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Acute graft-versus-host disease (aGvHD) is a major complication following hematopoietic stem cell transplant (HSCT) that contributes to high non-relapse mortality. The disease process is initiated by the migration of donor T cells to the host secondary lymphoid organs and their activation by allo-antigens on host antigen-presenting cells (APC).1 CCR7, a chemokine receptor, and its ligands CCL19 and CCL21 expressed by donor T cells is critically important for lymph node specific homing and activation of T cells by APCs.2
Previous reports demonstrated that a high proportion of CCR7+ donor T-cell subsets in the graft was an independent risk factors for aGvHD and correlated with poorer outcome.3
A study published by Carlos Cuesta-Mateos and colleagues explored whether apheresis with a low proportion of CCR7+ cells or blocking the function of CCR7 with an anti-human CCR7 monoclonal antibody (mAb) could prevent or treat aGvHD in preclinical models.4
In total, 103 donor–recipient pairs who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) were analyzed. Transplant characteristics are presented in Table 1.
Table 1. Selected transplant characteristics
BMSC, bone marrow stem cells; CsA, cyclosporin A; HLA, human leukocyte antigen; MMF, mycophenolate mofetil; MTX, methotrexate; PBSC, peripheral blood stem cells
Diagnosis of the underlying disease (Relapse rate, %)
Acute lymphoid leukemia
Acute myeloid leukemia
Chronic lymphocytic leukemia
Male to male
Female to female
HLA-identical (10/10) unrelated
HLA mismatched (9/10) unrelated
Source of graft
Infused CD34+ 106/kg of recipient weight
Infused CD3+ 106/kg of recipient weight
CsA and MTX
CsA and MMF
Correlating rate of transfused CCR7+ cells with induction of GvHD in humans and mice
In patients, apheresis with < 3.6% of CD4+ CCR7+ cells showed low risk of developing aGvHD, with 87.88% (75.23–100%) of patients not developing the complication. The cut off for CD8+ CCR7+ was < 2.2% cells in the apheresis, with 88.57% (76.60–100%) of patients free from chronic (c)GvHD.
In contrast, xenograft models of GvHD demonstrated that lowering the proportion of CCR7+ cells used for apheresis failed to prevent or delay GvHD. The median overall survival (OS) was 14 days for animals engrafted with apheresis products containing ≤3% of CD4+ CCR7+ (n = 6) vs 13 days for mice with apheresis around 20% of CCR7+ cells.
Using anti-CCR7 mAb impairs CCR7+ TN and TCM cells chemotaxis and induces CDC
The addition of anti-CCR7 mAb to PBMC reduced the migration of CCR7+ TN and TCM cells stimulated with CCL19 or CCL21. CCR7 ligands and anti-CCR7 mAb did not induce responses in TEM and TEMRA cells which were CCR7-. Moreover, in vitro assays using anti-CCR7 mAb with fresh hPBMC from apheresis demonstrated strong depletion of CCR7+ but not CCR7- human TN and TCM cells via CDC.
CCR7+ T-cells are not involved in CMV reactivation and GvL effect
In patients, the levels of donor CCR7+ T cells in the apheresis did not correlate with cytomegalovirus (CMV) reactivation within the first six months after transplantation or with a relapse of the underlying disease.
Anti-hCCR7 mAb prevents aGvHD in xenograft models
In xenogenic models of aGvHD induced by engrafting of hPBMC, early administration of anti-CCR7 mAb, after hPBMC inoculation, prevented the development of aGvHD. Animals treated later than on Day 5 after engraftment had infiltration of human T cells in all tissues, which was, however, lower than in control mice.
The authors of the article demonstrated that selective targeting of CCR7 with antibodies is a feasible and promising way to prevent donor T-cell migration to secondary lymphoid organs and to reduce the severity of aGVHD. Importantly, CCR7+ T cells seem not to be involved in the GvL effect or CMV reactivation. Other than in humans, xenograft models suggest that even small amounts of CCR7+ T cells can induce GvHD. The most profound anti-aGvHD effect was observed in transplanted mice, when an anti-hCCR7 mAb was administrated within the first five days after transplantation. This novel prophylactic approach could offer a benefit to patients in haploidentical settings, who have a particularly large unmet need for safe and effective therapies preventing GvHD.
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