5y(1-22), m:f-38:13. Donors were haploidentical (n-17) or matched unrelated (n-34). Only CMV seropositive donor/recipient pairs were eligible. Infusions of memory T-cells were planned at escalating doses (25x103/kg, 50x103/kg, 100x103/kg in haploidentical, and 100x103/kg, 200x103/kg, 300x103/kg, in MUD transplants), with monthly intervals. At the moment of 1st DLI all patients had stable graft function, no signs of active GVHD or severe infection. Memory T-cells were derived from G-CSF stimulated (n - 37) or unstimulated (n - 14) apheresis of the original donors. Apheresis product was processed with single-step CD45RA depletion procedure on CliniMACS Plus or Prodigy platform. CD45RA-depleted fraction was aliquoted and cryopreserved for further use. Beyond routine monitoring of CMV, EBV and Adenovirus DNA load, lymphocyte subset regeneration and hematopoietic chimerism, development of pathogen-specific (CMV, EBV, Adeno) immunity was monitored by the ELISPOT assay for IFN-gamma production in response to respective antigen stimulation.
Results: Between 26.09.14 and 18.04.2017, 51 patients received 131 memory T-cell infusions. The procedure of CD45RA depletion was effective with > 4,5 log depletion of CD45RA. Final product contained negligible numbers of CD45RA+ naive T-cells. Median day of the first infusion was +35 (20-70). Eight patients (35%) had first CMV viremia before DLI#1. Seven patients developed signs of acute GVHD grade ³ II and 5 - chronic GVHD after infusion. In a group of 47 patients without prior GVHD, СI of GVHD at +1,8 year FU was 9% (7-10). Acute GVHD was grade II in all cases with involvement of skin (n=2) or gut (n=2) or gut + skin (n=1). Two patients responded to the first line therapy, in 3 mild chronic GVHD developed. One patient required IST at last follow-up. In a group of 51 patients CI of TRM was 4% (1-15). Causes of death included generalized CMV infection (n=1) and multiorgan failure + generalized CMV+ ADV infection in a patient who had received massive immunosuppressive therapy for immune hemolysis. According to ELISPOT analysis, among patients with absent CMV-specific immune reactivity at baseline (n = 34) expansion of CMV-specific T-cells was demonstrated in 16 (47%) within 100 days.
Conclusions: This preliminary analysis suggests that transfusions of low-dose memory T-cells after engraftment in non-malignant recipients of ab T cell-depleted haploidentical and unrelated HSCT are safe and potentially may provide necessary antiviral reactivity. Prospective randomized trial is warranted to determine the clinical value of this approach.
Disclosure: Nothing to declare