Metabolic engineering against the arginine microenvironment enhances CAR-T cell proliferation and therapeutic activity
Hematological and solid cancers catabolize the semiessential amino acid arginine to drive cell proliferation. However, the resulting low arginine microenvironment also impairs chimeric antigen receptor T cells (CAR-T) cell proliferation, limiting their efficacy in clinical trials against hematologic...
Gespeichert in:
| Veröffentlicht in: | Blood Jg. 136; H. 10; S. 1155 |
|---|---|
| Hauptverfasser: | , , , , , , , , , , , , , , , |
| Format: | Journal Article |
| Sprache: | Englisch |
| Veröffentlicht: |
United States
03.09.2020
|
| Schlagworte: | |
| ISSN: | 1528-0020, 1528-0020 |
| Online-Zugang: | Weitere Angaben |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| Abstract | Hematological and solid cancers catabolize the semiessential amino acid arginine to drive cell proliferation. However, the resulting low arginine microenvironment also impairs chimeric antigen receptor T cells (CAR-T) cell proliferation, limiting their efficacy in clinical trials against hematological and solid malignancies. T cells are susceptible to the low arginine microenvironment because of the low expression of the arginine resynthesis enzymes argininosuccinate synthase (ASS) and ornithine transcarbamylase (OTC). We demonstrate that T cells can be reengineered to express functional ASS or OTC enzymes, in concert with different chimeric antigen receptors. Enzyme modifications increase CAR-T cell proliferation, with no loss of CAR cytotoxicity or increased exhaustion. In vivo, enzyme-modified CAR-T cells lead to enhanced clearance of leukemia or solid tumor burden, providing the first metabolic modification to enhance CAR-T cell therapies. |
|---|---|
| AbstractList | Hematological and solid cancers catabolize the semiessential amino acid arginine to drive cell proliferation. However, the resulting low arginine microenvironment also impairs chimeric antigen receptor T cells (CAR-T) cell proliferation, limiting their efficacy in clinical trials against hematological and solid malignancies. T cells are susceptible to the low arginine microenvironment because of the low expression of the arginine resynthesis enzymes argininosuccinate synthase (ASS) and ornithine transcarbamylase (OTC). We demonstrate that T cells can be reengineered to express functional ASS or OTC enzymes, in concert with different chimeric antigen receptors. Enzyme modifications increase CAR-T cell proliferation, with no loss of CAR cytotoxicity or increased exhaustion. In vivo, enzyme-modified CAR-T cells lead to enhanced clearance of leukemia or solid tumor burden, providing the first metabolic modification to enhance CAR-T cell therapies. Hematological and solid cancers catabolize the semiessential amino acid arginine to drive cell proliferation. However, the resulting low arginine microenvironment also impairs chimeric antigen receptor T cells (CAR-T) cell proliferation, limiting their efficacy in clinical trials against hematological and solid malignancies. T cells are susceptible to the low arginine microenvironment because of the low expression of the arginine resynthesis enzymes argininosuccinate synthase (ASS) and ornithine transcarbamylase (OTC). We demonstrate that T cells can be reengineered to express functional ASS or OTC enzymes, in concert with different chimeric antigen receptors. Enzyme modifications increase CAR-T cell proliferation, with no loss of CAR cytotoxicity or increased exhaustion. In vivo, enzyme-modified CAR-T cells lead to enhanced clearance of leukemia or solid tumor burden, providing the first metabolic modification to enhance CAR-T cell therapies.Hematological and solid cancers catabolize the semiessential amino acid arginine to drive cell proliferation. However, the resulting low arginine microenvironment also impairs chimeric antigen receptor T cells (CAR-T) cell proliferation, limiting their efficacy in clinical trials against hematological and solid malignancies. T cells are susceptible to the low arginine microenvironment because of the low expression of the arginine resynthesis enzymes argininosuccinate synthase (ASS) and ornithine transcarbamylase (OTC). We demonstrate that T cells can be reengineered to express functional ASS or OTC enzymes, in concert with different chimeric antigen receptors. Enzyme modifications increase CAR-T cell proliferation, with no loss of CAR cytotoxicity or increased exhaustion. In vivo, enzyme-modified CAR-T cells lead to enhanced clearance of leukemia or solid tumor burden, providing the first metabolic modification to enhance CAR-T cell therapies. |
| Author | Yogev, Orli Panetti, Silvia Stavrou, Victoria Chesler, Louis Fultang, Livingstone Scarpa, Ugo Southam, Andrew Lee, Steven P Mussai, Francis Jankevics, Andris De Santo, Carmela Lloyd, Gavin Booth, Sarah Tubb, Vanessa Martins da Costa, Barbara Dunn, Warwick B |
| Author_xml | – sequence: 1 givenname: Livingstone surname: Fultang fullname: Fultang, Livingstone organization: Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom – sequence: 2 givenname: Sarah surname: Booth fullname: Booth, Sarah organization: Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom – sequence: 3 givenname: Orli surname: Yogev fullname: Yogev, Orli organization: The Institute of Cancer Research, London, United Kingdom; and – sequence: 4 givenname: Barbara surname: Martins da Costa fullname: Martins da Costa, Barbara organization: The Institute of Cancer Research, London, United Kingdom; and – sequence: 5 givenname: Vanessa surname: Tubb fullname: Tubb, Vanessa organization: Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom – sequence: 6 givenname: Silvia surname: Panetti fullname: Panetti, Silvia organization: Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom – sequence: 7 givenname: Victoria surname: Stavrou fullname: Stavrou, Victoria organization: Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom – sequence: 8 givenname: Ugo surname: Scarpa fullname: Scarpa, Ugo organization: Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom – sequence: 9 givenname: Andris surname: Jankevics fullname: Jankevics, Andris organization: School of Biosciences and Phenome Centre Birmingham and – sequence: 10 givenname: Gavin surname: Lloyd fullname: Lloyd, Gavin organization: School of Biosciences and Phenome Centre Birmingham and – sequence: 11 givenname: Andrew surname: Southam fullname: Southam, Andrew organization: School of Biosciences and Phenome Centre Birmingham and – sequence: 12 givenname: Steven P surname: Lee fullname: Lee, Steven P organization: Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom – sequence: 13 givenname: Warwick B surname: Dunn fullname: Dunn, Warwick B organization: School of Biosciences and Phenome Centre Birmingham and – sequence: 14 givenname: Louis surname: Chesler fullname: Chesler, Louis organization: The Institute of Cancer Research, London, United Kingdom; and – sequence: 15 givenname: Francis surname: Mussai fullname: Mussai, Francis organization: Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom – sequence: 16 givenname: Carmela surname: De Santo fullname: De Santo, Carmela organization: Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/32573723$$D View this record in MEDLINE/PubMed |
| BookMark | eNpNUMtqwzAQFCWlebT3noqOvThdyfIjxxD6gpRCSc9mZa8TFVtOZTmQv69CU-hlZ9idnR12yka2s8TYrYC5ELl80E3XVXMJYgGgEoALNhGJzCMACaN_fMymff8FIFQskys2DjWLMxlP2OGNPOquMSUnuzWWyBm75bhFY3vP_Y44utAPE96a0nVkD8Z1tiXrw8YObUk9Xy0_og0vqWn43gWzmhx601mOtjp5ONzT4MMNLL05GH-8Zpc1Nj3dnHHGPp8eN6uXaP3-_LparqMyEZmPME4VqEplUOpqgUmsa8Q6zss8TxHqBWaBx1WqNKQ60YoqgoCkdQYZQS1n7P7XN8T6Hqj3RWv6U0601A19IZVIZSpzlQTp3Vk66JaqYu9Mi-5Y_P1K_gBNqXE6 |
| CitedBy_id | crossref_primary_10_1016_j_autrev_2024_103579 crossref_primary_10_1016_j_canlet_2022_215713 crossref_primary_10_1038_s41577_022_00719_y crossref_primary_10_3390_cancers12082030 crossref_primary_10_1172_JCI148546 crossref_primary_10_3390_cancers14215351 crossref_primary_10_1155_2020_8765028 crossref_primary_10_1186_s12967_024_05903_3 crossref_primary_10_3389_fimmu_2022_903562 crossref_primary_10_1016_j_addr_2022_114421 crossref_primary_10_1016_j_ijbiomac_2023_123927 crossref_primary_10_3390_cells11010140 crossref_primary_10_3390_cancers13236000 crossref_primary_10_1016_j_celrep_2024_115130 crossref_primary_10_1016_j_phrs_2025_107928 crossref_primary_10_3389_fimmu_2023_1166038 crossref_primary_10_1002_jimd_70009 crossref_primary_10_1631_jzus_B2200256 crossref_primary_10_1016_j_celrep_2024_113995 crossref_primary_10_3390_antib10020017 crossref_primary_10_1016_j_ymben_2024_10_009 crossref_primary_10_1038_s44318_025_00379_3 crossref_primary_10_1177_20406207241263489 crossref_primary_10_1016_j_canlet_2022_215668 crossref_primary_10_1016_j_coi_2021_02_010 crossref_primary_10_1016_j_canlet_2022_215948 crossref_primary_10_1038_s41571_023_00729_2 crossref_primary_10_1097_CM9_0000000000002513 crossref_primary_10_3390_ijms242417422 crossref_primary_10_1038_s41577_024_01098_2 crossref_primary_10_1111_imcb_12557 crossref_primary_10_1016_j_drudis_2024_103940 crossref_primary_10_1002_ctd2_179 crossref_primary_10_1016_j_ymthe_2020_09_015 crossref_primary_10_1158_1078_0432_CCR_23_3495 crossref_primary_10_2147_BTT_S252568 crossref_primary_10_1007_s00277_024_06117_9 crossref_primary_10_1016_j_mbs_2024_109141 crossref_primary_10_3390_cancers14010183 crossref_primary_10_1186_s13073_024_01405_5 crossref_primary_10_1007_s11684_023_1012_z crossref_primary_10_1038_s42255_024_00976_2 crossref_primary_10_1186_s12943_024_02032_9 crossref_primary_10_1097_CM9_0000000000003046 crossref_primary_10_1111_imr_13252 crossref_primary_10_1007_s11033_024_10061_2 crossref_primary_10_3390_cells11193103 crossref_primary_10_1016_j_phrs_2024_107506 crossref_primary_10_1080_17474086_2024_2420614 crossref_primary_10_1007_s00018_021_03828_4 crossref_primary_10_3389_fimmu_2023_1186383 crossref_primary_10_3389_fmicb_2022_880873 crossref_primary_10_15789_1563_0625_CTC_3155 crossref_primary_10_3389_fonc_2022_1046630 crossref_primary_10_1016_j_jgg_2022_05_005 crossref_primary_10_1186_s12964_025_02328_3 crossref_primary_10_1016_j_coph_2025_102524 crossref_primary_10_1016_j_jare_2025_09_025 crossref_primary_10_1136_jitc_2023_008434 crossref_primary_10_3389_fonc_2023_1186539 crossref_primary_10_1186_s12943_025_02407_6 crossref_primary_10_1126_sciimmunol_abq3016 crossref_primary_10_3390_ijms24119115 crossref_primary_10_3390_nu13124503 crossref_primary_10_1016_j_ejca_2023_113347 crossref_primary_10_1016_j_procbio_2024_09_010 crossref_primary_10_1038_s41576_021_00329_9 crossref_primary_10_3390_cancers14041078 crossref_primary_10_3389_fphar_2023_1145828 crossref_primary_10_1186_s13045_023_01453_1 crossref_primary_10_3390_ijms26020669 crossref_primary_10_1002_1878_0261_13691 crossref_primary_10_1016_j_intimp_2024_113412 crossref_primary_10_1182_bloodadvances_2022008272 crossref_primary_10_1002_INMD_20230047 crossref_primary_10_1136_jitc_2024_010094 crossref_primary_10_31083_j_fbl2704139 crossref_primary_10_3390_cancers14143331 crossref_primary_10_1016_j_talanta_2025_128177 crossref_primary_10_1038_s42255_024_01031_w crossref_primary_10_3390_cells11091454 crossref_primary_10_1038_s41577_021_00541_y crossref_primary_10_2147_LCTT_S335117 crossref_primary_10_3389_fimmu_2024_1462076 crossref_primary_10_1007_s00005_021_00633_6 crossref_primary_10_1038_s44319_025_00536_z crossref_primary_10_1016_j_heliyon_2024_e40492 crossref_primary_10_1038_s41388_025_03543_5 crossref_primary_10_1186_s13046_023_02845_4 crossref_primary_10_1016_j_trecan_2025_08_007 crossref_primary_10_1016_j_seminoncol_2025_152411 crossref_primary_10_1016_j_cels_2024_11_010 crossref_primary_10_1016_j_dyepig_2023_111288 crossref_primary_10_1111_pcmr_13042 crossref_primary_10_1097_HS9_0000000000000937 crossref_primary_10_1038_s41417_025_00931_7 crossref_primary_10_1186_s40364_025_00748_4 crossref_primary_10_1016_j_intimp_2023_110443 crossref_primary_10_1111_cas_15828 crossref_primary_10_1016_j_joca_2025_08_005 crossref_primary_10_1136_jitc_2022_006287 crossref_primary_10_3389_fcell_2021_828657 crossref_primary_10_1016_j_coisb_2021_100361 crossref_primary_10_1038_s41416_024_02601_1 crossref_primary_10_1016_j_canlet_2022_01_006 crossref_primary_10_1038_s41408_024_01193_6 crossref_primary_10_3389_fimmu_2023_1113882 crossref_primary_10_1016_j_bbcan_2024_189162 crossref_primary_10_3389_fimmu_2022_1090429 crossref_primary_10_3389_fonc_2020_01594 crossref_primary_10_3389_fonc_2021_674720 crossref_primary_10_3389_fcell_2022_1034257 crossref_primary_10_3389_fbioe_2023_1207576 crossref_primary_10_3389_fonc_2022_938847 crossref_primary_10_3390_cells10010014 crossref_primary_10_3389_fimmu_2025_1597888 crossref_primary_10_1186_s40164_024_00535_1 crossref_primary_10_1016_j_cellsig_2025_111593 crossref_primary_10_3389_fphar_2020_582587 |
| ContentType | Journal Article |
| Copyright | 2020 by The American Society of Hematology. |
| Copyright_xml | – notice: 2020 by The American Society of Hematology. |
| DBID | CGR CUY CVF ECM EIF NPM 7X8 |
| DOI | 10.1182/blood.2019004500 |
| DatabaseName | Medline MEDLINE MEDLINE (Ovid) MEDLINE MEDLINE PubMed MEDLINE - Academic |
| DatabaseTitle | MEDLINE Medline Complete MEDLINE with Full Text PubMed MEDLINE (Ovid) MEDLINE - Academic |
| DatabaseTitleList | MEDLINE MEDLINE - Academic |
| Database_xml | – sequence: 1 dbid: NPM name: PubMed url: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed sourceTypes: Index Database – sequence: 2 dbid: 7X8 name: MEDLINE - Academic url: https://search.proquest.com/medline sourceTypes: Aggregation Database |
| DeliveryMethod | no_fulltext_linktorsrc |
| Discipline | Medicine Chemistry Biology Anatomy & Physiology |
| EISSN | 1528-0020 |
| ExternalDocumentID | 32573723 |
| Genre | Research Support, Non-U.S. Gov't Journal Article |
| GrantInformation_xml | – fundername: Cancer Research UK grantid: 14610 – fundername: Cancer Research UK grantid: 22590 – fundername: Cancer Research UK grantid: 28278 – fundername: Medical Research Council grantid: MR/M009157/1 – fundername: Medical Research Council grantid: MC_PC_18051 – fundername: Medical Research Council grantid: MC_PC_16047 |
| GroupedDBID | --- -~X .55 0R~ 23N 2WC 34G 39C 4.4 53G 5GY 5RE 5VS 6J9 AAEDW AALRI AAXUO ABOCM ACGFO ACVFH ADBBV ADCNI ADVLN AENEX AEUPX AFETI AFOSN AFPUW AGCQF AIGII AITUG AKBMS AKRWK AKYEP ALMA_UNASSIGNED_HOLDINGS AMRAJ BAWUL BTFSW CGR CS3 CUY CVF DIK DU5 E3Z EBS ECM EFKBS EIF EJD EX3 F5P FDB FRP GS5 GX1 H13 IH2 K-O KQ8 L7B LSO MJL N9A NPM OK1 P2P R.V RHI ROL SJN THE TR2 TWZ W2D W8F WH7 WOQ WOW X7M YHG YKV 7X8 |
| ID | FETCH-LOGICAL-c517t-a36404d470cbd9a53bfaaf38c886a0f9a738c3d64b06b5b4ede0b5bebb707e0f2 |
| IEDL.DBID | 7X8 |
| ISICitedReferencesCount | 134 |
| ISICitedReferencesURI | http://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=Summon&SrcAuth=ProQuest&DestLinkType=CitingArticles&DestApp=WOS_CPL&KeyUT=000571446600009&url=https%3A%2F%2Fcvtisr.summon.serialssolutions.com%2F%23%21%2Fsearch%3Fho%3Df%26include.ft.matches%3Dt%26l%3Dnull%26q%3D |
| ISSN | 1528-0020 |
| IngestDate | Sun Sep 28 00:58:36 EDT 2025 Mon Jul 21 06:06:34 EDT 2025 |
| IsDoiOpenAccess | false |
| IsOpenAccess | true |
| IsPeerReviewed | true |
| IsScholarly | true |
| Issue | 10 |
| Language | English |
| License | 2020 by The American Society of Hematology. |
| LinkModel | DirectLink |
| MergedId | FETCHMERGED-LOGICAL-c517t-a36404d470cbd9a53bfaaf38c886a0f9a738c3d64b06b5b4ede0b5bebb707e0f2 |
| Notes | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
| OpenAccessLink | https://ashpublications.org/blood/article-pdf/136/10/1155/1756922/bloodbld2019004500.pdf |
| PMID | 32573723 |
| PQID | 2416262845 |
| PQPubID | 23479 |
| ParticipantIDs | proquest_miscellaneous_2416262845 pubmed_primary_32573723 |
| PublicationCentury | 2000 |
| PublicationDate | 2020-09-03 |
| PublicationDateYYYYMMDD | 2020-09-03 |
| PublicationDate_xml | – month: 09 year: 2020 text: 2020-09-03 day: 03 |
| PublicationDecade | 2020 |
| PublicationPlace | United States |
| PublicationPlace_xml | – name: United States |
| PublicationTitle | Blood |
| PublicationTitleAlternate | Blood |
| PublicationYear | 2020 |
| SSID | ssj0014325 |
| Score | 2.6425564 |
| Snippet | Hematological and solid cancers catabolize the semiessential amino acid arginine to drive cell proliferation. However, the resulting low arginine... |
| SourceID | proquest pubmed |
| SourceType | Aggregation Database Index Database |
| StartPage | 1155 |
| SubjectTerms | Animals Apoptosis Arginine - metabolism Argininosuccinate Synthase - genetics Argininosuccinate Synthase - metabolism Cell Proliferation Humans Immunotherapy, Adoptive - methods Leukemia, Myeloid, Acute - immunology Leukemia, Myeloid, Acute - metabolism Leukemia, Myeloid, Acute - pathology Leukemia, Myeloid, Acute - therapy Metabolic Engineering - methods Mice Mice, Nude Neuroblastoma - immunology Neuroblastoma - metabolism Neuroblastoma - pathology Neuroblastoma - therapy Ornithine Carbamoyltransferase - genetics Ornithine Carbamoyltransferase - metabolism Receptors, Chimeric Antigen - chemistry Receptors, Chimeric Antigen - immunology T-Lymphocytes - immunology T-Lymphocytes - metabolism T-Lymphocytes - transplantation Tumor Cells, Cultured Xenograft Model Antitumor Assays |
| Title | Metabolic engineering against the arginine microenvironment enhances CAR-T cell proliferation and therapeutic activity |
| URI | https://www.ncbi.nlm.nih.gov/pubmed/32573723 https://www.proquest.com/docview/2416262845 |
| Volume | 136 |
| WOSCitedRecordID | wos000571446600009&url=https%3A%2F%2Fcvtisr.summon.serialssolutions.com%2F%23%21%2Fsearch%3Fho%3Df%26include.ft.matches%3Dt%26l%3Dnull%26q%3D |
| hasFullText | |
| inHoldings | 1 |
| isFullTextHit | |
| isPrint | |
| link | http://cvtisr.summon.serialssolutions.com/2.0.0/link/0/eLvHCXMwpV1LaxsxEB7apq9LH07z6AsVSm8iykq7kk7BNQ292ISSgm9GWs0mhmbtxk6g_z4z8i7OpVDoZVcXgZA-zXzSzOgD-OydQ3KsTrqaNrmxCaU71rU0SP4lRW8bF7PYhJ1M3HTqz7oLt1WXVtnbxGyo06LmO_Ij8jTEvcmYlifL35JVozi62kloPIQdTVSGUW2n2yiC0Vl0lVyUk8yL-jClK45yWjhndnkmNUr9nWBmR3P68n-H-ApedBRTDDeYeA0PsB3A7rCl4_XVH_FF5KTPfJs-gCdf-9azUS_9NoCn4y7ivgu3Y1wTTn7Na4HbpwtFuAhzIpaC6KMI1xesMoHiipP77lXOUY9LBtVKjIY_5LngIIFYskxQgxvgidAmca8ETHCZBatZvIGfp9_OR99lp9Ug6_LYrmXQlVEmGavqmHwodWxCaLSrnauCanyw1NapMlFVsYwGEyr6Y4xWWVRNsQeP2kWLByBSFtQyRYHOmpSqWLGwafDom1TY0h_Cp376ZzQvPPbQ4uJmNdsuwCHsb9Zwttw82jEjKLAij377D73fwfOCj9UcN9LvYachS4Af4HF9u56vrj9mkNF3cja-A4Kh3fE |
| linkProvider | ProQuest |
| openUrl | ctx_ver=Z39.88-2004&ctx_enc=info%3Aofi%2Fenc%3AUTF-8&rfr_id=info%3Asid%2Fsummon.serialssolutions.com&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Metabolic+engineering+against+the+arginine+microenvironment+enhances+CAR-T+cell+proliferation+and+therapeutic+activity&rft.jtitle=Blood&rft.au=Fultang%2C+Livingstone&rft.au=Booth%2C+Sarah&rft.au=Yogev%2C+Orli&rft.au=Martins+da+Costa%2C+Barbara&rft.date=2020-09-03&rft.eissn=1528-0020&rft.volume=136&rft.issue=10&rft.spage=1155&rft_id=info:doi/10.1182%2Fblood.2019004500&rft_id=info%3Apmid%2F32573723&rft_id=info%3Apmid%2F32573723&rft.externalDocID=32573723 |
| thumbnail_l | http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/lc.gif&issn=1528-0020&client=summon |
| thumbnail_m | http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/mc.gif&issn=1528-0020&client=summon |
| thumbnail_s | http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/sc.gif&issn=1528-0020&client=summon |