Case report: Senescence as mechanism of resistance to Pembrolizumab in a Lymphoma patient who failed CD19-Targeted CAR-T cell therapy
BackgroundT cells engineered to target CD19 antigen on neoplastic B cells represent the most striking example of CAR-T cell therapy. The success rate of this therapy is affected by several limitations: target antigen loss, and/or acquisition of a senescent/exhausted phenotype by CAR and non-CAR T ce...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2022-10-01
|
| Series: | Frontiers in Immunology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2022.994731/full |
| _version_ | 1797997187843489792 |
|---|---|
| author | Serena De Matteis Beatrice Casadei Beatrice Casadei Ginevra Lolli Ginevra Lolli Michele Dicataldo Michele Dicataldo Francesco Barbato Francesco Barbato Elisa Dan Andrea Paccagnella Barbara Sinigaglia Clara Bertuzzi Annalisa Arcari Luca Zazzeroni Patrizia Bernuzzi Noemi Laprovitera Gianluca Storci Salvatore Nicola Bertuccio Manuela Ferracin Massimiliano Bonafè Pier Luigi Zinzani Pier Luigi Zinzani Francesca Bonifazi |
| author_facet | Serena De Matteis Beatrice Casadei Beatrice Casadei Ginevra Lolli Ginevra Lolli Michele Dicataldo Michele Dicataldo Francesco Barbato Francesco Barbato Elisa Dan Andrea Paccagnella Barbara Sinigaglia Clara Bertuzzi Annalisa Arcari Luca Zazzeroni Patrizia Bernuzzi Noemi Laprovitera Gianluca Storci Salvatore Nicola Bertuccio Manuela Ferracin Massimiliano Bonafè Pier Luigi Zinzani Pier Luigi Zinzani Francesca Bonifazi |
| author_sort | Serena De Matteis |
| collection | DOAJ |
| description | BackgroundT cells engineered to target CD19 antigen on neoplastic B cells represent the most striking example of CAR-T cell therapy. The success rate of this therapy is affected by several limitations: target antigen loss, and/or acquisition of a senescent/exhausted phenotype by CAR and non-CAR T cells.Case presentationWe report on a patient affected by refractory Diffuse Large B-cell Lymphoma who was resistant to CAR T-cell therapy and to two cycles post CAR-T of pembrolizumab (PBZ) due to the evolution into a B-cell Hodgkin-like lymphoma. Owing to the CD30 expression and the Hodgkin-like phenotype, the patient was ultimately treated with Brentuximab-Vedotin and finally underwent remission. Upon PBZ treatment, 100% of circulating CAR-T+ cells showed a persistent CD8+ senescent/exhausted phenotype, while an increase in the percentage of senescent cells was found in the non-CAR CD8+ T cells compartment.ConclusionsPBZ is not able to reinvigorate exhausted CAR+ T cells and to confer durable clinical response. We hypothesize that the phenomenon is due to the senescent phenotype of CAR+ T cells, which did not allow PBZ-induced reactivation and proliferative rescue. The phenomenon, together with the loss of CAR-T target CD19 and the shift of non-CAR CD8+ T cells towards a senescent phenotype likely contributed to set up an immune landscape with poor antitumor capacity. |
| first_indexed | 2024-04-11T10:29:05Z |
| format | Article |
| id | doaj.art-5193f10e256641b3abbbee36ff843823 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-04-11T10:29:05Z |
| publishDate | 2022-10-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-5193f10e256641b3abbbee36ff8438232022-12-22T04:29:29ZengFrontiers Media S.A.Frontiers in Immunology1664-32242022-10-011310.3389/fimmu.2022.994731994731Case report: Senescence as mechanism of resistance to Pembrolizumab in a Lymphoma patient who failed CD19-Targeted CAR-T cell therapySerena De Matteis0Beatrice Casadei1Beatrice Casadei2Ginevra Lolli3Ginevra Lolli4Michele Dicataldo5Michele Dicataldo6Francesco Barbato7Francesco Barbato8Elisa Dan9Andrea Paccagnella10Barbara Sinigaglia11Clara Bertuzzi12Annalisa Arcari13Luca Zazzeroni14Patrizia Bernuzzi15Noemi Laprovitera16Gianluca Storci17Salvatore Nicola Bertuccio18Manuela Ferracin19Massimiliano Bonafè20Pier Luigi Zinzani21Pier Luigi Zinzani22Francesca Bonifazi23IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, ItalyIRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, ItalyDepartment of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, ItalyIRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, ItalyDepartment of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, ItalyIRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, ItalyDepartment of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, ItalyIRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, ItalyDepartment of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, ItalyDepartment of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, ItalyDepartment of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, ItalyDepartment of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, ItalyIRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, ItalyHematology and Bone Marrow Transplant Unit, “Guglielmo da Saliceto” Hospital, Piacenza, ItalyDepartment of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, ItalyHematology and Bone Marrow Transplant Unit, “Guglielmo da Saliceto” Hospital, Piacenza, ItalyIRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, ItalyIRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, ItalyDepartment of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, ItalyDepartment of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, ItalyDepartment of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, ItalyIRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, ItalyDepartment of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, ItalyIRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, ItalyBackgroundT cells engineered to target CD19 antigen on neoplastic B cells represent the most striking example of CAR-T cell therapy. The success rate of this therapy is affected by several limitations: target antigen loss, and/or acquisition of a senescent/exhausted phenotype by CAR and non-CAR T cells.Case presentationWe report on a patient affected by refractory Diffuse Large B-cell Lymphoma who was resistant to CAR T-cell therapy and to two cycles post CAR-T of pembrolizumab (PBZ) due to the evolution into a B-cell Hodgkin-like lymphoma. Owing to the CD30 expression and the Hodgkin-like phenotype, the patient was ultimately treated with Brentuximab-Vedotin and finally underwent remission. Upon PBZ treatment, 100% of circulating CAR-T+ cells showed a persistent CD8+ senescent/exhausted phenotype, while an increase in the percentage of senescent cells was found in the non-CAR CD8+ T cells compartment.ConclusionsPBZ is not able to reinvigorate exhausted CAR+ T cells and to confer durable clinical response. We hypothesize that the phenomenon is due to the senescent phenotype of CAR+ T cells, which did not allow PBZ-induced reactivation and proliferative rescue. The phenomenon, together with the loss of CAR-T target CD19 and the shift of non-CAR CD8+ T cells towards a senescent phenotype likely contributed to set up an immune landscape with poor antitumor capacity.https://www.frontiersin.org/articles/10.3389/fimmu.2022.994731/fulllymphomasenescenceexhaustionchimeric antigen receptor (CAR T)pembrolizumabresistance |
| spellingShingle | Serena De Matteis Beatrice Casadei Beatrice Casadei Ginevra Lolli Ginevra Lolli Michele Dicataldo Michele Dicataldo Francesco Barbato Francesco Barbato Elisa Dan Andrea Paccagnella Barbara Sinigaglia Clara Bertuzzi Annalisa Arcari Luca Zazzeroni Patrizia Bernuzzi Noemi Laprovitera Gianluca Storci Salvatore Nicola Bertuccio Manuela Ferracin Massimiliano Bonafè Pier Luigi Zinzani Pier Luigi Zinzani Francesca Bonifazi Case report: Senescence as mechanism of resistance to Pembrolizumab in a Lymphoma patient who failed CD19-Targeted CAR-T cell therapy Frontiers in Immunology lymphoma senescence exhaustion chimeric antigen receptor (CAR T) pembrolizumab resistance |
| title | Case report: Senescence as mechanism of resistance to Pembrolizumab in a Lymphoma patient who failed CD19-Targeted CAR-T cell therapy |
| title_full | Case report: Senescence as mechanism of resistance to Pembrolizumab in a Lymphoma patient who failed CD19-Targeted CAR-T cell therapy |
| title_fullStr | Case report: Senescence as mechanism of resistance to Pembrolizumab in a Lymphoma patient who failed CD19-Targeted CAR-T cell therapy |
| title_full_unstemmed | Case report: Senescence as mechanism of resistance to Pembrolizumab in a Lymphoma patient who failed CD19-Targeted CAR-T cell therapy |
| title_short | Case report: Senescence as mechanism of resistance to Pembrolizumab in a Lymphoma patient who failed CD19-Targeted CAR-T cell therapy |
| title_sort | case report senescence as mechanism of resistance to pembrolizumab in a lymphoma patient who failed cd19 targeted car t cell therapy |
| topic | lymphoma senescence exhaustion chimeric antigen receptor (CAR T) pembrolizumab resistance |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2022.994731/full |
| work_keys_str_mv | AT serenadematteis casereportsenescenceasmechanismofresistancetopembrolizumabinalymphomapatientwhofailedcd19targetedcartcelltherapy AT beatricecasadei casereportsenescenceasmechanismofresistancetopembrolizumabinalymphomapatientwhofailedcd19targetedcartcelltherapy AT beatricecasadei casereportsenescenceasmechanismofresistancetopembrolizumabinalymphomapatientwhofailedcd19targetedcartcelltherapy AT ginevralolli casereportsenescenceasmechanismofresistancetopembrolizumabinalymphomapatientwhofailedcd19targetedcartcelltherapy AT ginevralolli casereportsenescenceasmechanismofresistancetopembrolizumabinalymphomapatientwhofailedcd19targetedcartcelltherapy AT micheledicataldo casereportsenescenceasmechanismofresistancetopembrolizumabinalymphomapatientwhofailedcd19targetedcartcelltherapy AT micheledicataldo casereportsenescenceasmechanismofresistancetopembrolizumabinalymphomapatientwhofailedcd19targetedcartcelltherapy AT francescobarbato casereportsenescenceasmechanismofresistancetopembrolizumabinalymphomapatientwhofailedcd19targetedcartcelltherapy AT francescobarbato casereportsenescenceasmechanismofresistancetopembrolizumabinalymphomapatientwhofailedcd19targetedcartcelltherapy AT elisadan casereportsenescenceasmechanismofresistancetopembrolizumabinalymphomapatientwhofailedcd19targetedcartcelltherapy AT andreapaccagnella casereportsenescenceasmechanismofresistancetopembrolizumabinalymphomapatientwhofailedcd19targetedcartcelltherapy AT barbarasinigaglia casereportsenescenceasmechanismofresistancetopembrolizumabinalymphomapatientwhofailedcd19targetedcartcelltherapy AT clarabertuzzi casereportsenescenceasmechanismofresistancetopembrolizumabinalymphomapatientwhofailedcd19targetedcartcelltherapy AT annalisaarcari casereportsenescenceasmechanismofresistancetopembrolizumabinalymphomapatientwhofailedcd19targetedcartcelltherapy AT lucazazzeroni casereportsenescenceasmechanismofresistancetopembrolizumabinalymphomapatientwhofailedcd19targetedcartcelltherapy AT patriziabernuzzi casereportsenescenceasmechanismofresistancetopembrolizumabinalymphomapatientwhofailedcd19targetedcartcelltherapy AT noemilaprovitera casereportsenescenceasmechanismofresistancetopembrolizumabinalymphomapatientwhofailedcd19targetedcartcelltherapy AT gianlucastorci casereportsenescenceasmechanismofresistancetopembrolizumabinalymphomapatientwhofailedcd19targetedcartcelltherapy AT salvatorenicolabertuccio casereportsenescenceasmechanismofresistancetopembrolizumabinalymphomapatientwhofailedcd19targetedcartcelltherapy AT manuelaferracin casereportsenescenceasmechanismofresistancetopembrolizumabinalymphomapatientwhofailedcd19targetedcartcelltherapy AT massimilianobonafe casereportsenescenceasmechanismofresistancetopembrolizumabinalymphomapatientwhofailedcd19targetedcartcelltherapy AT pierluigizinzani casereportsenescenceasmechanismofresistancetopembrolizumabinalymphomapatientwhofailedcd19targetedcartcelltherapy AT pierluigizinzani casereportsenescenceasmechanismofresistancetopembrolizumabinalymphomapatientwhofailedcd19targetedcartcelltherapy AT francescabonifazi casereportsenescenceasmechanismofresistancetopembrolizumabinalymphomapatientwhofailedcd19targetedcartcelltherapy |