Abstract
Acute myeloid leukemia (AML) that is relapsed and/or refractory post-allogeneic hematopoietic cell transplantation (HCT) is usually fatal. In a prior study, we demonstrated that AML relapse in high-risk patients was prevented by post-HCT immunotherapy with Epstein-Barr virus (EBV)-specific donor CD8(+) T cells engineered to express a high-affinity Wilms Tumor Antigen 1 (WT1)-specific T-cell receptor (T(TCR-C4)). However, in the present study, infusion of EBV- or Cytomegalovirus (CMV)-specific T(TCR-C4) did not clearly improve outcomes in fifteen patients with active disease post-HCT. TCR(C4)-transduced EBV-specific T cells persisted longer post-transfer than CMV-specific T cells. Persisting T(TCR-C4) skewed towards dysfunctional natural killer-like terminal differentiation, distinct from the dominant exhaustion programs reported for T-cell therapies targeting solid tumors. In one patient with active AML post-HCT, a sustained T(TCR-C4) effector-memory profile correlated with long-term T(TCR-C4) persistence and disease control. These findings reveal complex mechanisms underlying AML-induced T-cell dysfunction, informing future therapeutic strategies for addressing post-HCT relapse.