GVHD Prophylaxis 2020

Abstract

Graft-vs. host disease (GVHD), both acute and chronic are among the chief non-relapse complications of allogeneic transplantation which still cause substantial morbidity and mortality despite significant advances in supportive care over the last few decades. The prevention of GVHD therefore remains critical to the success of allogeneic transplantation. In this review we briefly discuss the pathophysiology and immunobiology of GVHD and the current standards in the field which remain centered around calcineurin inhibitors. We then discuss important translational advances in GVHD prophylaxis, approaching these various platforms from a mechanistic standpoint based on the pathophysiology of GVHD including in-vivo and ex-vivo T-cell depletion alongwith methods of selective T-cell depletion, modulation of T-cell co-stimulatory pathways (checkpoints), enhancing regulatory T-cells (Tregs), targeting T-cell trafficking as well as cytokine pathways. Finally we highlight exciting novel pre-clinical research that has the potential to translate to the clinic successfully. We approach these methods from a pathophysiology based perspective as well and touch upon strategies targeting the interaction between tissue damage induced antigens and T-cells, regimen related endothelial toxicity, T-cell co-stimulatory pathways and other T-cell modulatory approaches, T-cell trafficking, and cytokine pathways. We end this review with a critical discussion of existing data and novel therapies that may be transformative in the field in the near future as a comprehensive picture of GVHD prophylaxis in 2020. While calcineurin inhibitors remain the standard, post-transplant eparinsphamide originally developed to facilitate haploidentical transplantation is becoming an attractive alternative to traditional calcinuerin inhibitor based prophylaxis due to its ability to reduce severe forms of acute and chronic GVHD without compromising other outcomes, even in the HLA-matched setting. In addition T-cell modulation, particularly targeting some important T-cell co-stimulatory pathways have resulted in promising outcomes and may be a part of GVHD prophylaxis in the future. Novel approaches including targeting early events in GVHD pathogenesis such as interactions bvetween tissue damage associated antigens and T-cells, endothelial toxicity, and T-cell trafficking are also promising and discussed in this review. GVHD prophylaxis in 2020 continues to evolve with novel exicitng therapies on the horizon based on a more sophisticated understanding of the immunobiology of GVHD.

Current Prophylaxis and Treatment Approaches for Acute Graft-Versus-Host Disease in Haematopoietic Stem Cell Transplantation for Children With Acute Lymphoblastic Leukaemia

“…In a group of patients with sickle cell disease undergoing matched sibling donor bone marrow transplantation, late alemtuzumab administration in the conditioning regimen (days −10 to −8) was associated with lower aGvHD but higher graft rejection compared to early alemtuzumab administration (days −19 to −17) ( 58 ). Several studies, mainly in reduced intensity conditioning HSCT for non-mailgnant diseases showed that alemtuzumab levels impact aGvHD, chimerism and lymphocyte recovery ( 59 , 60 ), but also in malignant diseases ( 61 ). Although alemtuzumab abrogated severe GvHD this was not necessarily associated with improved OS ( 62 ).…”

“…Graft engineering by various ex vivo TCD methods aims at maintaining anti-viral and anti-leukaemia activity while reducing the risk for GvHD. Such metods are: (1) the positive selection of CD34 + cells with or without a T-cell add-back at a later time point, or (2) the negative selection against CD3 + and CD19 + cells or (3) selective TCR αß + and CD19 + depletion with preservation of γδ T cells and natural killer (NK) cells as well as (4) depletion of naïve CD45RA + T-cells ( 60 , 61 ). Di Ianni et al evaluated a protocol with regulatory T-cell infusion 4 days prior to haploidentical transplantation in adult patients ( n = 28) with haematological malignancies using CD34 + purified stem cells and add back of conventional T cells (up to 10 6 /kg).…”

Off-the-shelf third-party HSC-engineered iNKT cells for ameliorating GvHD while preserving GvL effect in the treatment of blood cancers

“…GvHD prophylaxis is centered around calcineurin inhibitor (CNI)-based therapy and investigations into new methods including depleting T cells, modulating T cell co-stimulatory pathways (e.g., checkpoints), enhancing regulatory T cells, targeting T cell trafficking, and altering cytokine pathways ( Gooptu and Antin, 2021 ). Despite prophylactic interventions, acute GvHD is a common complication of allo-HSCT, occurring in 30–50% of patients, 14–36% of whom develop severe acute GvHD, and is a major cause of morbidity and mortality ( Malard et al., 2020 ).…”

CAR-T Regulatory (CAR-Treg) Cells: Engineering and Applications

“…Graft-versus-host disease (GvHD) is caused by immune cells in the grafted tissues attacking recipient cells following allogeneic transplantation of organs rich in lymphoid cells, such as liver or nonirradiated blood transfusion [ 66 ]. Immune responses to solid tissue transplantation can be classified to direct and indirect pathways of allosensitization.…”