Development of multivalent CAR T cells as dual immunotherapy and conditioning agents
Hematopoietic stem cell transplantation (HSCT) is the only definitive cure for pediatric acute myeloid leukemia (AML). Despite adjustments in HSCT protocols and improvements in supportive care, 30% of high-risk patients who receive HSCT as part of their therapy still experience disease relapse with...
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Elsevier
2025-03-01
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| Series: | Molecular Therapy: Oncology |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S295032992500013X |
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| author | Quenton Rashawn Bubb Mohammad Balood Gabe Eduardo Seir Leah Swartzrock Ethan Haslett Katie Ho Peng Xu Saida G. Wiltz Elena Sotillo Tanja A. Gruber Rebecca M. Richards Crystal L. Mackall Agnieszka Czechowicz |
| author_facet | Quenton Rashawn Bubb Mohammad Balood Gabe Eduardo Seir Leah Swartzrock Ethan Haslett Katie Ho Peng Xu Saida G. Wiltz Elena Sotillo Tanja A. Gruber Rebecca M. Richards Crystal L. Mackall Agnieszka Czechowicz |
| author_sort | Quenton Rashawn Bubb |
| collection | DOAJ |
| description | Hematopoietic stem cell transplantation (HSCT) is the only definitive cure for pediatric acute myeloid leukemia (AML). Despite adjustments in HSCT protocols and improvements in supportive care, 30% of high-risk patients who receive HSCT as part of their therapy still experience disease relapse with high transplant-related mortality. Relapsed AML has a dismal prognosis, and novel therapies are needed. To improve upon the status quo, HSCT would more effectively eliminate relapse-initiating leukemic cells and be delivered with safer, non-genotoxic conditioning. Here, we investigate hematopoietic cytokine receptors (HCRs) and identify that KIT, MPL, and FLT3 are collectively highly expressed in virtually all pediatric AML samples studied. Further, we establish proof-of-concept of a first-in-class chimeric antigen receptor (CAR) T cell that enables simultaneous targeting of KIT, MPL, and FLT3 through a single receptor, which we term the extracellularly linked concatemeric trivalent cytokine (ELECTRIC) CAR. ELECTRIC CARs exhibit potent cytotoxicity against normal and malignant hematopoietic cells in vitro and display anti-HCR activity in a murine xenograft model. We propose that the ELECTRIC system can be the foundation to developing a non-genotoxic, anti-leukemic conditioning regimen to enable safer, more durable efficacy with minimal toxicity. |
| format | Article |
| id | doaj-art-830b87f661534ee69ef2e3285c628ee8 |
| institution | DOAJ |
| issn | 2950-3299 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Oncology |
| spelling | doaj-art-830b87f661534ee69ef2e3285c628ee82025-08-20T02:48:30ZengElsevierMolecular Therapy: Oncology2950-32992025-03-0133120094410.1016/j.omton.2025.200944Development of multivalent CAR T cells as dual immunotherapy and conditioning agentsQuenton Rashawn Bubb0Mohammad Balood1Gabe Eduardo Seir2Leah Swartzrock3Ethan Haslett4Katie Ho5Peng Xu6Saida G. Wiltz7Elena Sotillo8Tanja A. Gruber9Rebecca M. Richards10Crystal L. Mackall11Agnieszka Czechowicz12Stem Cell Biology and Regenerative Medicine Graduate Program, Medical Scientist Training Program, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Pediatrics, Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USADepartment of Pediatrics, Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USADepartment of Pediatrics, Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Bioengineering, Stanford University, Stanford, CA 94305, USADepartment of Pediatrics, Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USADepartment of Pediatrics, Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USADepartment of Pediatrics, Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USAStanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305, USADepartment of Pediatrics, Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USAStanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305, USADepartment of Pediatrics, Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USADepartment of Pediatrics, University of Wisconsin-Madison, Madison, WI 53792, USADepartment of Pediatrics, Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305, USA; Division of Blood and Stem Cell Transplantation and Cell Therapy, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USADepartment of Pediatrics, Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Corresponding author: Agnieszka Czechowicz, Department of Pediatrics, Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.Hematopoietic stem cell transplantation (HSCT) is the only definitive cure for pediatric acute myeloid leukemia (AML). Despite adjustments in HSCT protocols and improvements in supportive care, 30% of high-risk patients who receive HSCT as part of their therapy still experience disease relapse with high transplant-related mortality. Relapsed AML has a dismal prognosis, and novel therapies are needed. To improve upon the status quo, HSCT would more effectively eliminate relapse-initiating leukemic cells and be delivered with safer, non-genotoxic conditioning. Here, we investigate hematopoietic cytokine receptors (HCRs) and identify that KIT, MPL, and FLT3 are collectively highly expressed in virtually all pediatric AML samples studied. Further, we establish proof-of-concept of a first-in-class chimeric antigen receptor (CAR) T cell that enables simultaneous targeting of KIT, MPL, and FLT3 through a single receptor, which we term the extracellularly linked concatemeric trivalent cytokine (ELECTRIC) CAR. ELECTRIC CARs exhibit potent cytotoxicity against normal and malignant hematopoietic cells in vitro and display anti-HCR activity in a murine xenograft model. We propose that the ELECTRIC system can be the foundation to developing a non-genotoxic, anti-leukemic conditioning regimen to enable safer, more durable efficacy with minimal toxicity.http://www.sciencedirect.com/science/article/pii/S295032992500013XMT: Regular IssueCAR-TAMLpediatric AMLHSCTtrispecific |
| spellingShingle | Quenton Rashawn Bubb Mohammad Balood Gabe Eduardo Seir Leah Swartzrock Ethan Haslett Katie Ho Peng Xu Saida G. Wiltz Elena Sotillo Tanja A. Gruber Rebecca M. Richards Crystal L. Mackall Agnieszka Czechowicz Development of multivalent CAR T cells as dual immunotherapy and conditioning agents Molecular Therapy: Oncology MT: Regular Issue CAR-T AML pediatric AML HSCT trispecific |
| title | Development of multivalent CAR T cells as dual immunotherapy and conditioning agents |
| title_full | Development of multivalent CAR T cells as dual immunotherapy and conditioning agents |
| title_fullStr | Development of multivalent CAR T cells as dual immunotherapy and conditioning agents |
| title_full_unstemmed | Development of multivalent CAR T cells as dual immunotherapy and conditioning agents |
| title_short | Development of multivalent CAR T cells as dual immunotherapy and conditioning agents |
| title_sort | development of multivalent car t cells as dual immunotherapy and conditioning agents |
| topic | MT: Regular Issue CAR-T AML pediatric AML HSCT trispecific |
| url | http://www.sciencedirect.com/science/article/pii/S295032992500013X |
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