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تسجيل

CAR-T Combination with Immunomodulatory Agents: Lenalidomide

المؤلف:  Armin Ghobadi & John F. DiPersio

المصدر:  Gene and Cellular Immunotherapy for Cancer

الجزء والصفحة:  p75

2026-09-02

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Lenalidomide (LEN) is currently approved for the treatment of multiple myeloma (MM) and mantle cell lymphoma (MCL). LEN acts by inducing the degradation of transcription factors (such as Ikaros and Aiolos). This leads to modification of T cell responses by increasing IL-2 production, shifting the T helper 2 (Th2) response to Th1, and inhibiting the expansion of regulatory T cells (Treg). LEN was shown to increase the efficacy of CD19- and CD20-targeted CAR-T cells by increasing IFNg production and CD69 activation marker in vitro. It also resulted in increased antitumor activity in various murine models of B-cell non-Hodgkin lymphoma (B-NHL) . Similarly, LEN enhanced the immune functions of CAR-T cells targeting CS1 or B-cell maturation antigen (BCMA) for the treatment of MM by improving cytotoxicity, Th1 cytokine production, and immune synapse formation. Importantly, LEN maintained CAR-T activity in repeated stimulation assays, suggesting a possible role in curbing T cell exhaustion. Multiple clinical trials evaluating the effectiveness of CAR-T combination with LEN are currently underway. Among these are a phase 1 study of EGFRt/BCMA-CAR-T cells in patients with MM with or without LEN (NCT03070327) and a phase 3 trial that is evaluating the safety and efficacy of BiRd regimen (clarithromycin, LEN, dexamethasone and BCMA-CAR-T cells in MM patients (NCT04287660). The effect of LEN in promoting CAR-T cell activity against solid tumors was also recently tested in preclinical studies. CAR-T cells directed against CD133 and HER2 expressed in glioma and breast cancer exhibited superior killing of target cells, and enhanced CAR-T proliferation and cytokine secretion. However, these effects were only tested on human cancer cell lines in vitro and not in vivo in solid cancer models.