Brief research report: in-depth immunophenotyping reveals stability of CD19 CAR T-cells over time

Ivan Odak; Lâle M. Bayir; Lennart Riemann; Ruth Sikora; Jessica Schneider; Yankai Xiao; Nora Möhn; Thomas Skripuletz; Gernot Beutel; Matthias Eder; Arnold Ganser; Reinhold Förster; Christian R. Schultze-Florey; Christian Koenecke

doi:10.3389/fimmu.2024.1298598

journal article Open Access Jan 22, 2024

Brief research report: in-depth immunophenotyping reveals stability of CD19 CAR T-cells over time

Ivan Odak Lâle M. Bayir Lennart Riemann Ruth Sikora Jessica Schneider

Yankai Xiao Nora Möhn

Thomas Skripuletz

Gernot Beutel

Matthias Eder

Arnold Ganser Reinhold Förster Christian R. Schultze-Florey Christian Koenecke

Frontiers in Immunology Vol. 15 · Frontiers Media SA

View at Publisher Save 10.3389/fimmu.2024.1298598

Abstract

Variability or stability might have an impact on treatment success and toxicity of CD19 CAR T-cells. We conducted a prospective observational study of 12 patients treated with Tisagenlecleucel for CD19+ B-cell malignancies. Using a 31-color spectral flow cytometry panel, we analyzed differentiation stages and exhaustion markers of CAR T-cell subsets prior to CAR T-cell infusion and longitudinally during 6 months of follow-up. The majority of activation markers on CAR T-cells showed stable expression patterns over time and were not associated with response to therapy or toxicity. Unsupervised cluster analysis revealed an immune signature of CAR T-cell products associated with the development of immune cell-associated neurotoxicity syndrome. Warranting validation in an independent patient cohort, in-depth phenotyping of CAR T-cell products as well as longitudinal monitoring post cell transfer might become a valuable tool to increase efficacy and safety of CAR T-cell therapy.

Topics

No keywords indexed for this article. Browse by subject →

References

35

[1]

Tisagenlecleucel in Adult Relapsed or Refractory Diffuse Large B-Cell Lymphoma

Stephen J. Schuster, Michael R. Bishop, Constantine S. Tam et al.

New England Journal of Medicine 2019 10.1056/nejmoa1804980

[2]

Tisagenlecleucel in Children and Young Adults with B-Cell Lymphoblastic Leukemia

Shannon L. Maude, Theodore W. Laetsch, Jochen Buechner et al.

New England Journal of Medicine 2018 10.1056/nejmoa1709866

[3]

Bethge "GLA/DRST real-world outcome analysis of CAR-T cell therapies for large B-cell lymphoma in Germany" Blood (2022) 10.1182/blood.2021015209

[4]

Neelapu "Chimeric antigen receptor T-cell therapy — assessment and management of toxicities" Nat Rev Clin Oncol (2018) 10.1038/nrclinonc.2017.148

[5]

Schuster "Chimeric antigen receptor T cells in refractory B-cell lymphomas" N Engl J Med (2017) 10.1056/nejmoa1708566

[6]

Axicabtagene Ciloleucel CAR T-Cell Therapy in Refractory Large B-Cell Lymphoma

Sattva S. Neelapu, Frederick L. Locke, Nancy L. Bartlett et al.

New England Journal of Medicine 2017 10.1056/nejmoa1707447

[7]

ASTCT Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity Associated with Immune Effector Cells

Bianca D. Santomasso, Frederick L. Locke, Armin Ghobadi et al.

Biology of Blood and Marrow Transplantation 2019 10.1016/j.bbmt.2018.12.758

[8]

Yakoub-Agha "Management of adults and children undergoing chimeric antigen receptor T-cell therapy: best practice recommendations of the European Society for Blood and Marrow Transplantation (EBMT) and the Joint Accreditation Committee of ISCT and EBMT (JACIE)" Haematologica (2020) 10.3324/haematol.2019.229781

[9]

Pennisi "Comparing CAR T-cell toxicity grading systems: application of the ASTCT grading system and implications for management" Blood Adv (2020) 10.1182/bloodadvances.2019000952

[10]

Sterner "Immune effector cell associated neurotoxicity syndrome in chimeric antigen receptor-T cell therapy" Front Immunol (2022) 10.3389/fimmu.2022.879608

[11]

Möhn "Neurological management and work-up of neurotoxicity associated with CAR T cell therapy" Neurol Res Pract (2022) 10.1186/s42466-021-00166-5

[12]

Penack "Complications after CD19+ CAR T-cell therapy" Cancers (Basel) (2020) 10.3390/cancers12113445

[13]

Kinetics and biomarkers of severe cytokine release syndrome after CD19 chimeric antigen receptor–modified T-cell therapy

Kevin A. Hay, Laïla-Aïcha Hanafi, Daniel Li et al.

Blood 2017 10.1182/blood-2017-06-793141

[14]

Yan "Characteristics and risk factors of cytokine release syndrome in chimeric antigen receptor T cell treatment" Front Immunol (2021) 10.3389/fimmu.2021.611366

[15]

Identification of Predictive Biomarkers for Cytokine Release Syndrome after Chimeric Antigen Receptor T-cell Therapy for Acute Lymphoblastic Leukemia

David T. Teachey, Simon F. Lacey, Pamela A. Shaw et al.

Cancer Discovery 2016 10.1158/2159-8290.cd-16-0040

[16]

Cytokine release syndrome and associated neurotoxicity in cancer immunotherapy

Emma C. Morris, Sattva S. Neelapu, Theodoros Giavridis et al.

Nature Reviews Immunology 2022 10.1038/s41577-021-00547-6

[17]

Butt "A systematic framework for predictive biomarkers in immune effector cell-associated neurotoxicity syndrome" Front Neurol (2023) 10.3389/fneur.2023.1110647

[18]

Locke "Association of metabolic tumor volume (MTV) and clinical outcomes in second-line (2L) relapsed/refractory (R/R) large B-cell lymphoma (LBCL) following axicabtagene ciloleucel (Axi-cel) versus standard-of-care (SOC) therapy in ZUMA-7" Blood (2022) 10.1182/blood-2022-158492

[19]

García-Calderón "Monitoring of kinetics and exhaustion markers of circulating CAR-T cells as early predictive factors in patients with B-cell Malignancies" Front Immunol (2023) 10.3389/fimmu.2023.1152498

[20]

Recommendations for Initial Evaluation, Staging, and Response Assessment of Hodgkin and Non-Hodgkin Lymphoma: The Lugano Classification

Bruce D. Cheson, Richard I. Fisher, Sally F. Barrington et al.

Journal of Clinical Oncology 2014 10.1200/jco.2013.54.8800

[21]

Fuss "Isolation of whole mononuclear cells from peripheral blood and cord blood" Curr Protoc Immunol (2009) 10.1002/0471142735.im0701s85

[22]

Parks "A new “Logicle” display method avoids deceptive effects of logarithmic scaling for low signals and compensated data" Cytometry A (2006) 10.1002/cyto.a.20258

[23]

Monaco "flowAI: automatic and interactive anomaly discerning tools for flow cytometry data" Bioinformatics (2016) 10.1093/bioinformatics/btw191

[24]

Van Gassen "FlowSOM: Using self-organizing maps for visualization and interpretation of cytometry data" Cytom Part A (2015) 10.1002/cyto.a.22625

[25]

Schultze-Florey "Distribution of major lymphocyte subsets and memory T-cell subpopulations in healthy adults employing GLP-conforming multicolor flow cytometry" Leukemia (2021) 10.1038/s41375-021-01348-5

[26]

Odak "Spectral flow cytometry cluster analysis of therapeutic donor lymphocyte infusions identifies T cell subsets associated with outcome in patients with AML relapse" Front Immunol (2022) 10.3389/fimmu.2022.999163

[27]

Tumor Antigen Escape from CAR T-cell Therapy

Robbie G. Majzner, Crystal L. Mackall

Cancer Discovery 2018 10.1158/2159-8290.cd-18-0442

[28]

Endothelial Activation and Blood–Brain Barrier Disruption in Neurotoxicity after Adoptive Immunotherapy with CD19 CAR-T Cells

Juliane Gust, Kevin A. Hay, Laïla-Aïcha Hanafi et al.

Cancer Discovery 2017 10.1158/2159-8290.cd-17-0698

[29]

T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial

Daniel W Lee, James N Kochenderfer, Maryalice Stetler-Stevenson et al.

The Lancet 2015 10.1016/s0140-6736(14)61403-3

[30]

Klaver "T cell maturation stage prior to and during GMP processing informs on CAR T cell expansion in patients" Front Immunol (2016) 10.3389/fimmu.2016.00648

[31]

Cuesta-Mateos "CCR7 in blood cancers – review of its pathophysiological roles and the potential as a therapeutic target" Front Oncol (2021) 10.3389/fonc.2021.736758

[32]

Alrumaihi "The multi-functional roles of CCR7 in human immunology and as a promising therapeutic target for cancer therapeutics" Front Mol Biosci (2022) 10.3389/fmolb.2022.834149

[33]

Jiang "TIGIT is the central player in T-cell suppression associated with CAR T-cell relapse in mantle cell lymphoma" Mol Cancer (2022) 10.1186/s12943-022-01655-0

[34]

Stamper "Crystal structure of the B7-1/CTLA-4 complex that inhibits human immune responses" Nature (2001) 10.1038/35069118

[35]

Li "Immune checkpoint inhibitors and cellular treatment for lymphoma immunotherapy" Clin Exp Immunol (2021) 10.1111/cei.13592

Metrics

5

Citations

35

References

Details

Published: Jan 22, 2024
Vol/Issue: 15
License: View

Authors

I

Ivan Odak

Icahn School of Medicine at Mount Sinai, New York

Department of Neurosurgery, University Hospital Heidelberg, Germany;

University of Göttingen, Institute for Inorganic Chemistry, Tammannstraße 4, 37077 Göttingen, Germany

Division of Critical Care, Department of Pediatric Medicine, St Jude Children’s Research Hospital, Memphis, TN.

Christian R. Schultze-Florey

C

Christian Koenecke

Funding

Deutsche Forschungsgemeinschaft

Bundesministerium für Bildung und Forschung

Cite This Article

Ivan Odak, Lâle M. Bayir, Lennart Riemann, et al. (2024). Brief research report: in-depth immunophenotyping reveals stability of CD19 CAR T-cells over time. Frontiers in Immunology, 15. https://doi.org/10.3389/fimmu.2024.1298598

Brief research report: in-depth immunophenotyping reveals stability of CD19 CAR T-cells over time

You May Also Like