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ResearchIn-Press PreviewImmunologyTherapeutics
Open Access | 10.1172/JCI150807
1Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy
2Center for Omics Sciences, IRCCS San Raffaele Scientific Institute, Milan, Italy
3San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), IRCCS San Raffaele Scientific Institute, Milan, Italy
4Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy
5Department of Hematology and Stem Cell Transplantation, IRCCS San Raffaele Scientific Institute, Milan, Italy
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Arcangeli, S.
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1Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy
2Center for Omics Sciences, IRCCS San Raffaele Scientific Institute, Milan, Italy
3San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), IRCCS San Raffaele Scientific Institute, Milan, Italy
4Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy
5Department of Hematology and Stem Cell Transplantation, IRCCS San Raffaele Scientific Institute, Milan, Italy
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1Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy
2Center for Omics Sciences, IRCCS San Raffaele Scientific Institute, Milan, Italy
3San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), IRCCS San Raffaele Scientific Institute, Milan, Italy
4Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy
5Department of Hematology and Stem Cell Transplantation, IRCCS San Raffaele Scientific Institute, Milan, Italy
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1Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy
2Center for Omics Sciences, IRCCS San Raffaele Scientific Institute, Milan, Italy
3San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), IRCCS San Raffaele Scientific Institute, Milan, Italy
4Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy
5Department of Hematology and Stem Cell Transplantation, IRCCS San Raffaele Scientific Institute, Milan, Italy
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1Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy
2Center for Omics Sciences, IRCCS San Raffaele Scientific Institute, Milan, Italy
3San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), IRCCS San Raffaele Scientific Institute, Milan, Italy
4Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy
5Department of Hematology and Stem Cell Transplantation, IRCCS San Raffaele Scientific Institute, Milan, Italy
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Falcone, L.
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1Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy
2Center for Omics Sciences, IRCCS San Raffaele Scientific Institute, Milan, Italy
3San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), IRCCS San Raffaele Scientific Institute, Milan, Italy
4Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy
5Department of Hematology and Stem Cell Transplantation, IRCCS San Raffaele Scientific Institute, Milan, Italy
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Manfredi, F.
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1Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy
2Center for Omics Sciences, IRCCS San Raffaele Scientific Institute, Milan, Italy
3San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), IRCCS San Raffaele Scientific Institute, Milan, Italy
4Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy
5Department of Hematology and Stem Cell Transplantation, IRCCS San Raffaele Scientific Institute, Milan, Italy
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1Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy
2Center for Omics Sciences, IRCCS San Raffaele Scientific Institute, Milan, Italy
3San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), IRCCS San Raffaele Scientific Institute, Milan, Italy
4Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy
5Department of Hematology and Stem Cell Transplantation, IRCCS San Raffaele Scientific Institute, Milan, Italy
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1Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy
2Center for Omics Sciences, IRCCS San Raffaele Scientific Institute, Milan, Italy
3San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), IRCCS San Raffaele Scientific Institute, Milan, Italy
4Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy
5Department of Hematology and Stem Cell Transplantation, IRCCS San Raffaele Scientific Institute, Milan, Italy
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1Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy
2Center for Omics Sciences, IRCCS San Raffaele Scientific Institute, Milan, Italy
3San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), IRCCS San Raffaele Scientific Institute, Milan, Italy
4Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy
5Department of Hematology and Stem Cell Transplantation, IRCCS San Raffaele Scientific Institute, Milan, Italy
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Sanvito, F.
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1Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy
2Center for Omics Sciences, IRCCS San Raffaele Scientific Institute, Milan, Italy
3San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), IRCCS San Raffaele Scientific Institute, Milan, Italy
4Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy
5Department of Hematology and Stem Cell Transplantation, IRCCS San Raffaele Scientific Institute, Milan, Italy
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1Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy
2Center for Omics Sciences, IRCCS San Raffaele Scientific Institute, Milan, Italy
3San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), IRCCS San Raffaele Scientific Institute, Milan, Italy
4Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy
5Department of Hematology and Stem Cell Transplantation, IRCCS San Raffaele Scientific Institute, Milan, Italy
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Greco, B.
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1Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy
2Center for Omics Sciences, IRCCS San Raffaele Scientific Institute, Milan, Italy
3San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), IRCCS San Raffaele Scientific Institute, Milan, Italy
4Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy
5Department of Hematology and Stem Cell Transplantation, IRCCS San Raffaele Scientific Institute, Milan, Italy
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1Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy
2Center for Omics Sciences, IRCCS San Raffaele Scientific Institute, Milan, Italy
3San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), IRCCS San Raffaele Scientific Institute, Milan, Italy
4Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy
5Department of Hematology and Stem Cell Transplantation, IRCCS San Raffaele Scientific Institute, Milan, Italy
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Carrabba, M.
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1Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy
2Center for Omics Sciences, IRCCS San Raffaele Scientific Institute, Milan, Italy
3San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), IRCCS San Raffaele Scientific Institute, Milan, Italy
4Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy
5Department of Hematology and Stem Cell Transplantation, IRCCS San Raffaele Scientific Institute, Milan, Italy
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1Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy
2Center for Omics Sciences, IRCCS San Raffaele Scientific Institute, Milan, Italy
3San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), IRCCS San Raffaele Scientific Institute, Milan, Italy
4Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy
5Department of Hematology and Stem Cell Transplantation, IRCCS San Raffaele Scientific Institute, Milan, Italy
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1Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy
2Center for Omics Sciences, IRCCS San Raffaele Scientific Institute, Milan, Italy
3San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), IRCCS San Raffaele Scientific Institute, Milan, Italy
4Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy
5Department of Hematology and Stem Cell Transplantation, IRCCS San Raffaele Scientific Institute, Milan, Italy
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1Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy
2Center for Omics Sciences, IRCCS San Raffaele Scientific Institute, Milan, Italy
3San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), IRCCS San Raffaele Scientific Institute, Milan, Italy
4Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy
5Department of Hematology and Stem Cell Transplantation, IRCCS San Raffaele Scientific Institute, Milan, Italy
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Published May 3, 2022 - More info
Chimeric antigen receptor (CAR) T-cell expansion and persistence represent key factors to achieve complete responses and prevent relapses. These features are typical of early memory T cells, which can be highly enriched through optimized manufacturing protocols. Here, we investigated the efficacy and safety profiles of CAR T-cell products generated from pre-selected naive/stem memory T cells (TN/SCM), as compared to unselected T cells (TBULK). Notwithstanding their reduced effector signature in vitro, limiting CAR TN/SCM doses showed superior antitumor activity and the unique ability to counteract leukemia re-challenge in hematopoietic stem/precursor cell-humanized mice, featuring increased expansion rates and persistence, together with an ameliorated exhaustion and memory phenotype. Most relevantly, CAR TN/SCM proved to be intrinsically less prone to induce severe cytokine release syndrome, independently of the costimulatory endodomain employed. This safer profile was associated with milder T-cell activation, which translated in reduced monocyte activation and cytokine release. These data suggest that CAR TN/SCM are endowed with a wider therapeutic index compared to CAR TBULK.