PMID- 35138911
OWN - NLM
STAT- MEDLINE
DCOM- 20220426
LR  - 20220726
IS  - 1946-6242 (Electronic)
IS  - 1946-6234 (Linking)
VI  - 14
IP  - 631
DP  - 2022 Feb 9
TI  - CRISPR-based gene disruption and integration of high-avidity, WT1-specific T cell 
      receptors improve antitumor T cell function.
PG  - eabg8027
LID - 10.1126/scitranslmed.abg8027 [doi]
AB  - 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 alpha constant (TRAC) locus with TCR beta constant (TRBC) 
      knockout, thus avoiding TCRalphabeta 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.
FAU - Ruggiero, Eliana
AU  - Ruggiero E
AUID- ORCID: 0000-0002-2954-8278
AD  - Experimental Hematology Unit, Division of Immunology, Transplantation and 
      Infectious Diseases, Ospedale San Raffaele Scientific Institute, 20132 Milan, 
      Italy.
FAU - Carnevale, Erica
AU  - Carnevale E
AD  - Experimental Hematology Unit, Division of Immunology, Transplantation and 
      Infectious Diseases, Ospedale San Raffaele Scientific Institute, 20132 Milan, 
      Italy.
FAU - Prodeus, Aaron
AU  - Prodeus A
AUID- ORCID: 0000-0002-0719-3891
AD  - Intellia Therapeutics, Cambridge, MA 02139, USA.
FAU - Magnani, Zulma Irene
AU  - Magnani ZI
AUID- ORCID: 0000-0001-7612-6097
AD  - Experimental Hematology Unit, Division of Immunology, Transplantation and 
      Infectious Diseases, Ospedale San Raffaele Scientific Institute, 20132 Milan, 
      Italy.
FAU - Camisa, Barbara
AU  - Camisa B
AD  - Experimental Hematology Unit, Division of Immunology, Transplantation and 
      Infectious Diseases, Ospedale San Raffaele Scientific Institute, 20132 Milan, 
      Italy.
FAU - Merelli, Ivan
AU  - Merelli I
AD  - San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), Ospedale San 
      Raffaele Scientific Institute, 20132 Milan, Italy.
AD  - National Research Council, Institute for Biomedical Technologies, Segrate, Italy.
FAU - Politano, Claudia
AU  - Politano C
AUID- ORCID: 0000-0003-3471-3722
AD  - Experimental Hematology Unit, Division of Immunology, Transplantation and 
      Infectious Diseases, Ospedale San Raffaele Scientific Institute, 20132 Milan, 
      Italy.
FAU - Stasi, Lorena
AU  - Stasi L
AUID- ORCID: 0000-0001-8044-2295
AD  - Experimental Hematology Unit, Division of Immunology, Transplantation and 
      Infectious Diseases, Ospedale San Raffaele Scientific Institute, 20132 Milan, 
      Italy.
FAU - Potenza, Alessia
AU  - Potenza A
AUID- ORCID: 0000-0003-0298-7315
AD  - Experimental Hematology Unit, Division of Immunology, Transplantation and 
      Infectious Diseases, Ospedale San Raffaele Scientific Institute, 20132 Milan, 
      Italy.
AD  - School of Medicine and Surgery, Milano-Bicocca University, 20126 Milan, Italy.
FAU - Cianciotti, Beatrice Claudia
AU  - Cianciotti BC
AUID- ORCID: 0000-0002-1337-5915
AD  - Experimental Hematology Unit, Division of Immunology, Transplantation and 
      Infectious Diseases, Ospedale San Raffaele Scientific Institute, 20132 Milan, 
      Italy.
FAU - Manfredi, Francesco
AU  - Manfredi F
AUID- ORCID: 0000-0003-2409-944X
AD  - Experimental Hematology Unit, Division of Immunology, Transplantation and 
      Infectious Diseases, Ospedale San Raffaele Scientific Institute, 20132 Milan, 
      Italy.
AD  - Vita-Salute San Raffaele University, 20132 Milan, Italy.
FAU - Di Bono, Mattia
AU  - Di Bono M
AUID- ORCID: 0000-0003-4966-111X
AD  - Experimental Hematology Unit, Division of Immunology, Transplantation and 
      Infectious Diseases, Ospedale San Raffaele Scientific Institute, 20132 Milan, 
      Italy.
FAU - Vago, Luca
AU  - Vago L
AUID- ORCID: 0000-0003-4247-3175
AD  - Immunogenetics, Leukemia Genomics and Immunobiology Unit, Division of Immunology, 
      Transplantation and Infectious Diseases, Ospedale San Raffaele Scientific 
      Institute, 20132 Milan, Italy.
AD  - Hematology and Bone Marrow Transplantation Unit, Ospedale San Raffaele Scientific 
      Institute, 20132 Milan, Italy.
FAU - Tassara, Michela
AU  - Tassara M
AUID- ORCID: 0000-0003-3198-5773
AD  - Immunohematology and Transfusion Medicine Unit, Ospedale San Raffaele Scientific 
      Institute, 20132 Milan, Italy.
FAU - Mastaglio, Sara
AU  - Mastaglio S
AD  - Hematology and Bone Marrow Transplantation Unit, Ospedale San Raffaele Scientific 
      Institute, 20132 Milan, Italy.
FAU - Ponzoni, Maurilio
AU  - Ponzoni M
AD  - Vita-Salute San Raffaele University, 20132 Milan, Italy.
AD  - Pathology Unit, Ospedale San Raffaele Scientific Institute, 20132 Milan, Italy.
FAU - Sanvito, Francesca
AU  - Sanvito F
AUID- ORCID: 0000-0002-4046-8420
AD  - Pathology Unit, Ospedale San Raffaele Scientific Institute, 20132 Milan, Italy.
FAU - Liu, Dai
AU  - Liu D
AUID- ORCID: 0000-0002-7479-2237
AD  - Intellia Therapeutics, Cambridge, MA 02139, USA.
FAU - Balwani, Ishina
AU  - Balwani I
AD  - Intellia Therapeutics, Cambridge, MA 02139, USA.
FAU - Galli, Rossella
AU  - Galli R
AUID- ORCID: 0000-0001-9023-7033
AD  - Neural Stem Cell Biology Unit, Division of Neurosciences, Ospedale San Raffaele 
      Scientific Institute, 20132 Milan, Italy.
FAU - Genua, Marco
AU  - Genua M
AUID- ORCID: 0000-0002-0764-8163
AD  - Genomics of the Innate Immune System Unit, San Raffaele Telethon Institute for 
      Gene Therapy (SR-Tiget), Ospedale San Raffaele Scientific Institute, 20132 Milan, 
      Italy.
FAU - Ostuni, Renato
AU  - Ostuni R
AUID- ORCID: 0000-0003-0460-3426
AD  - Vita-Salute San Raffaele University, 20132 Milan, Italy.
AD  - Genomics of the Innate Immune System Unit, San Raffaele Telethon Institute for 
      Gene Therapy (SR-Tiget), Ospedale San Raffaele Scientific Institute, 20132 Milan, 
      Italy.
FAU - Doglio, Matteo
AU  - Doglio M
AD  - Experimental Hematology Unit, Division of Immunology, Transplantation and 
      Infectious Diseases, Ospedale San Raffaele Scientific Institute, 20132 Milan, 
      Italy.
FAU - O'Connell, Daniel
AU  - O'Connell D
AD  - Intellia Therapeutics, Cambridge, MA 02139, USA.
FAU - Dutta, Ivy
AU  - Dutta I
AD  - Intellia Therapeutics, Cambridge, MA 02139, USA.
FAU - Yazinski, Stephanie Ann
AU  - Yazinski SA
AD  - Intellia Therapeutics, Cambridge, MA 02139, USA.
FAU - McKee, Mark
AU  - McKee M
AUID- ORCID: 0000-0003-1061-915X
AD  - Intellia Therapeutics, Cambridge, MA 02139, USA.
FAU - Arredouani, Mohamed Simo
AU  - Arredouani MS
AD  - Intellia Therapeutics, Cambridge, MA 02139, USA.
FAU - Schultes, Birgit
AU  - Schultes B
AUID- ORCID: 0000-0002-2275-3383
AD  - Intellia Therapeutics, Cambridge, MA 02139, USA.
FAU - Ciceri, Fabio
AU  - Ciceri F
AUID- ORCID: 0000-0003-0873-0123
AD  - Vita-Salute San Raffaele University, 20132 Milan, Italy.
AD  - Hematology and Bone Marrow Transplantation Unit, Ospedale San Raffaele Scientific 
      Institute, 20132 Milan, Italy.
FAU - Bonini, Chiara
AU  - Bonini C
AUID- ORCID: 0000-0002-0772-1674
AD  - Experimental Hematology Unit, Division of Immunology, Transplantation and 
      Infectious Diseases, Ospedale San Raffaele Scientific Institute, 20132 Milan, 
      Italy.
AD  - Vita-Salute San Raffaele University, 20132 Milan, Italy.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20220209
PL  - United States
TA  - Sci Transl Med
JT  - Science translational medicine
JID - 101505086
RN  - 0 (Antigens, Neoplasm)
RN  - 0 (Receptors, Antigen, T-Cell)
RN  - 0 (Receptors, Antigen, T-Cell, alpha-beta)
RN  - 0 (WT1 Proteins)
RN  - 0 (WT1 protein, human)
SB  - IM
MH  - Antigens, Neoplasm
MH  - Humans
MH  - *Leukemia, Myeloid, Acute/genetics/therapy
MH  - Receptors, Antigen, T-Cell/genetics
MH  - Receptors, Antigen, T-Cell, alpha-beta/genetics
MH  - T-Lymphocytes
MH  - *WT1 Proteins/genetics/metabolism
EDAT- 2022/02/10 06:00
MHDA- 2022/04/27 06:00
CRDT- 2022/02/09 17:11
PHST- 2022/02/09 17:11 [entrez]
PHST- 2022/02/10 06:00 [pubmed]
PHST- 2022/04/27 06:00 [medline]
AID - 10.1126/scitranslmed.abg8027 [doi]
PST - ppublish
SO  - Sci Transl Med. 2022 Feb 9;14(631):eabg8027. doi: 10.1126/scitranslmed.abg8027. 
      Epub 2022 Feb 9.