Effective T-cell therapy against cancer is dependent on the formation of long-lived, stem cell–like T cells with the ability to self-renew and differentiate into potent effector cells. Here, we investigated the in vivo existence of stem cell–like antigen-specific T cells in allogeneic stem cell transplantation (allo-SCT) patients and their ex vivo generation for additive treatment posttransplant. Early after allo-SCT, CD8⁺ stem cell memory T cells targeting minor histocompatibility antigens (MiHAs) expressed by recipient tumor cells were not detectable, emphasizing the need for improved additive MiHA-specific T-cell therapy. Importantly, MiHA-specific CD8⁺ T cells with an early CCR7⁺CD62L⁺CD45RO⁺CD27⁺CD28⁺CD95⁺ memory-like phenotype and gene signature could be expanded from naive precursors by inhibiting Akt signaling during ex vivo priming and expansion. This resulted in a MiHA-specific CD8⁺ T-cell population containing a high proportion of stem cell–like T cells compared with terminal differentiated effector T cells in control cultures. Importantly, these Akt-inhibited MiHA-specific CD8⁺ T cells showed a superior expansion capacity in vitro and in immunodeficient mice and induced a superior antitumor effect in intrafemural multiple myeloma–bearing mice. These findings provide a rationale for clinical exploitation of ex vivo–generated Akt-inhibited MiHA-specific CD8⁺ T cells in additive immunotherapy to prevent or treat relapse in allo-SCT patients.