Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
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
_version_ 1785033141204811776
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
work_keys_str_mv AT garciacalderonclarabeatriz monitoringofkineticsandexhaustionmarkersofcirculatingcartcellsasearlypredictivefactorsinpatientswithbcellmalignancies
AT sierromartinezbelen monitoringofkineticsandexhaustionmarkersofcirculatingcartcellsasearlypredictivefactorsinpatientswithbcellmalignancies
AT garciaguerreroestefania monitoringofkineticsandexhaustionmarkersofcirculatingcartcellsasearlypredictivefactorsinpatientswithbcellmalignancies
AT sanojafloresluzalba monitoringofkineticsandexhaustionmarkersofcirculatingcartcellsasearlypredictivefactorsinpatientswithbcellmalignancies
AT munozgarciaraquel monitoringofkineticsandexhaustionmarkersofcirculatingcartcellsasearlypredictivefactorsinpatientswithbcellmalignancies
AT ruizmaldonadovictoria monitoringofkineticsandexhaustionmarkersofcirculatingcartcellsasearlypredictivefactorsinpatientswithbcellmalignancies
AT jimenezleonmariareyes monitoringofkineticsandexhaustionmarkersofcirculatingcartcellsasearlypredictivefactorsinpatientswithbcellmalignancies
AT delgadoserranojavier monitoringofkineticsandexhaustionmarkersofcirculatingcartcellsasearlypredictivefactorsinpatientswithbcellmalignancies
AT molinosquintanaagueda monitoringofkineticsandexhaustionmarkersofcirculatingcartcellsasearlypredictivefactorsinpatientswithbcellmalignancies
AT guijarroalbaladejobeatriz monitoringofkineticsandexhaustionmarkersofcirculatingcartcellsasearlypredictivefactorsinpatientswithbcellmalignancies
AT carrascobrocalinmaculada monitoringofkineticsandexhaustionmarkersofcirculatingcartcellsasearlypredictivefactorsinpatientswithbcellmalignancies
AT lucenajosemanuel monitoringofkineticsandexhaustionmarkersofcirculatingcartcellsasearlypredictivefactorsinpatientswithbcellmalignancies
AT garcialozanojoseraul monitoringofkineticsandexhaustionmarkersofcirculatingcartcellsasearlypredictivefactorsinpatientswithbcellmalignancies
AT blazquezgonicristina monitoringofkineticsandexhaustionmarkersofcirculatingcartcellsasearlypredictivefactorsinpatientswithbcellmalignancies
AT regueraortegajuanluis monitoringofkineticsandexhaustionmarkersofcirculatingcartcellsasearlypredictivefactorsinpatientswithbcellmalignancies
AT gonzalezescribanomariafrancisca monitoringofkineticsandexhaustionmarkersofcirculatingcartcellsasearlypredictivefactorsinpatientswithbcellmalignancies
AT reinososeguramarta monitoringofkineticsandexhaustionmarkersofcirculatingcartcellsasearlypredictivefactorsinpatientswithbcellmalignancies
AT brionesjavier monitoringofkineticsandexhaustionmarkersofcirculatingcartcellsasearlypredictivefactorsinpatientswithbcellmalignancies
AT perezsimonjoseantonio monitoringofkineticsandexhaustionmarkersofcirculatingcartcellsasearlypredictivefactorsinpatientswithbcellmalignancies
AT caballerovelazquezteresa monitoringofkineticsandexhaustionmarkersofcirculatingcartcellsasearlypredictivefactorsinpatientswithbcellmalignancies