Selection of optimal affinity enhanced T-cell receptors for cancer therapy

What is it about?

T-cells transduced with affinity-enhanced receptors for cancer antigens are emerging as a promising therapy for cancers that resist conventional therapies. However, this strategy can also cause unexpected reactions against health tissues due to T-cell receptor (TCR) crossreactivity. To mitigate this risk, we developed a mutational scan (“X-Scan”) involving peptides comprising all single amino acid variants of the original target for recognition by the TCR. By considering the tolerated single substitutions in all their possible combinations we generate a dataset of potentially crossreactive sequences which is used to search the human proteome. Here, this information helped to chose between two candidate TCRs which were indistinguishable by conventional assays, but differed by their number of potentially crossreactive genome matches. This method then helped to prioritize potentially crossreactive peptides and antigens for further preclinical testing of the ADP-A2M10 TCR, which is now in two patient trials.

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Why is it important?

Clinical trials have highlighted both promise and risks associated with the transfer of tumor-killing T cells into cancer patients. Many tumor-associated antigens are expressed at low levels and/or have led to tolerance of T cells carrying naturally selected high affinity receptors in patients. Genetically engineering T cell receptors can increase affinity but risks inducing reactivity with normal tissue, as shown in recent clinical trials. Because of differences in the antigenic repertoire, such cross-reactivities could not have been predicted from animal studies.