Capivasertib enhances chimeric antigen receptor T cell activity in preclinical models of B cell lymphoma
Phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling is involved in the growth of normal and cancer cells and is crucial for T cell activation. Previously, we have shown that AKT Inhibitor VIII, a selective AKT-1/2 inhibitor, during chimeric antigen receptor (CAR) T cell manufacturi...
Saved in:
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2025-03-01
|
| Series: | Molecular Therapy: Methods & Clinical Development |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2329050125000166 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1823864409986957312 |
|---|---|
| author | Hui-Ju Hsieh Ryan Urak Mary C. Clark Larry W. Kwak Stephen J. Forman Xiuli Wang |
| author_facet | Hui-Ju Hsieh Ryan Urak Mary C. Clark Larry W. Kwak Stephen J. Forman Xiuli Wang |
| author_sort | Hui-Ju Hsieh |
| collection | DOAJ |
| description | Phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling is involved in the growth of normal and cancer cells and is crucial for T cell activation. Previously, we have shown that AKT Inhibitor VIII, a selective AKT-1/2 inhibitor, during chimeric antigen receptor (CAR) T cell manufacturing, improves CAR T cell function in preclinical models. Although AKT Inhibitor VIII could enhance CAR T cell function, AKT Inhibitor VIII is not a clinical-grade compound. However, pan-AKT inhibitors have been applied against cancers with PIK3CA/AKT/PTEN alterations in clinical trials. We evaluated ex vivo and in vivo strategies of enhancing CAR T cell therapeutic effect using the pan-AKT inhibitor capivasertib. We found that ex vivo 0.25 μM capivasertib treatment during the period of T cell stimulation during manufacture enhanced the antitumor activity of CAR T cells in B cell lymphoma mouse models. Mechanistically, capivasertib changed gene and protein expression patterns related to the functions of memory and effector CAR T cells. Furthermore, in vivo combination therapy of capivasertib and CD19-specific CAR T cells led to improved early response to and persistence of functional CAR T cells in mice bearing PTEN-deficient lymphoma cells compared to CAR T cells alone. Capivasertib exerts a similar function to AKT Inhibitor VIII in modulating CAR T cells, and combining CAR T cell therapy with capivasertib both ex vivo and in vivo offers the potential to improve patient outcomes. Since PTEN deficiency is common in cancer and is the main mechanism for capivasertib function, combination therapy may provide an alternative solution for the challenges of CAR T cell therapy. |
| format | Article |
| id | doaj-art-7f7d330e0f6e440d906b58e62c2168ab |
| institution | Kabale University |
| issn | 2329-0501 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Methods & Clinical Development |
| spelling | doaj-art-7f7d330e0f6e440d906b58e62c2168ab2025-02-09T05:00:34ZengElsevierMolecular Therapy: Methods & Clinical Development2329-05012025-03-01331101421Capivasertib enhances chimeric antigen receptor T cell activity in preclinical models of B cell lymphomaHui-Ju Hsieh0Ryan Urak1Mary C. Clark2Larry W. Kwak3Stephen J. Forman4Xiuli Wang5Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA 91010, USADepartment of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA 91010, USADepartment of Clinical and Translational Project Development, City of Hope, Duarte, CA 91010, USAToni Stephenson Lymphoma Center, Department of Hematology and Hematopoietic Cell Transplantation, Beckman Research Institute of City of Hope, Duarte, CA 91010, USADepartment of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA 91010, USADepartment of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA 91010, USA; Corresponding author: Xiuli Wang, Department of Hematology and HCT, City of Hope National Medical Center, Duarte, CA 91010, USA.Phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling is involved in the growth of normal and cancer cells and is crucial for T cell activation. Previously, we have shown that AKT Inhibitor VIII, a selective AKT-1/2 inhibitor, during chimeric antigen receptor (CAR) T cell manufacturing, improves CAR T cell function in preclinical models. Although AKT Inhibitor VIII could enhance CAR T cell function, AKT Inhibitor VIII is not a clinical-grade compound. However, pan-AKT inhibitors have been applied against cancers with PIK3CA/AKT/PTEN alterations in clinical trials. We evaluated ex vivo and in vivo strategies of enhancing CAR T cell therapeutic effect using the pan-AKT inhibitor capivasertib. We found that ex vivo 0.25 μM capivasertib treatment during the period of T cell stimulation during manufacture enhanced the antitumor activity of CAR T cells in B cell lymphoma mouse models. Mechanistically, capivasertib changed gene and protein expression patterns related to the functions of memory and effector CAR T cells. Furthermore, in vivo combination therapy of capivasertib and CD19-specific CAR T cells led to improved early response to and persistence of functional CAR T cells in mice bearing PTEN-deficient lymphoma cells compared to CAR T cells alone. Capivasertib exerts a similar function to AKT Inhibitor VIII in modulating CAR T cells, and combining CAR T cell therapy with capivasertib both ex vivo and in vivo offers the potential to improve patient outcomes. Since PTEN deficiency is common in cancer and is the main mechanism for capivasertib function, combination therapy may provide an alternative solution for the challenges of CAR T cell therapy.http://www.sciencedirect.com/science/article/pii/S2329050125000166AKTcapivasertibCAR T cellPTENlymphoma |
| spellingShingle | Hui-Ju Hsieh Ryan Urak Mary C. Clark Larry W. Kwak Stephen J. Forman Xiuli Wang Capivasertib enhances chimeric antigen receptor T cell activity in preclinical models of B cell lymphoma Molecular Therapy: Methods & Clinical Development AKT capivasertib CAR T cell PTEN lymphoma |
| title | Capivasertib enhances chimeric antigen receptor T cell activity in preclinical models of B cell lymphoma |
| title_full | Capivasertib enhances chimeric antigen receptor T cell activity in preclinical models of B cell lymphoma |
| title_fullStr | Capivasertib enhances chimeric antigen receptor T cell activity in preclinical models of B cell lymphoma |
| title_full_unstemmed | Capivasertib enhances chimeric antigen receptor T cell activity in preclinical models of B cell lymphoma |
| title_short | Capivasertib enhances chimeric antigen receptor T cell activity in preclinical models of B cell lymphoma |
| title_sort | capivasertib enhances chimeric antigen receptor t cell activity in preclinical models of b cell lymphoma |
| topic | AKT capivasertib CAR T cell PTEN lymphoma |
| url | http://www.sciencedirect.com/science/article/pii/S2329050125000166 |
| work_keys_str_mv | AT huijuhsieh capivasertibenhanceschimericantigenreceptortcellactivityinpreclinicalmodelsofbcelllymphoma AT ryanurak capivasertibenhanceschimericantigenreceptortcellactivityinpreclinicalmodelsofbcelllymphoma AT marycclark capivasertibenhanceschimericantigenreceptortcellactivityinpreclinicalmodelsofbcelllymphoma AT larrywkwak capivasertibenhanceschimericantigenreceptortcellactivityinpreclinicalmodelsofbcelllymphoma AT stephenjforman capivasertibenhanceschimericantigenreceptortcellactivityinpreclinicalmodelsofbcelllymphoma AT xiuliwang capivasertibenhanceschimericantigenreceptortcellactivityinpreclinicalmodelsofbcelllymphoma |