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Monitoring of kinetics and exhaustion markers of circulating CAR-T cells as early predictive factors in patients with B-cell malignancies
PURPOSE: CAR-T cell therapy has proven to be a disruptive treatment in the hematology field, however, less than 50% of patients maintain long-term response and early predictors of outcome are still inconsistently defined. Here, we aimed to optimize the detection of CD19 CAR-T cells in blood and to i...
Autores principales: | , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10140355/ https://www.ncbi.nlm.nih.gov/pubmed/37122702 http://dx.doi.org/10.3389/fimmu.2023.1152498 |
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author | García-Calderón, Clara Beatriz Sierro-Martínez, Belén García-Guerrero, Estefanía Sanoja-Flores, Luzalba Muñoz-García, Raquel Ruiz-Maldonado, Victoria Jimenez-Leon, María Reyes Delgado-Serrano, Javier Molinos-Quintana, Águeda Guijarro-Albaladejo, Beatriz Carrasco-Brocal, Inmaculada Lucena, José-Manuel García-Lozano, José-Raúl Blázquez-Goñi, Cristina Reguera-Ortega, Juan Luis González-Escribano, María-Francisca Reinoso-Segura, Marta Briones, Javier Pérez-Simón, José Antonio Caballero-Velázquez, Teresa |
author_facet | García-Calderón, Clara Beatriz Sierro-Martínez, Belén García-Guerrero, Estefanía Sanoja-Flores, Luzalba Muñoz-García, Raquel Ruiz-Maldonado, Victoria Jimenez-Leon, María Reyes Delgado-Serrano, Javier Molinos-Quintana, Águeda Guijarro-Albaladejo, Beatriz Carrasco-Brocal, Inmaculada Lucena, José-Manuel García-Lozano, José-Raúl Blázquez-Goñi, Cristina Reguera-Ortega, Juan Luis González-Escribano, María-Francisca Reinoso-Segura, Marta Briones, Javier Pérez-Simón, José Antonio Caballero-Velázquez, Teresa |
author_sort | García-Calderón, Clara Beatriz |
collection | PubMed |
description | PURPOSE: CAR-T cell therapy has proven to be a disruptive treatment in the hematology field, however, less than 50% of patients maintain long-term response and early predictors of outcome are still inconsistently defined. Here, we aimed to optimize the detection of CD19 CAR-T cells in blood and to identify phenotypic features as early biomarkers associated with toxicity and outcomes. EXPERIMENTAL DESIGN: In this study, monitoring by flow cytometry and digital PCR (dPCR), and immunophenotypic characterization of circulating CAR-T cells from 48 patients treated with Tisa-cel or Axi-cel was performed. RESULTS: Validation of the flow cytometry reagent for the detection of CAR-T cells in blood revealed CD19 protein conjugated with streptavidin as the optimal detection method. Kinetics of CAR-T cell expansion in blood confirmed median day of peak expansion at seven days post-infusion by both flow cytometry and digital PCR. Circulating CAR-T cells showed an activated, proliferative, and exhausted phenotype at the time of peak expansion. Patients with increased expansion showed more severe CRS and ICANs. Immunophenotypic characterization of CAR-T cells at the peak expansion identified the increased expression of co-inhibitory molecules PD1 and LAG3 and reduced levels of the cytotoxicity marker CD107a as predictors of a better long-term disease control. CONCLUSIONS: These data show the importance of CAR-T cells in vivo monitoring and identify the expression of PD1LAG3 and CD107a as early biomarkers of long-term disease control after CAR-T cell therapy. |
format | Online Article Text |
id | pubmed-10140355 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-101403552023-04-29 Monitoring of kinetics and exhaustion markers of circulating CAR-T cells as early predictive factors in patients with B-cell malignancies García-Calderón, Clara Beatriz Sierro-Martínez, Belén García-Guerrero, Estefanía Sanoja-Flores, Luzalba Muñoz-García, Raquel Ruiz-Maldonado, Victoria Jimenez-Leon, María Reyes Delgado-Serrano, Javier Molinos-Quintana, Águeda Guijarro-Albaladejo, Beatriz Carrasco-Brocal, Inmaculada Lucena, José-Manuel García-Lozano, José-Raúl Blázquez-Goñi, Cristina Reguera-Ortega, Juan Luis González-Escribano, María-Francisca Reinoso-Segura, Marta Briones, Javier Pérez-Simón, José Antonio Caballero-Velázquez, Teresa Front Immunol Immunology PURPOSE: CAR-T cell therapy has proven to be a disruptive treatment in the hematology field, however, less than 50% of patients maintain long-term response and early predictors of outcome are still inconsistently defined. Here, we aimed to optimize the detection of CD19 CAR-T cells in blood and to identify phenotypic features as early biomarkers associated with toxicity and outcomes. EXPERIMENTAL DESIGN: In this study, monitoring by flow cytometry and digital PCR (dPCR), and immunophenotypic characterization of circulating CAR-T cells from 48 patients treated with Tisa-cel or Axi-cel was performed. RESULTS: Validation of the flow cytometry reagent for the detection of CAR-T cells in blood revealed CD19 protein conjugated with streptavidin as the optimal detection method. Kinetics of CAR-T cell expansion in blood confirmed median day of peak expansion at seven days post-infusion by both flow cytometry and digital PCR. Circulating CAR-T cells showed an activated, proliferative, and exhausted phenotype at the time of peak expansion. Patients with increased expansion showed more severe CRS and ICANs. Immunophenotypic characterization of CAR-T cells at the peak expansion identified the increased expression of co-inhibitory molecules PD1 and LAG3 and reduced levels of the cytotoxicity marker CD107a as predictors of a better long-term disease control. CONCLUSIONS: These data show the importance of CAR-T cells in vivo monitoring and identify the expression of PD1LAG3 and CD107a as early biomarkers of long-term disease control after CAR-T cell therapy. Frontiers Media S.A. 2023-04-14 /pmc/articles/PMC10140355/ /pubmed/37122702 http://dx.doi.org/10.3389/fimmu.2023.1152498 Text en Copyright © 2023 García-Calderón, Sierro-Martínez, García-Guerrero, Sanoja-Flores, Muñoz-García, Ruiz-Maldonado, Jimenez-Leon, Delgado-Serrano, Molinos-Quintana, Guijarro-Albaladejo, Carrasco-Brocal, Lucena, García-Lozano, Blázquez-Goñi, Reguera-Ortega, González-Escribano, Reinoso-Segura, Briones, Pérez-Simón and Caballero-Velázquez https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Immunology García-Calderón, Clara Beatriz Sierro-Martínez, Belén García-Guerrero, Estefanía Sanoja-Flores, Luzalba Muñoz-García, Raquel Ruiz-Maldonado, Victoria Jimenez-Leon, María Reyes Delgado-Serrano, Javier Molinos-Quintana, Águeda Guijarro-Albaladejo, Beatriz Carrasco-Brocal, Inmaculada Lucena, José-Manuel García-Lozano, José-Raúl Blázquez-Goñi, Cristina Reguera-Ortega, Juan Luis González-Escribano, María-Francisca Reinoso-Segura, Marta Briones, Javier Pérez-Simón, José Antonio Caballero-Velázquez, Teresa Monitoring of kinetics and exhaustion markers of circulating CAR-T cells as early predictive factors in patients with B-cell malignancies |
title | Monitoring of kinetics and exhaustion markers of circulating CAR-T cells as early predictive factors in patients with B-cell malignancies |
title_full | Monitoring of kinetics and exhaustion markers of circulating CAR-T cells as early predictive factors in patients with B-cell malignancies |
title_fullStr | Monitoring of kinetics and exhaustion markers of circulating CAR-T cells as early predictive factors in patients with B-cell malignancies |
title_full_unstemmed | Monitoring of kinetics and exhaustion markers of circulating CAR-T cells as early predictive factors in patients with B-cell malignancies |
title_short | Monitoring of kinetics and exhaustion markers of circulating CAR-T cells as early predictive factors in patients with B-cell malignancies |
title_sort | monitoring of kinetics and exhaustion markers of circulating car-t cells as early predictive factors in patients with b-cell malignancies |
topic | Immunology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10140355/ https://www.ncbi.nlm.nih.gov/pubmed/37122702 http://dx.doi.org/10.3389/fimmu.2023.1152498 |
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