“Ex‐vivo” T‐cell depletion in allogeneic hematopoietic stem cell transplantation: New clinical approaches for old challenges

Abstract

Allogeneic transplantation still remains as standard of care for patients with high‐risk hematological malignancies at diagnosis or after relapse. However, GvHD remains yet as the most relevant clinical complication in the early post‐transplant period. TCD allogeneic transplant is now considered a valid option to reduce severe GvHD and to provide a platform for cellular therapy to prevent relapse disease or to treat opportunistic infections.

The monoculture of cord-blood-derived CD34+ cells by an automated, membrane-based dynamic perfusion system with a novel cytokine cocktail

“…Various strategies for cell processing and expansion of CB-derived CD34 + have been proposed to reduce the incidence of GVHD and to increase the cell dose for engraftment in HSCT ( Diaz et al., 2021 ; Lang et al., 2014 ). More recent protocols involve both the selection of CD34 + cells and the retention of CD34 − fraction, which may contain immune modulatory cell types for co- or sequential administration ( Cohen et al., 2020 ).…”

“…CB-derived CD34 + stem cells and progenitor cells are typically selected for hematopoietic reconstitution as a result of their increased capacity for self-renewal and proliferation, longer telomeres, and lower incidence of graft-versus-host disease (GVHD) through a lower frequency of alloreactive T cells along with their ability to achieve rapid engraftment in hematological transplant recipients ( Gupta and Wagner, 2020 ). However, one of the challenges in this setting is to provide a sufficient number of T cell-depleted hematopoietic stem and progenitor cells, which are necessary to support mixed allogeneic hematopoietic stem cell transplantation (HSCT) ( Diaz et al., 2021 ; Singh et al., 2019 ). Only about 4%–5% of the CB units stored in CB banks contain a sufficient number of CD34 + cells for single-unit grafts (≥1.05 × 10 7 CD34 + cells) or for double-unit grafts (≥1.40 × 10 7 CD34 + cells) for 70-kg patients ( Politikos et al., 2020 ; Cohen et al., 2020 ; Barker et al., 2019 ).…”

Haploidentical vs. HLA-matched donor hematopoietic stem-cell transplantation for pediatric patients with acute lymphoblastic leukemia in second remission: A collaborative retrospective study of the Spanish Group for Bone Marrow Transplantation in Children (GETMON/GETH) and the Spanish Childhood Relapsed ALL Board (ReALLNet)

“…However, if we focus on specific data from children with ALL undergoing SCT in CR2, we can see that our estimated CIR is in line with that from previous studies, particularly after a non-TBI conditioning regimen ( Supplementary Table S13 ) ( 24 , 26 , 27 , 30 , 46 , 51 ). In order to prevent relapse after SCT, we will need to reduce the tumor burden before SCT through the application of modern leukemia treatment approaches, including specific monoclonal antibodies and chimeric antigen receptor T-cell therapy, improve the efficacy of the conditioning regimens, and explore the role of post-transplant interventions such as early withdrawal of immunosuppression and adoptive immunotherapy strategies ( 3 , 16 , 19 , 24 , 31 , 48 , 54 ). In this context, given the donor availability and proximity, haploidentical SCT offers an ideal platform for the design of such trials ( 4 , 14 , 20 , 24 ).…”

Is It Possible to Separate the Graft-Versus-Leukemia (GVL) Effect Against B Cell Acute Lymphoblastic Leukemia From Graft-Versus-Host Disease (GVHD) After Hematopoietic Cell Transplant?

“…The suppressive effects of T REGS appear to constrain new host-alloreactive effector T-cells both early and late after PTCy HCT, thus keeping severe aGVHD and cGVHD in check ( 27 ). (2) Highly proliferative host-alloreactive donor CD8 + effector T-cells are not eliminated after PTCy, but are intact and made functionally impaired, reducing their ability to cause GvHD ( 26 ). This impairment is likely related to both direct effects of PTCy (immediate) and preferential reconstitution of T REGS (late).…”

“…By comparison, ex-vivo graft manipulation to remove GVHD causing TCRαβ + T-cells (TCRαβ + /CD19 + depletion) has also gained traction in pediatric acute leukemia to overcome HLA disparity ( 60 ). The selective removal of most TCRαβ + T-cells appears to reduce both aGVHD and cGVHD, while maintaining NK cells and TCRγδ + T-cells that have less host alloreactivity but are able to mediate GVL ( 26 ). A number of potential mechanisms exist by which TCRγδ + T-cells and NK cells mediate GVL, including the shared presence of activating receptors (e.g., NKG2D) that are independent of tumor antigen recognition in the context of MHC, thus able to bypass tumor escape through MHC class I downregulation ( 27 ).…”