Genetic disruption of Blimp-1 drastically augments the antitumor efficacy of BCMA-targeting CAR T cells
Abstract: Chimeric antigen receptor (CAR) T cells directed against B-cell maturation antigen (BCMA) are an effective treatment for multiple myeloma (MM), but short persistence and frequent relapses are challenges for this immunotherapy. This lack of durability has been attributed to the premature te...
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| Format: | Article |
| Language: | English |
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Elsevier
2025-02-01
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| Series: | Blood Advances |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2473952924007122 |
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| author | Anthony M. Battram Joan Mañé-Pujol David F. Moreno Aina Oliver-Caldés Judit Carpio Oriol Cardus Luis Gerardo Rodríguez-Lobato Álvaro Urbano-Ispizua Carlos Fernández de Larrea |
| author_facet | Anthony M. Battram Joan Mañé-Pujol David F. Moreno Aina Oliver-Caldés Judit Carpio Oriol Cardus Luis Gerardo Rodríguez-Lobato Álvaro Urbano-Ispizua Carlos Fernández de Larrea |
| author_sort | Anthony M. Battram |
| collection | DOAJ |
| description | Abstract: Chimeric antigen receptor (CAR) T cells directed against B-cell maturation antigen (BCMA) are an effective treatment for multiple myeloma (MM), but short persistence and frequent relapses are challenges for this immunotherapy. This lack of durability has been attributed to the premature terminal differentiation of CAR T cells, which prevents the formation of long-lived memory cells that maintain antitumor responses. To improve long-term efficacy, we used CRISPR/CRISPR-associated protein 9-mediated gene editing to ablate the expression of the transcription factor Blimp-1. Blimp-1 knockout (KO) CAR T cells displayed a memory-like phenotype compared with control (Mock) CAR T cells, but had reduced effector function, with a striking loss of granzyme B. However, in a murine model of advanced MM, Blimp-1 KO CAR T cells effectively slowed or even prevented disease progression, significantly outperforming Mock CAR T cells in improving survival (P = .006). To understand this enhanced in vivo effectiveness, Blimp-1 KO CAR T cells were characterized after being repeatedly challenged with tumor cells in vitro. In this setting, Blimp-1 KO CAR T cells maintained a highly active state with high expression of memory markers, but, crucially, demonstrated enhanced effector function and increased energetic capacity. RNA-sequencing analysis of tumor-exposed Blimp-1 KO CAR T cells confirmed the presence of a memory-like transcriptomic signature and, additionally, revealed enhanced ribosome biogenesis and repressed CAR T-cell dysfunction as mechanisms that could contribute to improved antitumor activity. Put together, our findings show that dampening Blimp-1 expression altered the phenotype and function of anti-BCMA CAR T cells, leading to augmented therapeutic efficacy in MM. |
| format | Article |
| id | doaj-art-594b5bcb9f42404a9825a52013914944 |
| institution | Kabale University |
| issn | 2473-9529 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Blood Advances |
| spelling | doaj-art-594b5bcb9f42404a9825a520139149442025-02-05T04:32:29ZengElsevierBlood Advances2473-95292025-02-0193627641Genetic disruption of Blimp-1 drastically augments the antitumor efficacy of BCMA-targeting CAR T cellsAnthony M. Battram0Joan Mañé-Pujol1David F. Moreno2Aina Oliver-Caldés3Judit Carpio4Oriol Cardus5Luis Gerardo Rodríguez-Lobato6Álvaro Urbano-Ispizua7Carlos Fernández de Larrea8Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain; Correspondence: Anthony M. Battram, Institut d'Investigacions Biomèdiques August Pi i Sunyer, C/Rosselló 149-153, 08036 Barcelona, Spain;Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain; Faculty of Medicine and Medical Sciences, University of Barcelona, Barcelona, SpainInstitut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain; Department of Hematology, Amyloidosis and Myeloma Unit, Hospital Clínic of Barcelona, Barcelona, SpainInstitut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain; Department of Hematology, Amyloidosis and Myeloma Unit, Hospital Clínic of Barcelona, Barcelona, SpainInstitut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, SpainInstitut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain; Faculty of Medicine and Medical Sciences, University of Barcelona, Barcelona, SpainInstitut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain; Department of Hematology, Amyloidosis and Myeloma Unit, Hospital Clínic of Barcelona, Barcelona, SpainInstitut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain; Department of Hematology, Amyloidosis and Myeloma Unit, Hospital Clínic of Barcelona, Barcelona, Spain; Josep Carreras Leukaemia Research Institute, Barcelona, Spain; Department of Hematology, University of Barcelona, Barcelona, SpainInstitut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain; Faculty of Medicine and Medical Sciences, University of Barcelona, Barcelona, Spain; Department of Hematology, Amyloidosis and Myeloma Unit, Hospital Clínic of Barcelona, Barcelona, Spain; Department of Hematology, University of Barcelona, Barcelona, Spain; Carlos Fernández de Larrea, Amyloidosis and Myeloma Unit, Department of Hematology, Hospital Clínic of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, C/Rosselló 149-153, 08036 Barcelona, Spain;Abstract: Chimeric antigen receptor (CAR) T cells directed against B-cell maturation antigen (BCMA) are an effective treatment for multiple myeloma (MM), but short persistence and frequent relapses are challenges for this immunotherapy. This lack of durability has been attributed to the premature terminal differentiation of CAR T cells, which prevents the formation of long-lived memory cells that maintain antitumor responses. To improve long-term efficacy, we used CRISPR/CRISPR-associated protein 9-mediated gene editing to ablate the expression of the transcription factor Blimp-1. Blimp-1 knockout (KO) CAR T cells displayed a memory-like phenotype compared with control (Mock) CAR T cells, but had reduced effector function, with a striking loss of granzyme B. However, in a murine model of advanced MM, Blimp-1 KO CAR T cells effectively slowed or even prevented disease progression, significantly outperforming Mock CAR T cells in improving survival (P = .006). To understand this enhanced in vivo effectiveness, Blimp-1 KO CAR T cells were characterized after being repeatedly challenged with tumor cells in vitro. In this setting, Blimp-1 KO CAR T cells maintained a highly active state with high expression of memory markers, but, crucially, demonstrated enhanced effector function and increased energetic capacity. RNA-sequencing analysis of tumor-exposed Blimp-1 KO CAR T cells confirmed the presence of a memory-like transcriptomic signature and, additionally, revealed enhanced ribosome biogenesis and repressed CAR T-cell dysfunction as mechanisms that could contribute to improved antitumor activity. Put together, our findings show that dampening Blimp-1 expression altered the phenotype and function of anti-BCMA CAR T cells, leading to augmented therapeutic efficacy in MM.http://www.sciencedirect.com/science/article/pii/S2473952924007122 |
| spellingShingle | Anthony M. Battram Joan Mañé-Pujol David F. Moreno Aina Oliver-Caldés Judit Carpio Oriol Cardus Luis Gerardo Rodríguez-Lobato Álvaro Urbano-Ispizua Carlos Fernández de Larrea Genetic disruption of Blimp-1 drastically augments the antitumor efficacy of BCMA-targeting CAR T cells Blood Advances |
| title | Genetic disruption of Blimp-1 drastically augments the antitumor efficacy of BCMA-targeting CAR T cells |
| title_full | Genetic disruption of Blimp-1 drastically augments the antitumor efficacy of BCMA-targeting CAR T cells |
| title_fullStr | Genetic disruption of Blimp-1 drastically augments the antitumor efficacy of BCMA-targeting CAR T cells |
| title_full_unstemmed | Genetic disruption of Blimp-1 drastically augments the antitumor efficacy of BCMA-targeting CAR T cells |
| title_short | Genetic disruption of Blimp-1 drastically augments the antitumor efficacy of BCMA-targeting CAR T cells |
| title_sort | genetic disruption of blimp 1 drastically augments the antitumor efficacy of bcma targeting car t cells |
| url | http://www.sciencedirect.com/science/article/pii/S2473952924007122 |
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