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.

Case report: Senescence as mechanism of resistance to Pembrolizumab in a Lymphoma patient who failed CD19-Targeted CAR-T cell therapy / De Matteis, Serena; Casadei, Beatrice; Lolli, Ginevra; Dicataldo, Michele; Barbato, Francesco; Dan, Elisa; Paccagnella, Andrea; Sinigaglia, Barbara; Bertuzzi, Clara; Arcari, Annalisa; Zazzeroni, Luca; Bernuzzi, Patrizia; Laprovitera, Noemi; Storci, Gianluca; Bertuccio, Salvatore Nicola; Ferracin, Manuela; Bonafe, Massimiliano; Zinzani, Pier Luigi; Bonifazi, Francesca. - In: FRONTIERS IN IMMUNOLOGY. - ISSN 1664-3224. - ELETTRONICO. - 13:(2022), pp. 994731.1-994731.5. [10.3389/fimmu.2022.994731]

Case report: Senescence as mechanism of resistance to Pembrolizumab in a Lymphoma patient who failed CD19-Targeted CAR-T cell therapy

Casadei, Beatrice;Lolli, Ginevra;Dicataldo, Michele;Barbato, Francesco;Dan, Elisa;Paccagnella, Andrea;Sinigaglia, Barbara;Bertuzzi, Clara;Zazzeroni, Luca;Bertuccio, Salvatore Nicola;Ferracin, Manuela;Bonafe, Massimiliano;Zinzani, Pier Luigi;
2022

Abstract

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.
2022
Case report: Senescence as mechanism of resistance to Pembrolizumab in a Lymphoma patient who failed CD19-Targeted CAR-T cell therapy / De Matteis, Serena; Casadei, Beatrice; Lolli, Ginevra; Dicataldo, Michele; Barbato, Francesco; Dan, Elisa; Paccagnella, Andrea; Sinigaglia, Barbara; Bertuzzi, Clara; Arcari, Annalisa; Zazzeroni, Luca; Bernuzzi, Patrizia; Laprovitera, Noemi; Storci, Gianluca; Bertuccio, Salvatore Nicola; Ferracin, Manuela; Bonafe, Massimiliano; Zinzani, Pier Luigi; Bonifazi, Francesca. - In: FRONTIERS IN IMMUNOLOGY. - ISSN 1664-3224. - ELETTRONICO. - 13:(2022), pp. 994731.1-994731.5. [10.3389/fimmu.2022.994731]
De Matteis, Serena; Casadei, Beatrice; Lolli, Ginevra; Dicataldo, Michele; Barbato, Francesco; Dan, Elisa; Paccagnella, Andrea; Sinigaglia, Barbara; Bertuzzi, Clara; Arcari, Annalisa; Zazzeroni, Luca; Bernuzzi, Patrizia; Laprovitera, Noemi; Storci, Gianluca; Bertuccio, Salvatore Nicola; Ferracin, Manuela; Bonafe, Massimiliano; Zinzani, Pier Luigi; Bonifazi, Francesca
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11585/902102
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