AKT inhibition generates potent polyfunctional clinical grade AUTO1 CAR T-cells, enhancing function and survival
Background AUTO1 is a fast off-rate CD19-targeting chimeric antigen receptor (CAR), which has been successfully tested in adult lymphoblastic leukemia. Tscm/Tcm-enriched CAR-T populations confer the best expansion and persistence, but Tscm/Tcm numbers are poor in heavily pretreated adult patients. T...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMJ Publishing Group
2023-09-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/11/9/e007002.full |
| _version_ | 1797669491742605312 |
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| author | Harry Dolstra Claire Roddie Martin A Pule Vedika Mehra Giulia Agliardi Juliana Dias Alves Pinto Manar S Shafat Amaia Cadinanos Garai Louisa Green Alastair Hotblack Fred Arce Vargas Karl S Peggs Anniek B van der Waart |
| author_facet | Harry Dolstra Claire Roddie Martin A Pule Vedika Mehra Giulia Agliardi Juliana Dias Alves Pinto Manar S Shafat Amaia Cadinanos Garai Louisa Green Alastair Hotblack Fred Arce Vargas Karl S Peggs Anniek B van der Waart |
| author_sort | Harry Dolstra |
| collection | DOAJ |
| description | Background AUTO1 is a fast off-rate CD19-targeting chimeric antigen receptor (CAR), which has been successfully tested in adult lymphoblastic leukemia. Tscm/Tcm-enriched CAR-T populations confer the best expansion and persistence, but Tscm/Tcm numbers are poor in heavily pretreated adult patients. To improve this, we evaluate the use of AKT inhibitor (VIII) with the aim of uncoupling T-cell expansion from differentiation, to enrich Tscm/Tcm subsets.Methods VIII was incorporated into the AUTO1 manufacturing process based on the semiautomated the CliniMACS Prodigy platform at both small and cGMP scale.Results AUTO1 manufactured with VIII showed Tscm/Tcm enrichment, improved expansion and cytotoxicity in vitro and superior antitumor activity in vivo. Further, VIII induced AUTO1 Th1/Th17 skewing, increased polyfunctionality, and conferred a unique metabolic profile and a novel signature for autophagy to support enhanced expansion and cytotoxicity. We show that VIII-cultured AUTO1 products from B-ALL patients on the ALLCAR19 study possess superior phenotype, metabolism, and function than parallel control products and that VIII-based manufacture is scalable to cGMP.Conclusion Ultimately, AUTO1 generated with VIII may begin to overcome the product specific factors contributing to CD19+relapse. |
| first_indexed | 2024-03-11T20:45:10Z |
| format | Article |
| id | doaj.art-304fa86b5512400a84f30e4d82b38677 |
| institution | Directory Open Access Journal |
| issn | 2051-1426 |
| language | English |
| last_indexed | 2024-03-11T20:45:10Z |
| publishDate | 2023-09-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj.art-304fa86b5512400a84f30e4d82b386772023-10-01T16:10:07ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262023-09-0111910.1136/jitc-2023-007002AKT inhibition generates potent polyfunctional clinical grade AUTO1 CAR T-cells, enhancing function and survivalHarry Dolstra0Claire Roddie1Martin A Pule2Vedika Mehra3Giulia Agliardi4Juliana Dias Alves Pinto5Manar S Shafat6Amaia Cadinanos Garai7Louisa Green8Alastair Hotblack9Fred Arce Vargas10Karl S Peggs11Anniek B van der Waart12Department of Laboratory Medicine, Laboratory of Hematology, Radboud Institute for Molecular Life Sciences, Radboudumc, Nijmegen, The NetherlandsResearch Department of Haematology, University College London, London, UKResearch Department of Haematology, University College London, London, UKResearch Department of Haematology, University College London, London, UKResearch Department of Haematology, University College London, London, UKResearch Department of Haematology, University College London, London, UKResearch Department of Haematology, University College London, London, UKResearch Department of Haematology, University College London, London, UKResearch Department of Haematology, University College London, London, UKResearch Department of Haematology, University College London, London, UKAutolus Ltd, London, UKResearch Department of Haematology, University College London, London, UKDepartment of Laboratory Medicine, Laboratory of Hematology, Radboud Institute for Molecular Life Sciences, Radboudumc, Nijmegen, The NetherlandsBackground AUTO1 is a fast off-rate CD19-targeting chimeric antigen receptor (CAR), which has been successfully tested in adult lymphoblastic leukemia. Tscm/Tcm-enriched CAR-T populations confer the best expansion and persistence, but Tscm/Tcm numbers are poor in heavily pretreated adult patients. To improve this, we evaluate the use of AKT inhibitor (VIII) with the aim of uncoupling T-cell expansion from differentiation, to enrich Tscm/Tcm subsets.Methods VIII was incorporated into the AUTO1 manufacturing process based on the semiautomated the CliniMACS Prodigy platform at both small and cGMP scale.Results AUTO1 manufactured with VIII showed Tscm/Tcm enrichment, improved expansion and cytotoxicity in vitro and superior antitumor activity in vivo. Further, VIII induced AUTO1 Th1/Th17 skewing, increased polyfunctionality, and conferred a unique metabolic profile and a novel signature for autophagy to support enhanced expansion and cytotoxicity. We show that VIII-cultured AUTO1 products from B-ALL patients on the ALLCAR19 study possess superior phenotype, metabolism, and function than parallel control products and that VIII-based manufacture is scalable to cGMP.Conclusion Ultimately, AUTO1 generated with VIII may begin to overcome the product specific factors contributing to CD19+relapse.https://jitc.bmj.com/content/11/9/e007002.full |
| spellingShingle | Harry Dolstra Claire Roddie Martin A Pule Vedika Mehra Giulia Agliardi Juliana Dias Alves Pinto Manar S Shafat Amaia Cadinanos Garai Louisa Green Alastair Hotblack Fred Arce Vargas Karl S Peggs Anniek B van der Waart AKT inhibition generates potent polyfunctional clinical grade AUTO1 CAR T-cells, enhancing function and survival Journal for ImmunoTherapy of Cancer |
| title | AKT inhibition generates potent polyfunctional clinical grade AUTO1 CAR T-cells, enhancing function and survival |
| title_full | AKT inhibition generates potent polyfunctional clinical grade AUTO1 CAR T-cells, enhancing function and survival |
| title_fullStr | AKT inhibition generates potent polyfunctional clinical grade AUTO1 CAR T-cells, enhancing function and survival |
| title_full_unstemmed | AKT inhibition generates potent polyfunctional clinical grade AUTO1 CAR T-cells, enhancing function and survival |
| title_short | AKT inhibition generates potent polyfunctional clinical grade AUTO1 CAR T-cells, enhancing function and survival |
| title_sort | akt inhibition generates potent polyfunctional clinical grade auto1 car t cells enhancing function and survival |
| url | https://jitc.bmj.com/content/11/9/e007002.full |
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