Abstract
Adoptive transfer of T cells transgenic for tumor-reactive T-cell receptors (TCR) is an attractive immunotherapeutic approach. However, clinical translation is so far limited due to challenges in the identification of suitable target antigens as well as TCRs that are concurrent safe and efficient. Definition of key characteristics relevant for effective and specific tumor rejection is essential to improve current TCR-based adoptive T-cell immunotherapies. We here characterized in-depth two TCRs derived from the human leukocyte antigen (HLA)-mismatched allogeneic repertoire targeting two different myeloperoxidase (MPO)-derived peptides presented by the same HLA-restriction element side by side comprising state of the art biochemical and cellular in vitro, in vivo, and in silico experiments. In vitro experiments reveal comparable functional avidities, off-rates, and cytotoxic activities for both TCRs. However, we observed differences especially with respect to cytokine secretion and cross-reactivity as well as in vivo activity. Biochemical and in silico analyses demonstrate different binding qualities of MPO-peptides to the HLA-complex determining TCR qualities. We conclude from our biochemical and in silico analyses of peptide-HLA-binding that rigid and high-affinity binding of peptides is one of the most important factors for isolation of TCRs with high specificity and tumor rejection capacity from the MHC-mismatched repertoire. Based on our results, we developed a workflow for selection of such TCRs with high potency and safety profile suitable for clinical translation.
Highlights
Adoptive T-cell transfer of immune receptor transgenic T cells has demonstrated high clinical potential especially for chimeric antigen receptors (CAR) [1]
We have previously identified a leukemia-associated HLAB0702-restricted epitope derived from MPO (MPO466−474 named MPO5) by mass spectrometry (MS) as well as the TCR2.5D6 derived from the single human leukocyte antigen (HLA)-mismatched allorestricted approach (sHLAm) T-cell repertoire with high peptide specificity and leukemic reactivity suitable for clinical application in the context of allogeneic stem cell transplantation [27]
In our MS-based approach additional MPO epitopes presented on myeloid tumor cells have been identified [27] and selected for stimulation in sHLAm approaches to identify new MPO-specific T-cell receptors (TCR)
Summary
Adoptive T-cell transfer of immune receptor transgenic T cells has demonstrated high clinical potential especially for chimeric antigen receptors (CAR) [1]. A number of candidate TCRs have been proposed [2,3,4], only a few clinical trials have been published [5, 6] likely explainable by the challenging selection process for suitable peptide antigens as well as potent and safe TCRs. Diverse qualities of TCRs have been described to be essential and potentially predict anti-tumor reactivity in vivo as especially functional avidity and affinity of TCRs [7,8,9,10,11]. There are less recommendations for high avidity TCRs deriving from the allogeneic or xenogeneic environment or selected by affinity maturation. This is especially important as these TCR may harbor an enhanced risk profile for crossreactivity and toxicity [13, 14]. The functionality and efficiency of transferred TCR cell-surface expression depend on the intrinsic quality of the TCR complex [15] and the Tcell specificity might be affected by the formation of mixed heterodimers composed of endogenous and transgenic TCR chains [16]
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