Rapid memory T-cell reconstitution recapitulating CD45RA-depleted haploidentical transplant graft content in patients with hematologic malignancies

Abstract

T-cell depletion of an HLA-haploidentical graft is often used to prevent graft-vs.-host disease (GvHD), but the procedure may lead to increased graft failure, relapse, and infections due to delayed immune recovery. We hypothesized that selective depletion of the CD45RA+ subset can effectively reduce GvHD through removal of naïve T cells, while providing improved donor immune reconstitution through adoptive transfer of CD45RA– memory T cells. Herein, we present results from the first 17 patients with poor-prognosis hematologic malignancy who received haploidentical donor transplantation with CD45RA-depleted progenitor cell grafts following a novel reduced intensity conditioning regimen without total body irradiation or serotherapy. Extensive depletion of CD45RA+ T cells and B cells, with preservation of abundant memory T cells, was consistently achieved in all 17 products. Neutrophil engraftment (median day +10) and full donor chimerism (median day +11) was rapidly achieved post-transplantation. Early T-cell reconstitution directly correlated with the CD45RA-depleted graft content. T-cell function recovered rapidly with broad TCR Vβ spectra. There was no infection-related mortality in this heavily pretreated population, and no patient developed acute GvHD despite infusion of a median of >100 million per kilogram haploidentical T cells.

Overview of the progress on haploidentical hematopoietic transplantation

“…Ex vivo depletion of CD45RA + T-cells and adoptive transfer of CD45RA-memory T cells hasten the immune reconstitution post-transplant, enhances the GVL effect while abrogating GVHD. This strategy was recently evaluated in a study of 17 adults with high risk hematologic malignancies (16 AML and 1 myelodysplasia) with KIR receptor-ligand mismatched haploidentical donor[38]. The conditioning regimen included total lymphoid irradiation (8 Gy), fludarabine (150 mg/m 2 ), cyclophosphamide (60 mg/kg), thiotepa (10 mg/kg) and melphalan (140 mg/m 2 ).…”

Outcomes of acute leukemia patients transplanted with naive T cell–depleted stem cell grafts

“…Following the completion of conditioning, patients received a graft composed of CD34-selected PBSCs (≥5 × 10 If randomized trials confirm the substantial reduction in cGVHD with T N depletion observed in our trial, without impairment of other important HCT outcomes, this approach could be used at most HCT centers. During the period of patient accrual in our trial, 3 small pilot studies of T N depletion in recipients of HLA-mismatched or haploidentical HCT were initiated at other centers and published (59)(60)(61). Two of these studies administered antithymocyte globulin or alemtuzumab to provide additional TCD (59,60), and the third study incorporated total lymphoid irradiation in the conditioning regimen and NK cell infusions after HCT (61).…”

“…During the period of patient accrual in our trial, 3 small pilot studies of T N depletion in recipients of HLA-mismatched or haploidentical HCT were initiated at other centers and published (59)(60)(61). Two of these studies administered antithymocyte globulin or alemtuzumab to provide additional TCD (59,60), and the third study incorporated total lymphoid irradiation in the conditioning regimen and NK cell infusions after HCT (61). The small sizes of these studies; differences in the patient populations, donor sources, and conditioning; and the inclusion of T celldepleting antibodies, total lymphoid irradiation, or additional cell infusions preclude comparisons of the reported patient outcomes with the results of our trial.…”

CMV-specific immune reconstitution following allogeneic stem cell transplantation

“…These include addback of ex vivo allodepleted T cells and na€ ıve T cell depletion of stem cell products via CD45RA or TCRa/b depletion. [111][112][113] Incorporation of safety switches into T cells prior to infusion allows selective deletion of genemodified cells if GVHD occurs. 114,115 Other immunomodulatory approaches to GVHD include induction of anergy or administration of regulatory T cells but the effect of these strategies on CMV immunity has not been studied.…”