Overall survival benefits provided by lenalidomide maintenance after chimeric antigen receptor T cell therapy in patients with refractory/relapsed diffuse large B-cell lymphoma

Abstract

Background: Chimeric antigen receptor T cell (CAR-T) therapy has achieved remarkable effects in refractory/relapsed (R/R) diffuse large B-cell lymphoma (DLBCL). However, many patients receiving CAR-T therapy still eventually die of disease recurrence or progression due to target antigen loss or exhaustion of CAR-T cells. Therefore, maintaining the efficacy of CAR-T has become a particular research focus. As lenalidomide can regulate T cell function, we conducted a study to evaluate the efficacy of lenalidomide maintenance after CAR-T therapy in R/R DLBCL patients.Methods: Seven R/R DLBCL patients who received lenalidomide maintenance after CAR-T therapy and nine DLBCL patients that underwent CAR-T treatment alone were included. The clinical data of all subjects were collected to evaluate the efficacy of lenalidomide maintenance. In order to understand the possible mechanisms of lenalidomide in CAR-T therapy, CAR-T copies of peripheral blood were regularly detected by quantitative real-time polymerase chain reaction, and an in vitro test was also conducted.Results: Overall survival (OS) was significantly prolonged in the lenalidomide maintenance group. Furthermore, one case responding to CAR-T therapy initially but suffering a relapse shortly achieved complete remission again after lenalidomide exposure, with an increase in the number of CAR-T copies detected. The in vitro test showed that lenalidomide could delay the exhaustion of CAR-T cells.Conclusions: Lenalidomide maintenance after CAR-T therapy is a safe and effective choice for R/R DLBCL patients. We confirmed that lenalidomide maintenance can improve patients' OS, and the delayed exhaustion of CAR-T cells may contribute to this OS benefit.

CAR T‐cell therapy induces a high rate of prolonged remission in relapsed primary CNS lymphoma: Real‐life results of the LOC network

“…Even if the outcome of patients treated with CAR T-cells appears much better than the outcome of patients treated by other therapies, it still needs to be improved. Combining CAR T-cells with other immunotherapies such as anti-PD-1 43,44 or with immunomodulating agents such as IMiDS 45,46 or BTK inhibitors 47,48 severe neurotoxicity following CAR T-cell therapy. As reported in systemic lymphomas, ICANS occurred a few days later than CRS and was reversible in a few days in most cases.…”

“…Even if the outcome of patients treated with CAR T‐cells appears much better than the outcome of patients treated by other therapies, it still needs to be improved. Combining CAR T‐cells with other immunotherapies such as anti‐PD‐1 43,44 or with immunomodulating agents such as IMiDS 45,46 or BTK inhibitors 47,48 seems interesting in other types of B‐cell lymphomas, notably by fighting against the tumoral immunosuppressive microenvironment. These drugs have previously shown efficacy in PCNSL as single agents 5,6,14,49 and could be tried in association with CAR T‐cells.…”

Degradation of IKAROS prevents epigenetic progression of T cell exhaustion in a novel antigen-specific assay

“…Interestingly, cereblon E3 ligase modulators (CELMoDs), currently in trials for multiple myeloma 17 and acute myeloid leukemia 39 , are known to activate T cell function by inducing the degradation of IKAROS and its family member Aiolos (IKZF3) through cereblon E3 ligase 40 . Additionally, the previous-generation IKAROS degrader lenalidomide has shown beneficial effects in enhancing CAR-T cell function in a small clinical trial 41 . Indeed, upon follow-up CRISPR knockout of IKAROS, the loss of IKAROS protein (Suppl.…”

Innovation in BCMA CAR-T therapy: Building beyond the Model T

“…Unlike in autologous stem cell transplantation where the role of maintenance therapy with the immunomodulatory drug (IMiD) lenalidomide is a well-established tool to prolong responses (79), it is unknown whether planned IMiD maintenance can improve outcomes after BCMA CAR-T therapy. Table 2 summarizes existing evidence as well some of the theoretical advantages and disadvantages of IMiD maintenance following BCMA CAR-T therapy (39,(80)(81)(82)(83)(84)(85)(86)(87)(88). The upcoming BMT-CTN 1902 trial of ide-cel and CARTITUDE-6 trial of cilta-cel will incorporate lenalidomide maintenance in some way after CAR-T therapy, albeit not in a randomized maintenance versus no-maintenance approach (89, 90).…”