Naive T-Cell Depletion to Prevent Chronic Graft-Versus-Host Disease

Abstract

PURPOSE Graft-versus-host disease (GVHD) causes morbidity and mortality following allogeneic hematopoietic cell transplantation. Naive T cells (TN) cause severe GVHD in murine models. We evaluated chronic GVHD (cGVHD) and other outcomes in three phase II clinical trials of TN-depletion of peripheral blood stem-cell (PBSC) grafts. METHODS One hundred thirty-eight patients with acute leukemia received TN-depleted PBSC from HLA-matched related or unrelated donors following conditioning with high- or intermediate-dose total-body irradiation and chemotherapy. GVHD prophylaxis was with tacrolimus, with or without methotrexate or mycophenolate mofetil. Subjects received CD34-selected PBSC and a defined dose of memory T cells depleted of TN. Median follow-up was 4 years. The primary outcome of the analysis of cumulative data from the three trials was cGVHD. RESULTS cGVHD was very infrequent and mild (3-year cumulative incidence total, 7% [95% CI, 2 to 11]; moderate, 1% [95% CI, 0 to 2]; severe, 0%). Grade III and IV acute GVHD (aGVHD) occurred in 4% (95% CI, 1 to 8) and 0%, respectively. The cumulative incidence of grade II aGVHD, which was mostly stage 1 upper gastrointestinal GVHD, was 71% (95% CI, 64 to 79). Recipients of matched related donor and matched unrelated donor grafts had similar rates of grade III aGVHD (5% [95% CI, 0 to 9] and 4% [95% CI, 0 to 9]) and cGVHD (7% [95% CI, 2 to 13] and 6% [95% CI, 0 to 12]). Overall survival, cGVHD-free, relapse-free survival, relapse, and nonrelapse mortality were, respectively, 77% (95% CI, 71 to 85), 68% (95% CI, 61 to 76), 23% (95% CI, 16 to 30), and 8% (95% CI, 3 to 13) at 3 years. CONCLUSION Depletion of TN from PBSC allografts results in very low incidences of severe acute and any cGVHD, without apparent excess risks of relapse or nonrelapse mortality, distinguishing this novel graft engineering strategy from other hematopoietic cell transplantation approaches.

Rapid Manufacturing of Highly Cytotoxic Clinical-Grade SARS-CoV-2-specific T Cell Products Covering SARS-CoV-2 and Its Variants for Adoptive T Cell Therapy

“…Virus-specific T cells manufactured using CliniMACS Prodigy and CCS IFN-gamma enriches for memory T cells and reduces the number of naïve T cells, which could be confirmed by the results of this study. Assuming that naive T cells are mainly responsible for GvHD, enrichment of antiviral T cells by IFN-γ secretion will significantly lower GvHD risk while preserving immune memory against viral infections ( Teschner et al, 2014 ; Bleakley et al, 2014 ; Bleakley et al, 2022 ). This is further supported by two literature reports ( Feuchtinger et al, 2006 ; Aïssi-Rothé et al, 2010 ) showing that enrichment for virus-specific T cells reduced proliferation stimulated by a mixed lymphocyte culture with HLA mismatched PBMCs by one to two logs compared with the original lymphocyte harvest.…”

Naïve T-Cell Depletion to Prevent GVHD: Searching for a Better Mousetrap

“…15 So how does the strategy of CD34-selected graft plus addback of the CD45RA T-cell-depleted CD34-negative product (enriched for T M cells) plus calcineurin inhibitor prophylaxis reported herein compare with CD34 selection alone as reported in PROGRESS II? 1,3 Hematopoietic engraftment was excellent with both approaches with low rates of secondary graft failure. Grade III-IV acute GVHD was reported to be 4% and 2.9% in naïve TCD and CD34 selection alone, respectively.…”

“…The naïve TCD depletion process described by Bleakley et al 1 is distinct from pan TCD with broad monoclonal antibodies, elutriation, or CD34-positive selection. Indeed, although naïve CD45RA depletion is novel, the idea of selectively targeting T-cell subsets is not new.…”

“…The rationale behind the approach taken by Bleakley et al 1 in the accompanying article is based on the observation that in mice, naïve T cells (T N ) cause more severe GVHD than memory T cells (T M ). 13,14 Evidence suggests that T N have a more diverse T-cell receptor repertoire than T M cells and are enriched for cells with minor H reactivity.…”

“…Although naïve TCD as described by Bleakley et al 1 may indeed outperform CD34 selection alone, to gain traction, it will need to prove its superiority to other approaches to GVHD prevention commonly in use, namely, antithymocyte globulin (ATG)/anti–T-lymphocyte globulin (ATLG) and now post-transplant cyclophosphamide (PTCy). Five randomized studies of calcineurin inhibitor–based prophylaxis with or without ATG or ATLG have demonstrated a reduction in moderate-severe cGVHD with no compromise of DFS or OS in four of them.…”