Scientist Icahn School of Medicine at Mount Sinai, New York, United States
Introduction: Anti-B Cell maturation antigen (BCMA) targeting Chimeric Antigen Receptor T Cells (CAR-T) is a highly effective cellular therapy for Multiple Myeloma (MM). Despite CAR-T being a promising treatment, relapse is common and there is a subset of patients that do not respond at all. Our prior studies (Oekelen et al, Blood 2021) have shown that Iberdomide can activate T and NK cells while reducing exhaustion markers (TIGIT) in MM patients. Based on this, we hypothesize that Iberdomide, could improve anti-BCMA CAR-T cell therapy in anti-MM cytotoxicity.
Methods: In this in vitro study, we evaluated the impact of Iberdomide on the persistence, proliferation, and activation of Anti-BCMA CAR-T cells. Using custom spectral flow cytometry panels, we captured dynamics of the CAR-T cell phenotypic composition and proliferation in response to Iberdomide treatment. Additionally, we analyzed the functional effect of Iberdomide on CAR-T cells by quantifying antigen specific cytokine production and cytotoxic activity.
Results: Our results demonstrate that treatment with Iberdomide significantly decreases the presence of transcription factors Ikaros and Aiolos in CAR-T cells by 24 hours (p < 0.01). Incubation with Iberdomide promoted persistence and proliferation in IL-2 starved cells in vitro. After 96 hours, CAR-T cells treated with Iberdomide expressed significantly more Ki67 expression (p < 0.01) and were significantly more viable compared to control (median viability 80% compared to 30%, p< 0.001). The presence of Iberdomide resulted in increased activation of CAR-T cells with an increase of hallmark activation markers such as HLADR, and CD69 (p < 0.05) and decrease in the expression of TIGIT (p=0.041). Iberdomide increased antigen specific cytokine production against BCMA expressing MM cells by 6 hours, specifically increasing the antigen specific production of IL-2, IL-17a, and TNFa by CAR-T cells (p < 0.01). Iberdomide enhanced antigen specific toxicity by CAR-T cells by 46% compared to control by 48 hours (p < 0.001). These findings suggest that Iberdomide can keep CAR-T cells in an activated state counteracting exhaustion and promote the survival and function of CAR-T cells, addressing two major mechanisms underlying CAR-T failure and resistance.
Conclusions: Our study provides evidence that combination treatment with Iberdomide can enhance the persistence and proliferation of anti-BCMA CAR-T cells in vitro. Moreover, Iberdomide induced activation of CAR-T cells leads to improved antigen specific cytokine production and cytotoxic activity. These findings highlight the potential of Iberdomide as an adjunctive therapy to overcome CAR-T cell resistance ultimately improving the therapeutic efficacy of anti-BCMA CAR-T therapy in patients with MM. We are planning further studies to validate these promising results in vivo to ultimately translate into clinical application.
