Delayed Transfer of Immune Cells or the Art of Donor Lymphocyte Infusion (DLI) 2.0

AbstractIn the context of an allogeneic hematopoietic cell transplantation (HCT), the interplay between host and donor immune cells is considered to be the primary mechanism responsible for graft-versus-leukemia (GVL) reactivity and also able to mediate graft-versus-host disease (GVHD) (Schmid et al. 2021). The tissue specificity of the immune response determines the balance between GVL and GVHD, as well as tropism of GVHD. The main population for success and failure of HCT and DLIs originates from αβT cells. Other subsets are also key modulators of efficacy. For example, NK cells most likely provide acute control of leukemia and of infections like CMV. However, NK cells become rapidly educated over time (Orr and Lanier 2010) and lose their antileukemia activity. Thus, donor transfer of NK cells is obsolete and needs additional, for example, genetic modification to engineer long-term efficacy (Laskowski et al. 2022; Liu et al. 2020). Other subsets, like γδT cells, appear to have a more prolonged antileukemia effect (Handgretinger and Schilbach 2018; Sebestyen et al. 2020) and are also helpful in controlling CMV reactivation (Scheper et al. 2013; de Witte et al. 2018). However, also, donor γδT cells can lose activity over time, and sustainable activity requires, outside the context of an HCT, most likely further modifications (Sebestyen et al. 2020; Li et al. 2023). NKT cells, like regulatory T cells, have been mainly reported to influence GVHD. While an increase in NKT cells in the graft associates with a reduced GVHD incidence (Malard et al. 2016), depletion of regulatory T cells in donor lymphocyte infusions (DLI) improves GVL effects, although it augments the risk of GVHD (Maury et al. 2010). Thus, lymphocyte infusions as part of the graft at the time of transplantation, or delayed as DLI, have multiple effector cells that need to be considered in terms of different alloreactive effects (for review see also (Schmid et al. 2021)).