CAR T expansion and systemic inflammation: diverging impacts on large B-cell lymphoma therapy in the multicenter CART SIE study

Chimeric antigen receptor (CAR) T expansion has been linked to anti-tumor response in relapsed/refractory large B-cell lymphoma both in clinical trials and smaller real-world studies. Here, we present the largest multicenter real-world analysis to date, evaluating 262 patients treated with tisagenlecleucel or axicabtagene ciloleucel in second or subsequent relapse. Our findings underscore the complementary roles of multiparameter flow cytometry and droplet digital polymerase chain reaction in monitoring CAR T cells. While droplet digital polymerase chain reaction accurately quantifies transgene copies, multiparameter flow cytometry provides critical phenotypic details, revealing CAR T-cell subpopulations that are associated with its efficacy. Consistent with prior studies, we confirm the association of CAR T expansion with response rates, progression-free survival, and toxicities. However, we reveal that expansion alone does not ensure efficacy. Elevated markers of systemic inflammation, such as ferritin and C-reactive protein, are linked to poorer outcomes despite robust expansion. These markers correlate with reduced cytotoxic CD8+ T cells with central memory features among in vivo expanded CAR T-cell populations, with similar associations observed in manufactured and leukapheresis products. Importantly, patients with high baseline inflammation who achieved significant expansion demonstrated progression-free survival outcomes comparable to those with limited expansion, highlighting the negative impact of inflammation on CAR T-cell efficacy. Interestingly, ferritin and C-reactive protein levels were similar among responding patients, regardless of differences in CAR T expansion. Collectively, our findings indicate that systemic inflammation is associated with the phenotypic quality of T and CAR T cells. While functional validation is warranted, these results underscore the need to address inflammatory pathways to improve treatment outcomes.

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Publication Details

Journal
Haematologica
Published
2025-05-29
DOI
https://doi.org/10.3324/haematol.2025.287528
Citations
4
Primary Topic
CAR-T cell therapy research
Type
article
Field-Weighted Citation Impact
4.18
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article

CAR T expansion and systemic inflammation: diverging impacts on large B-cell lymphoma therapy in the multicenter CART SIE study

Giada Zanirato, Ilaria Cutini, Massimo Massaia, Giulia Bertolini et al.
4 citations
Haematologica
CAR-T cell therapy research
4.18
article

CAR T expansion and systemic inflammation: diverging impacts on large B-cell lymphoma therapy in the multicenter CART SIE study

Giada Zanirato, Ilaria Cutini, Massimo Massaia, Giulia Bertolini, Luca Arcaini, Angelica Barone, Silva Ljevar, Mauro Krampera, Anna Dodero, Mirko Farina, Massimiliano Bonafè, Maria Chiara Tisi, Giovanni Grillo, Martina Magni, Anisa Bermema, Stéfania Bramanti, Paolo Corradini, Annalisa Chiappella, Mattia Novo, Serena De Matteis, Francesca Bonifazi, Massimo Vincenzo Martino, Federico Stella, Cristiana Carniti, Pier Luigi Zinzani, Sadhana Jonnalagadda
article en
4 citations

Abstract

Chimeric antigen receptor (CAR) T expansion has been linked to anti-tumor response in relapsed/refractory large B-cell lymphoma both in clinical trials and smaller real-world studies. Here, we present the largest multicenter real-world analysis to date, evaluating 262 patients treated with tisagenlecleucel or axicabtagene ciloleucel in second or subsequent relapse. Our findings underscore the complementary roles of multiparameter flow cytometry and droplet digital polymerase chain reaction in monitoring CAR T cells. While droplet digital polymerase chain reaction accurately quantifies transgene copies, multiparameter flow cytometry provides critical phenotypic details, revealing CAR T-cell subpopulations that are associated with its efficacy. Consistent with prior studies, we confirm the association of CAR T expansion with response rates, progression-free survival, and toxicities. However, we reveal that expansion alone does not ensure efficacy. Elevated markers of systemic inflammation, such as ferritin and C-reactive protein, are linked to poorer outcomes despite robust expansion. These markers correlate with reduced cytotoxic CD8+ T cells with central memory features among in vivo expanded CAR T-cell populations, with similar associations observed in manufactured and leukapheresis products. Importantly, patients with high baseline inflammation who achieved significant expansion demonstrated progression-free survival outcomes comparable to those with limited expansion, highlighting the negative impact of inflammation on CAR T-cell efficacy. Interestingly, ferritin and C-reactive protein levels were similar among responding patients, regardless of differences in CAR T expansion. Collectively, our findings indicate that systemic inflammation is associated with the phenotypic quality of T and CAR T cells. While functional validation is warranted, these results underscore the need to address inflammatory pathways to improve treatment outcomes.

HaematologicaVol. 110(11)
University of Verona (IT), University of Milan (IT), University of Pavia (IT), Brescia University (US), Azienda Ospedaliera Citta' della Salute e della Scienza di Torino (IT), Azienda Socio Sanitaria Territoriale Grande Ospedale Metropolitano Niguarda (IT), Azienda ospedaliera "Bianchi-Melacrino-Morelli" (IT), Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia (IT), Istituto di Ematologia di Bologna (IT), Azienda Sanitaria Ospedaliera S.Croce e Carle Cuneo (IT), Policlinico San Matteo Fondazione (IT), Ospedale San Bortolo (IT), Istituti di Ricovero e Cura a Carattere Scientifico (IT), Fondazione IRCCS Istituto Nazionale dei Tumori (IT), Gruppo Italiano per il Trapianto di Midollo Osseo (IT), IRCCS Humanitas Research Hospital (IT), University of Brescia (IT), University of Bologna (IT)
No poverty
Openalex Percentile: Top 6%
CAR-T cell therapy research
4.18
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