Boosting CAR T-Cell Efficacy by Blocking Proteasomal Degradation of Membrane Antigens
Chimeric antigen receptor (CAR) T cells exhibit high response rates in B cell malignancies, but most patients eventually relapse. A key mechanism of treatment failure is the loss or downregulation of tumor antigen expression, yet strategies to modulate cell surface levels of CAR T cell targets remai...
Saved in:
| Published in: | Blood |
|---|---|
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
| Format: | Journal Article |
| Language: | English |
| Published: |
United States
10.07.2025
|
| ISSN: | 1528-0020, 1528-0020 |
| Online Access: | Get more information |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| Abstract | Chimeric antigen receptor (CAR) T cells exhibit high response rates in B cell malignancies, but most patients eventually relapse. A key mechanism of treatment failure is the loss or downregulation of tumor antigen expression, yet strategies to modulate cell surface levels of CAR T cell targets remain largely unexplored. Here we identify B cell maturation antigen (BCMA), a central CAR T cell target in multiple myeloma (MM), as a highly short-lived protein that undergoes K48-linked polyubiquitylation at the plasma membrane, leading to its p97-dependent degradation via the ubiquitin-proteasome system (UPS). This previously unprecedented mechanism of plasma membrane protein regulation enables significant enhancement of BCMA expression via proteasome inhibitors (PI). The clinically approved PI carfilzomib (CFZ) significantly enhances the efficacy of BCMA-directed CAR T cells against both PI-sensitive and refractory MM cells in vitro and in vivo. Notably, treatment of ten patients with CFZ under the compassionate use CarCAR protocol - after relapse following BCMA CAR T cell therapy - resulted in increased BCMA expression in all patients. However, clinical responses were observed only in those with residual and/or expanding CAR T cells, suggesting restored CAR T cell function. These findings provide a rationale for the use of CFZ treatment in relapsed or refractory MM following BCMA CAR T therapy, advocate for future trials combining CFZ with BCMA CAR T cells and provide a framework for exploring UPS-dependent degradation of other immunotherapy antigens. |
|---|---|
| AbstractList | Chimeric antigen receptor (CAR) T cells exhibit high response rates in B cell malignancies, but most patients eventually relapse. A key mechanism of treatment failure is the loss or downregulation of tumor antigen expression, yet strategies to modulate cell surface levels of CAR T cell targets remain largely unexplored. Here we identify B cell maturation antigen (BCMA), a central CAR T cell target in multiple myeloma (MM), as a highly short-lived protein that undergoes K48-linked polyubiquitylation at the plasma membrane, leading to its p97-dependent degradation via the ubiquitin-proteasome system (UPS). This previously unprecedented mechanism of plasma membrane protein regulation enables significant enhancement of BCMA expression via proteasome inhibitors (PI). The clinically approved PI carfilzomib (CFZ) significantly enhances the efficacy of BCMA-directed CAR T cells against both PI-sensitive and refractory MM cells in vitro and in vivo. Notably, treatment of ten patients with CFZ under the compassionate use CarCAR protocol - after relapse following BCMA CAR T cell therapy - resulted in increased BCMA expression in all patients. However, clinical responses were observed only in those with residual and/or expanding CAR T cells, suggesting restored CAR T cell function. These findings provide a rationale for the use of CFZ treatment in relapsed or refractory MM following BCMA CAR T therapy, advocate for future trials combining CFZ with BCMA CAR T cells and provide a framework for exploring UPS-dependent degradation of other immunotherapy antigens.Chimeric antigen receptor (CAR) T cells exhibit high response rates in B cell malignancies, but most patients eventually relapse. A key mechanism of treatment failure is the loss or downregulation of tumor antigen expression, yet strategies to modulate cell surface levels of CAR T cell targets remain largely unexplored. Here we identify B cell maturation antigen (BCMA), a central CAR T cell target in multiple myeloma (MM), as a highly short-lived protein that undergoes K48-linked polyubiquitylation at the plasma membrane, leading to its p97-dependent degradation via the ubiquitin-proteasome system (UPS). This previously unprecedented mechanism of plasma membrane protein regulation enables significant enhancement of BCMA expression via proteasome inhibitors (PI). The clinically approved PI carfilzomib (CFZ) significantly enhances the efficacy of BCMA-directed CAR T cells against both PI-sensitive and refractory MM cells in vitro and in vivo. Notably, treatment of ten patients with CFZ under the compassionate use CarCAR protocol - after relapse following BCMA CAR T cell therapy - resulted in increased BCMA expression in all patients. However, clinical responses were observed only in those with residual and/or expanding CAR T cells, suggesting restored CAR T cell function. These findings provide a rationale for the use of CFZ treatment in relapsed or refractory MM following BCMA CAR T therapy, advocate for future trials combining CFZ with BCMA CAR T cells and provide a framework for exploring UPS-dependent degradation of other immunotherapy antigens. Chimeric antigen receptor (CAR) T cells exhibit high response rates in B cell malignancies, but most patients eventually relapse. A key mechanism of treatment failure is the loss or downregulation of tumor antigen expression, yet strategies to modulate cell surface levels of CAR T cell targets remain largely unexplored. Here we identify B cell maturation antigen (BCMA), a central CAR T cell target in multiple myeloma (MM), as a highly short-lived protein that undergoes K48-linked polyubiquitylation at the plasma membrane, leading to its p97-dependent degradation via the ubiquitin-proteasome system (UPS). This previously unprecedented mechanism of plasma membrane protein regulation enables significant enhancement of BCMA expression via proteasome inhibitors (PI). The clinically approved PI carfilzomib (CFZ) significantly enhances the efficacy of BCMA-directed CAR T cells against both PI-sensitive and refractory MM cells in vitro and in vivo. Notably, treatment of ten patients with CFZ under the compassionate use CarCAR protocol - after relapse following BCMA CAR T cell therapy - resulted in increased BCMA expression in all patients. However, clinical responses were observed only in those with residual and/or expanding CAR T cells, suggesting restored CAR T cell function. These findings provide a rationale for the use of CFZ treatment in relapsed or refractory MM following BCMA CAR T therapy, advocate for future trials combining CFZ with BCMA CAR T cells and provide a framework for exploring UPS-dependent degradation of other immunotherapy antigens. |
| Author | Purcarea, Anna Schwamborn, Kristina Vogelsang, Carolin Füchsl, Franziska Waldschmidt, Johannes M Augsburger, Abirami Driessen, Christoph Friedel, Sabrina Besse, Andrej Hecker, Judith S Irlinger, Kilian Barbian, Nicolas Mathis Pfeuffer, Lisa Karpiuk, Oleksandra Glaisner, Nadine Konetzki, Verena Giansanti, Piero Kuster, Bernhard Tietje, Marlene Hudecek, Michael Theurich, Sebastian Högner, Marion Faber, Melanie Schulze, Tobias Rieger, Leonie Steiger, Katja Buchner, Maike Besse, Lenka Kortüm, Klaus Martin Krackhardt, Angela Stotz, Sonja Bassermann, Florian Einsele, Hermann |
| Author_xml | – sequence: 1 givenname: Leonie orcidid: 0000-0003-3263-801X surname: Rieger fullname: Rieger, Leonie organization: Technical University of Munich, TUM University Hospital, München, Germany – sequence: 2 givenname: Kilian orcidid: 0009-0007-2025-5384 surname: Irlinger fullname: Irlinger, Kilian organization: Technical University of Munich, TUM University Hospital, München, Germany – sequence: 3 givenname: Franziska orcidid: 0000-0001-5069-1442 surname: Füchsl fullname: Füchsl, Franziska organization: Technical University of Munich, München, Germany – sequence: 4 givenname: Marlene orcidid: 0009-0008-2396-3252 surname: Tietje fullname: Tietje, Marlene organization: Technical University of Munich, TUM University Hospital, München, Germany – sequence: 5 givenname: Anna surname: Purcarea fullname: Purcarea, Anna organization: Technical University of Munich, TUM University Hospital, München, Germany – sequence: 6 givenname: Nicolas Mathis surname: Barbian fullname: Barbian, Nicolas Mathis organization: Technical University of Munich, München, Germany – sequence: 7 givenname: Melanie orcidid: 0009-0005-0322-4637 surname: Faber fullname: Faber, Melanie organization: Technical University of Munich, TUM University Hospital, München, Germany – sequence: 8 givenname: Carolin surname: Vogelsang fullname: Vogelsang, Carolin organization: Technical University of Munich, München, Germany – sequence: 9 givenname: Lisa orcidid: 0000-0003-4962-7755 surname: Pfeuffer fullname: Pfeuffer, Lisa organization: Klinikum rechts der Isar, TU Munich, Munich, Germany – sequence: 10 givenname: Sonja surname: Stotz fullname: Stotz, Sonja organization: Technical University of Munich, TUM University Hospital, München, Germany – sequence: 11 givenname: Oleksandra surname: Karpiuk fullname: Karpiuk, Oleksandra organization: Technical University of Munich, München, Germany – sequence: 12 givenname: Tobias orcidid: 0000-0002-1134-3127 surname: Schulze fullname: Schulze, Tobias organization: Technical University of Munich, München, Germany – sequence: 13 givenname: Abirami surname: Augsburger fullname: Augsburger, Abirami organization: Technical University of Munich, TUM University Hospital, München, Germany – sequence: 14 givenname: Nadine surname: Glaisner fullname: Glaisner, Nadine organization: Technical University of Munich, TUM University Hospital, München, Germany – sequence: 15 givenname: Verena orcidid: 0000-0001-7936-7937 surname: Konetzki fullname: Konetzki, Verena organization: Universitätsklinikum Würzburg, Würzburg, Germany – sequence: 16 givenname: Sabrina orcidid: 0000-0003-4276-2268 surname: Friedel fullname: Friedel, Sabrina organization: Universitätsklinikum Würzburg, Würzburg, Germany – sequence: 17 givenname: Andrej surname: Besse fullname: Besse, Andrej organization: Masaryk University, Brno, Czech Republic – sequence: 18 givenname: Lenka orcidid: 0000-0003-4739-7618 surname: Besse fullname: Besse, Lenka organization: Masaryk University, Brno, Czech Republic – sequence: 19 givenname: Christoph surname: Driessen fullname: Driessen, Christoph organization: Cantonal Hospital St Gallen, St Gallen, Switzerland – sequence: 20 givenname: Maike orcidid: 0000-0002-4196-096X surname: Buchner fullname: Buchner, Maike organization: TUM University Hospital Rechts der Isar, Munich, Germany – sequence: 21 givenname: Kristina orcidid: 0000-0003-3717-0823 surname: Schwamborn fullname: Schwamborn, Kristina organization: Institute of Pathology, Technical University of Munich, School of Medicine and Health, Munich, Germany – sequence: 22 givenname: Katja orcidid: 0000-0002-7269-5433 surname: Steiger fullname: Steiger, Katja organization: Technische Universität München, Munich, Germany – sequence: 23 givenname: Piero orcidid: 0000-0003-2857-0841 surname: Giansanti fullname: Giansanti, Piero organization: Klinikum rechts der Isar, TU Munich, Munich, Germany – sequence: 24 givenname: Sebastian orcidid: 0000-0001-5706-8258 surname: Theurich fullname: Theurich, Sebastian organization: University Hospital, LMU Munich, Munich, Germany – sequence: 25 givenname: Johannes M orcidid: 0000-0001-5340-1818 surname: Waldschmidt fullname: Waldschmidt, Johannes M organization: University Hospital Würzburg, Germany – sequence: 26 givenname: Klaus Martin orcidid: 0000-0002-7011-0286 surname: Kortüm fullname: Kortüm, Klaus Martin organization: University Hospital Würzburg, Würzburg, Germany – sequence: 27 givenname: Michael orcidid: 0000-0002-2280-2202 surname: Hudecek fullname: Hudecek, Michael organization: Universitaetsklinikum Wuerzburg, Wuerzburg, Germany – sequence: 28 givenname: Hermann surname: Einsele fullname: Einsele, Hermann organization: Universitätsklinikum Würzburg, Würzburg, Germany – sequence: 29 givenname: Marion surname: Högner fullname: Högner, Marion organization: Technical University of Munich, Munich, Germany – sequence: 30 givenname: Bernhard surname: Kuster fullname: Kuster, Bernhard organization: Technische Universitat Munchen, Freising, Germany – sequence: 31 givenname: Angela orcidid: 0000-0002-4752-0543 surname: Krackhardt fullname: Krackhardt, Angela organization: Munich, Munich, Germany – sequence: 32 givenname: Judith S orcidid: 0000-0002-1531-0517 surname: Hecker fullname: Hecker, Judith S organization: TUM Klinikum Rechts der Isar, Munich, Germany – sequence: 33 givenname: Florian orcidid: 0000-0003-4435-2609 surname: Bassermann fullname: Bassermann, Florian organization: Technical University of Munich, München, Germany |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/40638685$$D View this record in MEDLINE/PubMed |
| BookMark | eNpNUE1Lw0AUXKRiP_TuSfboJXX3ZTfJHttYP6CiSHsOu5u3JZpkazY99N8bsYIwMA9mGObNlIxa3yIh15zNOc_gztTel3NgIBikCU_OyIRLyCLGgI3-3WMyDeGDMS5ikBdkLFgSZ0kmJ2S79D70Vbuj-eKdbqIc65qunKustkdqjnRZe_v5o791vkcdfKNreo-7Tpe6r3xLvaMv2JhOt0gXbV_tsA2X5NzpOuDViWdk-7Da5E_R-vXxOV-sIxszlUSplUZIBlpop5wrnVYMhSkx04ZrIZ1xKrUgUJYYKztAMg5SSgOpVZmDGbn9zd13_uuAoS-aKtjhhaGMP4QiBlDARQrxYL05WQ-mwbLYd1Wju2PxNwV8A7TcYpk |
| CitedBy_id | crossref_primary_10_1007_s43152_025_00064_x |
| ContentType | Journal Article |
| Copyright | Copyright © 2025 American Society of Hematology. |
| Copyright_xml | – notice: Copyright © 2025 American Society of Hematology. |
| DBID | NPM 7X8 |
| DOI | 10.1182/blood.2024027616 |
| DatabaseName | PubMed MEDLINE - Academic |
| DatabaseTitle | PubMed MEDLINE - Academic |
| DatabaseTitleList | MEDLINE - Academic PubMed |
| 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 | 40638685 |
| Genre | Journal Article |
| GroupedDBID | --- -~X .55 0R~ 23N 2WC 34G 39C 4.4 5GY 5RE 6J9 AAEDW AALRI AAXUO ABOCM ACGFO ACVFH ADBBV ADCNI AENEX AFETI AFOSN AGCQF AITUG AKRWK ALMA_UNASSIGNED_HOLDINGS AMRAJ BAWUL BTFSW CS3 DIK DU5 E3Z EBS 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 WH7 WOQ WOW X7M YHG YKV 7X8 EFKBS |
| ID | FETCH-LOGICAL-c3096-7c5b4502a4af9ffdfa90e4bde8ab1a45fbf97c24e5de39c39c5012555b27c98f2 |
| IEDL.DBID | 7X8 |
| ISSN | 1528-0020 |
| IngestDate | Thu Oct 02 22:23:41 EDT 2025 Sat Jul 12 03:51:58 EDT 2025 |
| IsDoiOpenAccess | false |
| IsOpenAccess | true |
| IsPeerReviewed | true |
| IsScholarly | true |
| Language | English |
| License | Copyright © 2025 American Society of Hematology. |
| LinkModel | DirectLink |
| MergedId | FETCHMERGED-LOGICAL-c3096-7c5b4502a4af9ffdfa90e4bde8ab1a45fbf97c24e5de39c39c5012555b27c98f2 |
| Notes | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
| ORCID | 0000-0002-1134-3127 0000-0001-5069-1442 0009-0005-0322-4637 0000-0003-3717-0823 0000-0003-4276-2268 0000-0002-4196-096X 0000-0002-7269-5433 0000-0001-7936-7937 0009-0007-2025-5384 0000-0002-4752-0543 0009-0008-2396-3252 0000-0003-3263-801X 0000-0003-4739-7618 0000-0003-2857-0841 0000-0001-5706-8258 0000-0001-5340-1818 0000-0003-4435-2609 0000-0002-7011-0286 0000-0002-1531-0517 0000-0003-4962-7755 0000-0002-2280-2202 |
| OpenAccessLink | https://dx.doi.org/10.1182/blood.2024027616 |
| PMID | 40638685 |
| PQID | 3229214723 |
| PQPubID | 23479 |
| ParticipantIDs | proquest_miscellaneous_3229214723 pubmed_primary_40638685 |
| PublicationCentury | 2000 |
| PublicationDate | 2025-Jul-10 |
| PublicationDateYYYYMMDD | 2025-07-10 |
| PublicationDate_xml | – month: 07 year: 2025 text: 2025-Jul-10 day: 10 |
| PublicationDecade | 2020 |
| PublicationPlace | United States |
| PublicationPlace_xml | – name: United States |
| PublicationTitle | Blood |
| PublicationTitleAlternate | Blood |
| PublicationYear | 2025 |
| SSID | ssj0014325 |
| Score | 2.4850473 |
| SecondaryResourceType | online_first |
| Snippet | Chimeric antigen receptor (CAR) T cells exhibit high response rates in B cell malignancies, but most patients eventually relapse. A key mechanism of treatment... |
| SourceID | proquest pubmed |
| SourceType | Aggregation Database Index Database |
| Title | Boosting CAR T-Cell Efficacy by Blocking Proteasomal Degradation of Membrane Antigens |
| URI | https://www.ncbi.nlm.nih.gov/pubmed/40638685 https://www.proquest.com/docview/3229214723 |
| hasFullText | |
| inHoldings | 1 |
| isFullTextHit | |
| isPrint | |
| link | http://cvtisr.summon.serialssolutions.com/2.0.0/link/0/eLvHCXMwpV1La-MwEB62r-1edttk-9hHUaH0JmrLkh-nJckm7GETQmlLbkGWJSgkdlu3hfz7zig2PRUKBWN8EZalseabB98HcJYGkQujUHFLFoyQ2vJUW8Ez7w9Ck4S-efzmfzKZpLNZNm0SbnXTVtmeif6gLipDOfILNLyMNHVE9OfunpNqFFVXGwmNDdiKEMqQVSez1yqCjLzoKrqolBMuasuUqbjwbeEYHlJxASP5-G2A6R3N6NtHp7gHXxuIyXprm9iHT7bsQLdXYni9XLFz5ps-fTa9Azv99ml30Eq_deDzuKm4d-G6X1U1tUazQe-SXfGBXSzYkHgntFmxfMX66A0p3c6mxPig62qJ7_5LFBRrtSZWOTa2SwzKS8t65SOxf9bf4Xo0vBr8440UAzcRBjk8MSqXKhBaapc5VzidBVbmhU11HmqpXO6yxAhpVWGjzOCl0PMppXKRmCx14gA2y6q0R8CUjosgdlZqQg-I7XGMlCp3sQ4LK-wxnLarO8fPpvoFTrB6quev63sMh-stmt-tOTnmkqBXnKof7xj9E74IUvEleszgF2w5_NHtb9g2z4-39cOJtyG8T6bjF-wazxw |
| 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=Boosting+CAR+T-Cell+Efficacy+by+Blocking+Proteasomal+Degradation+of+Membrane+Antigens&rft.jtitle=Blood&rft.au=Rieger%2C+Leonie&rft.au=Irlinger%2C+Kilian&rft.au=F%C3%BCchsl%2C+Franziska&rft.au=Tietje%2C+Marlene&rft.date=2025-07-10&rft.eissn=1528-0020&rft_id=info:doi/10.1182%2Fblood.2024027616&rft_id=info%3Apmid%2F40638685&rft_id=info%3Apmid%2F40638685&rft.externalDocID=40638685 |
| 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 |