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

Background: T 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 Presentation: We 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.
Conclusions: PBZ 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.
Competing Interests: PZ: scientific advisory boards: Secura Bio, Celltrion, Gilead, Janssen-Cilag, BMS, Servier, Sandoz, MSD, TG Therap., Takeda, Roche, EUSA Pharma, Kiowa Kirin, Novartis, ADC Therap., Incyte, Beigene; consultancy: EUSA Pharma, MSD, Novartis; speaker’s bureau: Celltrion, Gilead, Janssen-Cilag, BMS, Servier, MSD, TG Therap., Takeda, Roche, EUSA Pharma, Kiowa Kirin, Novartis, Incyte, Beigene. FB: scientific advisory boards and speaker fees: NEOVII, NOVARTIS, KITE, GILEAD, PFIZER, CELGENE, MSD. MB: Research Grant from NEOVII. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
(Copyright © 2022 De Matteis, Casadei, Lolli, Dicataldo, Barbato, Dan, Paccagnella, Sinigaglia, Bertuzzi, Arcari, Zazzeroni, Bernuzzi, Laprovitera, Storci, Bertuccio, Ferracin, Bonafè, Zinzani and Bonifazi.)