Feasibility Of αβT- Cell Depleted Allogeneic Stem Cell Transplantations From Matched Related and Unrelated Donor Grafts and Engraftment In Patients With Poor Risk Leukemia
Authors: Boome Liane te , Wagen Lotte van der , Westinga Kasper , Slaper-Cortenbach Ineke , Kuball Jurgen H 
Published: October 2019

Abstract

Rationale
αβT- cell depleted allogeneic haematopoietic stem cell transplantations (allo-SCT) have so far been reported in haploidentical stem cell transplantations. First results have been promising with a good engraftment and low incidence of GVHD. However, high rates of life-threatening GVHD are still observed within the context of matched related (MRD) and unrelated (MUD) donors. Therefore we aimed to assess the feasibility of αβT-cell depletion in the context of MUD and MRD and aimed to establish a transplantation regimen for patients with MRD and MUD undergoing an αβT- cell depleted allo-SCT.

Objective
To test feasibility of the generation of αβT- cell depleted grafts from MRD and MUD and assess the engraftment in the context of different conditioning regimens after allo-SCT in patients with poor risk leukemia.

Method
Initial proof runs for the generation of αβT-cell and CD19 depleted grafts have been performed in 4 healthy donors. Grafts for transplantation of the first 5 patients (cohort I) have been depleted with GMP-grade anti-αβTCR and anti-CD19 antibodies. The subsequent grafts for patients in cohort II (n=4) and III (n=2) have been selectively depleted with GMP-grade anti-αβTCRs antibodies. Three conditioning regimens have been investigated (I): fludarabine 120 mg/m2 + cyclophosfamide 4800 mg/m2, (II): fludarabine 120 mg/m2 + busilvex AUC=90 and (III): ATG (Genzyme®) 4 mg/m2 + fludarabine 120 mg/m2 + busilvex AUC=90 followed by αβT- cell depleted grafts from matched related or unrelated donors. No additional immune suppression was given after allo-SCT.
Main study parameters/endpoints: (1) Feasibility to generate an αβT-cell depleted graft form MRD and MUD. (2) Engraftment and reconstitution of T-cells within the context of different transplantation regimens.

Results
Products for 11 patients have been successfully processed and used for αβT-cell depleted allo-SCT between 2011 and 2013. A ∼4 log depletion of αβT-cells has been observed in the product with a recovery of ∼75% of CD34+ cells. In cohort I, primary engraftment (chimerism > 95%) was 40%. Engrafted patients showed a rapid reconstitution of γδT-cells and αβT-cells with a broad αβT-cell repertoire as determined by spectratyping. Therefore the next cohort was dose-intensified and the CD19-depletion omitted (cohort II). 75% of cohort II showed a swift engraftment. Again a dominance of γδT-cells was observed which associated with a rapidly reconstituting αβT-cell repertoire. Omitting CD19-depletion did not result in severe EBV-reactivations. One patient had an EBV reactivation under a short course of prednisone; however EBV was rapidly cleared after tapering steroids. In order to further increase engraftment cohort III was additionally treated with an early application of ATG (day -10/-9) and no graft failure has been observed so far.

Conclusion
αβT-cell depletion is feasible in the context of MRD and MUD. An intensified conditioning with additional host T-cell depletion seems to be beneficial for a profound engraftment. αβT-cell depletion associates with a swift and dominant reconstitution of γδT-cells as well as a rapidly restoring αβT-cell repertoire which is able to control viral re-activations.

Disclosures:
Kuball: Miltenyi: GMP product development Other.