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

Erlend Strønen, Mireille Toebes, Sander Kelderman, Marit M van Buuren, Weiwen Yang, Nienke van Rooij, Marco Donia, Maxi-Lu Böschen, Fridtjof Lund-Johansen, Johanna Olweus, Ton N Schumacher

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. Here, we demonstrate that naïve T cell repertoires of healthy blood donors provide a source of neoantigen-specific T cells, responding to 11/57 predicted HLA-A2-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 re-directed 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.