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Blood. 2017 Aug 3;130(5):606-618. doi: 10.1182/blood-2016-08-732636. Epub 2017 Jun 21.

NY-ESO-1 TCR single edited stem and central memory T cells to treat multiple myeloma without graft-versus-host disease.

Author information

1
Experimental Hematology Unit, Division of Immunology, Transplantation and Infectious Diseases, Program in Immunology and Bio-immunotherapy of Cancer.
2
Hematology and Bone Marrow Transplantation Unit, and.
3
Telethon Institute for Gene Therapy, Ospedale San Raffaele Scientific Institute, Milan, Italy.
4
Vita-Salute San Raffaele University, Milan, Italy.
5
Sangamo BioSciences, Richmond, CA; and.
6
Pathology Unit.
7
Innovative Immunotherapies Unit, Division of Immunology, Transplantation and Infectious Diseases, Program in Immunology and Bio-immunotherapy of Cancer.
8
Medical Physics Department and Centre for Experimental Imaging.
9
Lymphocyte Activation Unit, Division of Immunology, Transplantation and Infectious Diseases.
10
Unit of Immunogenetics, Leukemia Genomics and Immunobiology, Division of Regenerative Medicine, Stem Cells and Gene Therapy, and.
11
Leukemia Unit, Ospedale San Raffaele Scientific Institute, Milan, Italy.

Abstract

Transfer of T-cell receptors (TCRs) specific for tumor-associated antigens is a promising approach for cancer immunotherapy. We developed the TCR gene editing technology that is based on the knockout of the endogenous TCR α and β genes, followed by the introduction of tumor-specific TCR genes, and that proved safer and more effective than conventional TCR gene transfer. Although successful, complete editing requires extensive cell manipulation and 4 transduction procedures. Here we propose a novel and clinically feasible TCR "single editing" (SE) approach, based on the disruption of the endogenous TCR α chain only, followed by the transfer of genes encoding for a tumor-specific TCR. We validated SE with the clinical grade HLA-A2 restricted NY-ESO-1157-165-specific TCR. SE allowed the rapid production of high numbers of tumor-specific T cells, with optimal TCR expression and preferential stem memory and central memory phenotype. Similarly to unedited T cells redirected by TCR gene transfer (TCR transferred [TR]), SE T cells efficiently killed NY-ESO-1pos targets; however, although TR cells proved highly alloreactive, SE cells showed a favorable safety profile. Accordingly, when infused in NSG mice previously engrafted with myeloma, SE cells mediated tumor rejection without inducing xenogeneic graft-versus-host disease, thus resulting in significantly higher survival than that observed in mice treated with TR cells. Overall, single TCR gene editing represents a clinically feasible approach that is able to increase the safety and efficacy of cancer adoptive immunotherapy.

PMID:
28637663
DOI:
10.1182/blood-2016-08-732636
[Indexed for MEDLINE]
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