Key Points• Inhibition of Akt signaling promotes generation of superior tumor-reactive T cells with stem cell-like properties.• Adoptive transfer of Akt-inhibited tumor-reactive T cells results in superior antitumor effect.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 1 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 1 T cells with an early1 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 1 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 MiHAspecific CD81 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 1 T cells in additive immunotherapy to prevent or treat relapse in allo-SCT patients. (Blood. 2014;124(23):3490-3500)

In renal transplantation, polymorphic amino acids on mismatched donor HLA molecules can lead to the induction of de novo donor‐specific antibodies (DSA), which are associated with inferior graft survival. To ultimately prevent de novo DSA formation without unnecessarily precluding transplants it is essential to define which polymorphic amino acid mismatches can actually induce an antibody response. To facilitate this, we developed a user‐friendly software program that establishes HLA class I and class II compatibility between donor and recipient on the amino acid level. HLA epitope mismatch algorithm (HLA‐EMMA) is a software program that compares simultaneously the HLA class I and class II amino acid sequences of the donor with the HLA amino acid sequences of the recipient and determines the polymorphic solvent accessible amino acid mismatches that are likely to be accessible to B cell receptors. Analysis can be performed for a large number of donor‐recipient pairs at once. As proof of principle, a previously described study cohort of 191 lymphocyte immunotherapy recipients was analysed with HLA‐EMMA and showed a higher frequency of DSA formation with higher number of solvent accessible amino acids mismatches. Overall, HLA‐EMMA can be used to analyse compatibility on amino acid level between donor and recipient HLA class I and class II simultaneously for large cohorts to ultimately determine the most immunogenic amino acid mismatches.

Recent data suggest that HLA epitope matching is beneficial for the prevention of de novo donor specific antibody (DSA) formation after transplantation. In this review, different approaches to predict the immunogenicity of an HLA mismatch will be discussed. The parameters used in these models are often called epitopes but the actual antibody epitope is far more complex. Exact knowledge of the antibody epitope is crucial if epitope matching is also used as a tool to select compatible donors for (highly) sensitized patients. Evidence is provided that it is not always possible to give an exact definition of an antibody epitope. We conclude that HLA "epitope" matching is superior over HLA antigen matching with respect to the prevention of de novo DSA formation and will enhance the prediction of acceptable HLA mismatches for sensitized patients. However, epitope matching at our current level of knowledge will not solve all histocompatibility problems as unexpected antibody reactivity still may occur.

No abstract