By longitudinal monitoring of T cell functionality and dynamics in 15 healthy donors, we isolated 19 TCRs specific for Wilms' tumor antigen 1 (WT1), which is overexpressed by several tumor types. However, the need for TCRs specific for shared oncogenic antigens and the need for manufacturing protocols able to redirect T cell specificity while preserving T cell fitness remain limiting factors. T cell receptor (TCR)-based therapy has the potential to induce durable clinical responses in patients with cancer by targeting intracellular tumor antigens with high sensitivity and by promoting T cell survival. 12 Genomics of the Innate Immune System Unit, San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), Ospedale San Raffaele Scientific Institute, 20132 Milan, Italy.11 Neural Stem Cell Biology Unit, Division of Neurosciences, Ospedale San Raffaele Scientific Institute, 20132 Milan, Italy.10 Pathology Unit, Ospedale San Raffaele Scientific Institute, 20132 Milan, Italy.9 Immunohematology and Transfusion Medicine Unit, Ospedale San Raffaele Scientific Institute, 20132 Milan, Italy.8 Hematology and Bone Marrow Transplantation Unit, Ospedale San Raffaele Scientific Institute, 20132 Milan, Italy.7 Immunogenetics, Leukemia Genomics and Immunobiology Unit, Division of Immunology, Transplantation and Infectious Diseases, Ospedale San Raffaele Scientific Institute, 20132 Milan, Italy.6 Vita-Salute San Raffaele University, 20132 Milan, Italy.5 School of Medicine and Surgery, Milano-Bicocca University, 20126 Milan, Italy.4 National Research Council, Institute for Biomedical Technologies, Segrate, Italy.3 San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), Ospedale San Raffaele Scientific Institute, 20132 Milan, Italy.

2 Intellia Therapeutics, Cambridge, MA 02139, USA.1 Experimental Hematology Unit, Division of Immunology, Transplantation and Infectious Diseases, Ospedale San Raffaele Scientific Institute, 20132 Milan, Italy.

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