Clonal expansion of T memory stem cells determines early anti-leukemic responses and long-term CAR T cell persistence in patients.
Journal
Nature cancer
ISSN: 2662-1347
Titre abrégé: Nat Cancer
Pays: England
ID NLM: 101761119
Informations de publication
Date de publication:
06 2021
06 2021
Historique:
entrez:
4
8
2021
pubmed:
5
8
2021
medline:
5
8
2021
Statut:
ppublish
Résumé
Low-affinity CD19 chimeric antigen receptor (CAR) T cells display enhanced expansion and persistence, enabling fate tracking through integration site analysis. Here we show that integration sites from early (1 month) and late (>3yr) timepoints cluster separately, suggesting different clonal contribution to early responses and prolonged anti-leukemic surveillance. CAR T central and effector memory cells in patients with long-term persistence remained highly polyclonal, whereas diversity dropped rapidly in patients with limited CAR T persistence. Analysis of shared integrants between the CAR T cell product and post-infusion demonstrated that, despite their low frequency, T memory stem cell clones in the product contributed substantially to the circulating CAR T cell pools, during both early expansion and long-term persistence. Our data may help identify patients at risk of early loss of CAR T cells and highlight the critical role of T memory stem cells both in mediating early anti-leukemic responses and in long-term surveillance by CAR T cells.
Identifiants
pubmed: 34345830
doi: 10.1038/s43018-021-00207-7
pmc: PMC7611448
mid: EMS130862
pii: 10.1038/s43018-021-00207-7
doi:
Substances chimiques
Antigens, CD19
0
Receptors, Antigen, T-Cell
0
Receptors, Chimeric Antigen
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Pagination
629-642Subventions
Organisme : Blood Cancer UK
ID : 09013
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 104807
Pays : United Kingdom
Déclaration de conflit d'intérêts
Competing interests The authors declare no competing interests.
Références
Sallusto, F., Lenig, D., Förster, R., Lipp, M. & Lanzavecchia, A. Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature https://doi.org/10.1038/35005534 (1999).
Gattinoni, L. et al. A human memory T cell subset with stem cell-like properties. Nat. Med. 17, 1290–1297 (2011).
doi: 10.1038/nm.2446
Heslop, H. E. et al. Long-term outcome of EBV-specific T-cell infusions to prevent or treat EBV-related lymphoproliferative disease in transplant recipients. Blood https://doi.org/10.1182/blood-2009-08-239186 (2010).
Berger, C. et al. Adoptive transfer of effector CD8
Biasco, L. et al. In vivo tracking of T cells in humans unveils decade-long survival and activity of genetically modified T memory stem cells. Sci. Transl. Med. 7, 273ra13 (2015).
doi: 10.1126/scitranslmed.3010314
Oliveira, G. et al. Tracking genetically engineered lymphocytes long-term reveals the dynamics of T cell immunological memory. Sci. Transl. Med. 7, 317ra198 (2015).
doi: 10.1126/scitranslmed.aac8265
Maude, S. L. et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N. Engl. J. Med. https://doi.org/10.1056/NEJMoa1407222 (2014).
Lee, D. W. et al. T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial. Lancet https://doi.org/10.1016/S0140-6736(14)61403-3 (2015).
Gardner, R. A. et al. Intent-to-treat leukemia remission by CD19 CAR T cells of defined formulation and dose in children and young adults. Blood https://doi.org/10.1182/blood-2017-02-769208 (2017).
Maude, S. L. et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N. Engl. J. Med. https://doi.org/10.1056/NEJMoa1709866 (2018).
Mueller, K. T. et al. Cellular kinetics of CTL019 in relapsed/refractory B-cell acute lymphoblastic leukemia and chronic lymphocytic leukemia. Blood https://doi.org/10.1182/blood-2017-06-786129 (2017).
Sommermeyer, D. et al. Chimeric antigen receptor-modified T cells derived from defined CD8
Turtle, C. J. et al. CD19 CAR-T cells of defined CD4
Xu, Y. et al. Closely related T-memory stem cells correlate with in vivo expansion of CAR.CD19-T cells and are preserved by IL-7 and IL-15. Blood https://doi.org/10.1182/blood-2014-01-552174 (2014).
Sheih, A. et al. Clonal kinetics and single-cell transcriptional profiling of CAR-T cells in patients undergoing CD19 CAR-T immunotherapy. Nat. Commun. 11, 219 (2020).
doi: 10.1038/s41467-019-13880-1
Ghorashian, S. et al. Enhanced CAR T cell expansion and prolonged persistence in pediatric patients with ALL treated with a low-affinity CD19 CAR. Nat. Med. https://doi.org/10.1038/s41591-019-0549-5 (2019).
Fraietta, J. A. et al. Disruption of TET2 promotes the therapeutic efficacy of CD19-targeted T cells. Nature https://doi.org/10.1038/s41586-018-0178-z (2018).
Aiuti, A. et al. Lentiviral hematopoietic stem cell gene therapy in patients with Wiskott-Aldrich syndrome. Science 341, 6148 (2013).
doi: 10.1126/science.1233151
Scala, S. et al. Dynamics of genetically engineered hematopoietic stem and progenitor cells after autologous transplantation in humans. Nat. Med. 24, 1683–1690 (2018).
doi: 10.1038/s41591-018-0195-3
Biasco, L. et al. In vivo tracking of human hematopoiesis reveals patterns of clonal dynamics during early and steady-state reconstitution phases. Cell Stem Cell 19, 107–119 (2016).
doi: 10.1016/j.stem.2016.04.016
Milone, M. C. et al. Chimeric receptors containing CD137 signal transduction domains mediate enhanced survival of T cells and increased antileukemic efficacy in vivo. Mol. Ther. https://doi.org/10.1038/mt.2009.83 (2009).
Long, A. H. et al. 4-1BB costimulation ameliorates T cell exhaustion induced by tonic signaling of chimeric antigen receptors. Nat. Med. https://doi.org/10.1038/nm.3838 (2015).
Biasco, L. Integration site analysis in gene therapy patients: expectations and reality. Hum. Gene Ther. 28, 1122–1129 (2017).
doi: 10.1089/hum.2017.183