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.
De Matteis, S., Casadei, B., Lolli, G., Dicataldo, M., Barbato, F., Dan, E., et al. (2022). Case report: Senescence as mechanism of resistance to Pembrolizumab in a Lymphoma patient who failed CD19-Targeted CAR-T cell therapy. FRONTIERS IN IMMUNOLOGY, 13, 1-5 [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.File | Dimensione | Formato | |
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