Targeting of cancer neoantigens with donor-derived T cell receptor repertoires

Accumulating evidence suggests that clinically efficacious cancer immunotherapies are driven by T cell reactivity against DNA mutation -derived neoantigens. However, among the large number of predicted neoantigens, only a minority is recognized by autologous patient T cells, and strategies to broaden neoantigen-specific T cell responses are therefore attractive. We found that naive T cell repertoires of healthy blood donors provide a source of neoantigen-specific T cells, responding to 11 of 57 predicted human leukocyte antigen (HLA)-A*02:01-binding epitopes from three patients. Many of the T cell reactivities involved epitopes that in vivo were neglected by patient autologous tumor -infiltrating lymphocytes. Finally, T cells redirected with T cell receptors identified from donor -derived T cells efficiently recognized patient -derived melanoma cells harboring the relevant mutations, providing a rationale for the use of such outsourced immune responses in cancer immunotherapy.