Depletion of naive T cells using clinical grade magnetic CD45RA beads: a new approach for GVHD prophylaxis

Abstract

Depletion of naive T cells from donor leukapheresis products (LPs) aims at the reduction of alloreactivity, while preserving memory T-cell reactivity (for example, to pathogens). This study established the immunomagnetic depletion procedure under clean room conditions using CD45RA beads and analyzed LPs of six donors for cell composition and functional immune responses. CD45RA depletion resulted in 3.4-4.7 log (median 4.4) reduction of CD45RA þ T cells, thereby eliminating naive and late effector T cells. B cells were also completely removed, whereas significant proportions of NK cells, monocytes and granulocytes persisted. CD45RA-depleted LPs contained effector and central memory CD4 þ and CD8 þ T cells that showed sustained IFN-g secretion to CMV, EBV, Aspergillus and Candida Ags. Alloreactivity was measured in MLRs between donors with complete HLA-mismatch. Alloreactive CD8 þ T cells were strongly reduced (median 41-log) upon CD45RA depletion, whereas alloreactive CD4 þ T cells persisted in significant numbers. In conclusion, clinical grade depletion of CD45RA þ naive T cells from donor LPs is feasible and highly efficient. The depleted products show sustained CD4 þ and CD8 þ T-cell reactivity to pathogens and effectively reduced CD8-mediated alloreactivity. Prophylactic and preemptive infusions after allogeneic SCT may improve T-cell reconstitution and pathogen-specific immunosurveillance, along with lower risk of inducing GVHD.

Generation of memory T cells for adoptive transfer using clinical-grade anti-CD62L magnetic beads

“…6 These findings offer the opportunity of using memory T cells to enhance immune reconstitution following allo-SCT and provide broad immunity to multiple pathogens without the risk of GVHD. The feasibility of naive T-cell removal from donor leukaphereses using commercially available CD45RA reagents has also recently been reported, 7,8 although how products lacking CD45RA + cells compare with those lacking CD62L + cells is not known. In this current study, we demonstrate for the first time the feasibility of clinical-grade immunomagnetic selection of CD62L − cells under good manufacturing practice (GMP) conditions and describe the composition and functions of the resulting product.…”

The MEK inhibitor trametinib separates murine graft-versus-host disease from graft-versus-tumor effects

“…Therefore, methods to selectively deplete CD45RA + naive T cells from the graft to reduce acute and chronic GVHD are being developed (12,13). However, the cost of ex vivo selective depletion is high, and it is unclear whether this method can reduce chronic GVHD because chronic GVHD is assumed to originate from T cells that differentiate from graft-derived hematopoietic stem cells.…”

“…In mice, the transfer of naive T cells results in GVHD, whereas that of memory T cells does not (8)(9)(10), but still preserves GVT effects (11). In humans, selective depletion of naive T cells suppresses alloreactivity in vitro (12,13), while memory T cells are involved in antimicrobial immunity (14). Thus, selective suppression of…”

Selective, efficient modulation of activated CD4+ αβT cells by the novel humanized antibody GZ-αβTCR targeting human αβTCR

“…42,43 The observed preferential depletion of those T cells that are detrimental in transplant settings directly relates to emerging clinical trials performing CD45RA depletion from the haematopoietic graft to prevent a GvHD. 22,23 This will allow us to significantly reduce the risk of allograft rejection but spare memory T cells, desirable pathogen-reactive immunity, in the patient.…”