Allogeneic hematopoietic cell transplantation (HCT) is a potentially curative treatment for patients with hematologic malignancies [1]. The immunological graft-versus-leukemia (GVL) effect mediated by donor lymphocytes provides protection from relapse, particularly after one-year post-HCT, and for patients receiving lower-intensity conditioning. GVL-mediating donor T cells recognize a variety of non-donor self-antigens on recipient cells [2], including nonshared human leukocyte antigen (HLA) recognized directly (mismatched HLA complexed with self or other peptide) or indirectly (peptide epitopes from mismatched HLA presented on shared HLA) in HLA-mismatched HCT, and minor histocompatibility (H) antigens, HLA-presented polymorphic peptides derived from normal self-proteins differing in amino acid sequence between donor and recipient due to genetic polymorphisms, in HLA-matched HCT. Donor T cells specific for nonpolymorphic leukemia antigens or neoantigens may also contribute to GVL responses. Natural killer (NK) cells play an especially crucial role in GVL after HLA haploidentical HCT: in this context, inhibitory killer cell Ig-like receptors (KIR) on donor NK cells detect the absence of the non-shared self-HLA class I alleles on recipient cells, leading to NK-alloreactivity, and produce antileukemic effects [3].

Although HCT can cure patients, graft-versus-host disease (GVHD) and relapse remain the leading causes of post-HCT morbidity and mortality. Targeted maintenance therapy has reduced relapse in subsets of patients with specific molecular abnormalities [4] but is not yet widely applicable. Post-HCT relapse, when it occurs, poses a significant clinical challenge, and survival for patients with post-HCT relapse is only approximately four months [2] despite treatment. Alloreactive lymphocytes, chiefly T cells, can cause GVHD as well as GVL. New approaches to GVHD prevention, such as post-HCT cyclophosphamide (PTCy) [5], graft engineering [6], co-stimulatory blockade 7, 8, and co-administration of regulatory T cells (Tregs) with the allograft 9, 10, 11 show promise in reducing serious GVHD without excessive relapse. Moreover, improving knowledge of the mechanisms of immune evasion leading to post-HCT relapse and a growing ability to engineer and manipulate lymphocytes have opened the doors to new strategies to prevent and treat post-HCT relapse without exacerbating GVHD. This review addresses several recent innovations in the field (Figure 1).