Mitigating T-cell mitochondrial dysfunction in CLL to augment CAR T-cell therapy: evaluation in an immunocompetent model
Abstract: An unmet clinical need in chronic lymphocytic leukemia (CLL) is emerging due to the rapidly expanding group of patients with double refractory (Bruton's tyrosine kinase- and B-cell lymphoma 2-inhibitor) disease. So far, autologous T-cell–based therapies, including chimeric antigen rec...
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| Format: | Article |
| Language: | English |
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Elsevier
2025-05-01
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| Series: | Blood Advances |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2473952925000990 |
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| author | Wael Gamal Nienke B. Goedhart Helga Simon-Molas Melanie Mediavilla-Varela Angimar Uriepero-Palma Fleur S. Peters Kamira Maharaj Julio C. Chavez John Powers Alyssa Obermayer Timothy I. Shaw José R. Conejo-Garcia Paulo C. Rodriguez Eva Sahakian Javier Pinilla-Ibarz Arnon P. Kater |
| author_facet | Wael Gamal Nienke B. Goedhart Helga Simon-Molas Melanie Mediavilla-Varela Angimar Uriepero-Palma Fleur S. Peters Kamira Maharaj Julio C. Chavez John Powers Alyssa Obermayer Timothy I. Shaw José R. Conejo-Garcia Paulo C. Rodriguez Eva Sahakian Javier Pinilla-Ibarz Arnon P. Kater |
| author_sort | Wael Gamal |
| collection | DOAJ |
| description | Abstract: An unmet clinical need in chronic lymphocytic leukemia (CLL) is emerging due to the rapidly expanding group of patients with double refractory (Bruton's tyrosine kinase- and B-cell lymphoma 2-inhibitor) disease. So far, autologous T-cell–based therapies, including chimeric antigen receptor (CAR) T cells, have limited success in CLL, which has been attributed to an acquired CLL-mediated T-cell dysfunction and subset skewing toward effector cells at the expense of memory formation. T-cell responses rely on dynamic metabolic processes, particularly mitochondrial fitness. Although mitochondrial disruptions have been observed in solid tumor–infiltrating lymphocytes, their impact on T-cell immunity in lymphoproliferative disorders is unknown. Recent findings indicate that mitochondrial mass in CAR T cells correlates with CLL clinical outcomes. This prompted our investigation into the mitochondrial fitness in CLL T cells. Integrated metabolic and functional analyses revealed impaired, depolarized mitochondria across all T-cell subsets in untreated patients with CLL, leading to further ex vivo and in vivo mouse studies on the underlying signaling alterations. Multiomics profiling of transcriptome and epigenome revealed significant alterations in mitochondrial signaling, diminished adenosine monophosphate-activated protein kinase and autophagy activity, and upregulated glycolysis coupled with hyperactivation of Akt. Inhibition of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway during CLL T-cell culture induced metabolic reprogramming, enhancing mitochondrial activity, expression of peroxisome proliferator-activated receptor-gamma coactivator 1-alpha, and memory differentiation. Underscoring clinical relevance, supplementation with the PI3Kδ inhibitor idelalisib during CAR T-cell manufacturing improved persistence and long-term leukemia-free remissions in an immunocompetent murine model. Our study suggests that modulating the abnormal CLL T-cell metabolism can enhance the efficacy of autologous T-cell therapies. |
| format | Article |
| id | doaj-art-2c768aa2f4d346d295914fa8a83f8c1e |
| institution | OA Journals |
| issn | 2473-9529 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Blood Advances |
| spelling | doaj-art-2c768aa2f4d346d295914fa8a83f8c1e2025-08-20T02:33:20ZengElsevierBlood Advances2473-95292025-05-019102511252910.1182/bloodadvances.2024014822Mitigating T-cell mitochondrial dysfunction in CLL to augment CAR T-cell therapy: evaluation in an immunocompetent modelWael Gamal0Nienke B. Goedhart1Helga Simon-Molas2Melanie Mediavilla-Varela3Angimar Uriepero-Palma4Fleur S. Peters5Kamira Maharaj6Julio C. Chavez7John Powers8Alyssa Obermayer9Timothy I. Shaw10José R. Conejo-Garcia11Paulo C. Rodriguez12Eva Sahakian13Javier Pinilla-Ibarz14Arnon P. Kater15Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL; Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FLDepartments of Hematology and Experimental Immunology and Cancer Center Amsterdam, Amsterdam University Medical Centers, University of Amsterdam, The NetherlandsDepartments of Hematology and Experimental Immunology and Cancer Center Amsterdam, Amsterdam University Medical Centers, University of Amsterdam, The NetherlandsDepartment of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FLDepartment of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FLDepartments of Hematology and Experimental Immunology and Cancer Center Amsterdam, Amsterdam University Medical Centers, University of Amsterdam, The NetherlandsDepartment of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FLDepartment of Malignant Hematology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FLDepartment of Tumor Microenvironment and Metastasis, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FLDepartment of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FLDepartment of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FLDepartment of Integrative Immunobiology, Duke School of Medicine, Durham, NCDepartment of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FLDepartment of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL; Department of Malignant Hematology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL; Eva Sahakian, H. Lee Moffitt Cancer Center & Research Institute, 12902 USF Magnolia Dr, Tampa, FL 33612;Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL; Department of Malignant Hematology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL; Correspondence: Javier Pinilla-Ibarz, H. Lee Moffitt Cancer Center & Research Institute, 12902 USF Magnolia Dr, Tampa, FL 33612;Departments of Hematology and Experimental Immunology and Cancer Center Amsterdam, Amsterdam University Medical Centers, University of Amsterdam, The NetherlandsAbstract: An unmet clinical need in chronic lymphocytic leukemia (CLL) is emerging due to the rapidly expanding group of patients with double refractory (Bruton's tyrosine kinase- and B-cell lymphoma 2-inhibitor) disease. So far, autologous T-cell–based therapies, including chimeric antigen receptor (CAR) T cells, have limited success in CLL, which has been attributed to an acquired CLL-mediated T-cell dysfunction and subset skewing toward effector cells at the expense of memory formation. T-cell responses rely on dynamic metabolic processes, particularly mitochondrial fitness. Although mitochondrial disruptions have been observed in solid tumor–infiltrating lymphocytes, their impact on T-cell immunity in lymphoproliferative disorders is unknown. Recent findings indicate that mitochondrial mass in CAR T cells correlates with CLL clinical outcomes. This prompted our investigation into the mitochondrial fitness in CLL T cells. Integrated metabolic and functional analyses revealed impaired, depolarized mitochondria across all T-cell subsets in untreated patients with CLL, leading to further ex vivo and in vivo mouse studies on the underlying signaling alterations. Multiomics profiling of transcriptome and epigenome revealed significant alterations in mitochondrial signaling, diminished adenosine monophosphate-activated protein kinase and autophagy activity, and upregulated glycolysis coupled with hyperactivation of Akt. Inhibition of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway during CLL T-cell culture induced metabolic reprogramming, enhancing mitochondrial activity, expression of peroxisome proliferator-activated receptor-gamma coactivator 1-alpha, and memory differentiation. Underscoring clinical relevance, supplementation with the PI3Kδ inhibitor idelalisib during CAR T-cell manufacturing improved persistence and long-term leukemia-free remissions in an immunocompetent murine model. Our study suggests that modulating the abnormal CLL T-cell metabolism can enhance the efficacy of autologous T-cell therapies.http://www.sciencedirect.com/science/article/pii/S2473952925000990 |
| spellingShingle | Wael Gamal Nienke B. Goedhart Helga Simon-Molas Melanie Mediavilla-Varela Angimar Uriepero-Palma Fleur S. Peters Kamira Maharaj Julio C. Chavez John Powers Alyssa Obermayer Timothy I. Shaw José R. Conejo-Garcia Paulo C. Rodriguez Eva Sahakian Javier Pinilla-Ibarz Arnon P. Kater Mitigating T-cell mitochondrial dysfunction in CLL to augment CAR T-cell therapy: evaluation in an immunocompetent model Blood Advances |
| title | Mitigating T-cell mitochondrial dysfunction in CLL to augment CAR T-cell therapy: evaluation in an immunocompetent model |
| title_full | Mitigating T-cell mitochondrial dysfunction in CLL to augment CAR T-cell therapy: evaluation in an immunocompetent model |
| title_fullStr | Mitigating T-cell mitochondrial dysfunction in CLL to augment CAR T-cell therapy: evaluation in an immunocompetent model |
| title_full_unstemmed | Mitigating T-cell mitochondrial dysfunction in CLL to augment CAR T-cell therapy: evaluation in an immunocompetent model |
| title_short | Mitigating T-cell mitochondrial dysfunction in CLL to augment CAR T-cell therapy: evaluation in an immunocompetent model |
| title_sort | mitigating t cell mitochondrial dysfunction in cll to augment car t cell therapy evaluation in an immunocompetent model |
| url | http://www.sciencedirect.com/science/article/pii/S2473952925000990 |
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