CRISPR-based gene disruption and integration of high-avidity, WT1-specific T cell receptors improve antitumor T cell function.

Autor:	Ruggiero E; Experimental Hematology Unit, Division of Immunology, Transplantation and Infectious Diseases, Ospedale San Raffaele Scientific Institute, 20132 Milan, Italy., Carnevale E; Experimental Hematology Unit, Division of Immunology, Transplantation and Infectious Diseases, Ospedale San Raffaele Scientific Institute, 20132 Milan, Italy., Prodeus A; Intellia Therapeutics, Cambridge, MA 02139, USA., Magnani ZI; Experimental Hematology Unit, Division of Immunology, Transplantation and Infectious Diseases, Ospedale San Raffaele Scientific Institute, 20132 Milan, Italy., Camisa B; Experimental Hematology Unit, Division of Immunology, Transplantation and Infectious Diseases, Ospedale San Raffaele Scientific Institute, 20132 Milan, Italy., Merelli I; San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), Ospedale San Raffaele Scientific Institute, 20132 Milan, Italy.; National Research Council, Institute for Biomedical Technologies, Segrate, Italy., Politano C; Experimental Hematology Unit, Division of Immunology, Transplantation and Infectious Diseases, Ospedale San Raffaele Scientific Institute, 20132 Milan, Italy., Stasi L; Experimental Hematology Unit, Division of Immunology, Transplantation and Infectious Diseases, Ospedale San Raffaele Scientific Institute, 20132 Milan, Italy., Potenza A; Experimental Hematology Unit, Division of Immunology, Transplantation and Infectious Diseases, Ospedale San Raffaele Scientific Institute, 20132 Milan, Italy.; School of Medicine and Surgery, Milano-Bicocca University, 20126 Milan, Italy., Cianciotti BC; Experimental Hematology Unit, Division of Immunology, Transplantation and Infectious Diseases, Ospedale San Raffaele Scientific Institute, 20132 Milan, Italy., Manfredi F; Experimental Hematology Unit, Division of Immunology, Transplantation and Infectious Diseases, Ospedale San Raffaele Scientific Institute, 20132 Milan, Italy.; Vita-Salute San Raffaele University, 20132 Milan, Italy., Di Bono M; Experimental Hematology Unit, Division of Immunology, Transplantation and Infectious Diseases, Ospedale San Raffaele Scientific Institute, 20132 Milan, Italy., Vago L; Immunogenetics, Leukemia Genomics and Immunobiology Unit, Division of Immunology, Transplantation and Infectious Diseases, Ospedale San Raffaele Scientific Institute, 20132 Milan, Italy.; Hematology and Bone Marrow Transplantation Unit, Ospedale San Raffaele Scientific Institute, 20132 Milan, Italy., Tassara M; Immunohematology and Transfusion Medicine Unit, Ospedale San Raffaele Scientific Institute, 20132 Milan, Italy., Mastaglio S; Hematology and Bone Marrow Transplantation Unit, Ospedale San Raffaele Scientific Institute, 20132 Milan, Italy., Ponzoni M; Vita-Salute San Raffaele University, 20132 Milan, Italy.; Pathology Unit, Ospedale San Raffaele Scientific Institute, 20132 Milan, Italy., Sanvito F; Pathology Unit, Ospedale San Raffaele Scientific Institute, 20132 Milan, Italy., Liu D; Intellia Therapeutics, Cambridge, MA 02139, USA., Balwani I; Intellia Therapeutics, Cambridge, MA 02139, USA., Galli R; Neural Stem Cell Biology Unit, Division of Neurosciences, Ospedale San Raffaele Scientific Institute, 20132 Milan, Italy., Genua M; Genomics of the Innate Immune System Unit, San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), Ospedale San Raffaele Scientific Institute, 20132 Milan, Italy., Ostuni R; Vita-Salute San Raffaele University, 20132 Milan, Italy.; Genomics of the Innate Immune System Unit, San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), Ospedale San Raffaele Scientific Institute, 20132 Milan, Italy., Doglio M; Experimental Hematology Unit, Division of Immunology, Transplantation and Infectious Diseases, Ospedale San Raffaele Scientific Institute, 20132 Milan, Italy., O'Connell D; Intellia Therapeutics, Cambridge, MA 02139, USA., Dutta I; Intellia Therapeutics, Cambridge, MA 02139, USA., Yazinski SA; Intellia Therapeutics, Cambridge, MA 02139, USA., McKee M; Intellia Therapeutics, Cambridge, MA 02139, USA., Arredouani MS; Intellia Therapeutics, Cambridge, MA 02139, USA., Schultes B; Intellia Therapeutics, Cambridge, MA 02139, USA., Ciceri F; Vita-Salute San Raffaele University, 20132 Milan, Italy.; Hematology and Bone Marrow Transplantation Unit, Ospedale San Raffaele Scientific Institute, 20132 Milan, Italy., Bonini C; Experimental Hematology Unit, Division of Immunology, Transplantation and Infectious Diseases, Ospedale San Raffaele Scientific Institute, 20132 Milan, Italy.; Vita-Salute San Raffaele University, 20132 Milan, Italy.
Jazyk:	angličtina
Zdroj:	Science translational medicine [Sci Transl Med] 2022 Feb 09; Vol. 14 (631), pp. eabg8027. Date of Electronic Publication: 2022 Feb 09.
DOI:	10.1126/scitranslmed.abg8027
Abstrakt:	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. 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. 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. TCRs recognized several peptides restricted by common human leukocyte antigen (HLA) alleles and displayed a wide range of functional avidities. We selected five high-avidity HLA-A*02:01-restricted TCRs, three that were specific to the less explored immunodominant WT1 37-45 and two that were specific to the noncanonical WT1 -78-64 epitopes, both naturally processed by primary acute myeloid leukemia (AML) blasts. With CRISPR-Cas9 genome editing tools, we combined TCR-targeted integration into the TCR α constant ( TRAC ) locus with TCR β constant ( TRBC ) knockout, thus avoiding TCRαβ mispairing and maximizing TCR expression and function. The engineered lymphocytes were enriched in memory stem T cells. A unique WT1 37-45 -specific TCR showed antigen-specific responses and efficiently killed AML blasts, acute lymphoblastic leukemia blasts, and glioblastoma cells in vitro and in vivo in the absence of off-tumor toxicity. T cells engineered to express this receptor are being advanced into clinical development for AML immunotherapy and represent a candidate therapy for other WT1-expressing tumors.
Databáze:	MEDLINE
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