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ResearchIn-Press PreviewImmunologyTherapeutics Open Access | 10.1172/JCI150807

CAR T-cell manufacturing from naive/stem memory T-lymphocytes enhances antitumor responses while curtailing cytokine release syndrome

Silvia Arcangeli,1 Camilla Bove,1 Claudia Mezzanotte,1 Barbara Camisa,1 Laura Falcone,1 Francesco Manfredi,1 Eugenia Bezzecchi,2 Rita El Khoury,1 Rossana Norata,3 Francesca Sanvito,4 Maurilio Ponzoni,4 Beatrice Greco,1 Marta Angiola Moresco,1 Matteo G. Carrabba,5 Fabio Ciceri,5 Chiara Bonini,1 Attilio Bondanza,1 and Monica Casucci1

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

Find articles by Arcangeli, S. in: JCI | PubMed | Google Scholar |

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

Find articles by Bove, C. in: JCI | PubMed | Google Scholar

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

Find articles by Mezzanotte, C. in: JCI | PubMed | Google Scholar

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

Find articles by Camisa, B. in: JCI | PubMed | Google Scholar

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

Find articles by Falcone, L. in: JCI | PubMed | Google Scholar |

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

Find articles by Manfredi, F. in: JCI | PubMed | Google Scholar |

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

Find articles by Bezzecchi, E. in: JCI | PubMed | Google Scholar

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

Find articles by El Khoury, R. in: JCI | PubMed | Google Scholar

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

Find articles by Norata, R. in: JCI | PubMed | Google Scholar

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

Find articles by Sanvito, F. in: JCI | PubMed | Google Scholar |

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

Find articles by Ponzoni, M. in: JCI | PubMed | Google Scholar

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

Find articles by Greco, B. in: JCI | PubMed | Google Scholar |

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

Find articles by Moresco, M. in: JCI | PubMed | Google Scholar

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

Find articles by Carrabba, M. in: JCI | PubMed | Google Scholar |

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

Find articles by Ciceri, F. in: JCI | PubMed | Google Scholar

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

Find articles by Bonini, C. in: JCI | PubMed | Google Scholar

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

Find articles by Bondanza, A. in: JCI | PubMed | Google Scholar

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

Find articles by Casucci, M. in: JCI | PubMed | Google Scholar

Published May 3, 2022 - More info

J Clin Invest. https://doi.org/10.1172/JCI150807.
Copyright © 2022, Arcangeli et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published May 3, 2022 - Version history
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Abstract

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.

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  • Version 1 (May 3, 2022): In-Press Preview
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