Centro Ricerca Tettamanti, Clinica Pediatrica, Università Milano Bicocca, Osp. San Gerardo/Fondazione MBBM, Monza, Italy.
Ludwig Institute for Cancer Research, Lausanne, Switzerland.
Leuk Lymphoma. 2022 Jul;63(7):1566-1579. doi: 10.1080/10428194.2022.2043299. Epub 2022 Mar 8.
Chimeric antigen receptors (CAR)-modified T cells are an emerging therapeutic tool for chronic lymphocytic leukemia (CLL). However, in patients with CLL, well-known T-cell defects and the inhibitory properties of the tumor microenvironment (TME) hinder the efficacy of CAR T cells. We explored a novel approach combining CARs with lenalidomide, an immunomodulatory drug that tempers the immunosuppressive activity of the CLL TME. T cells from patients with CLL were engineered to express a CAR specific for CD23, a promising target antigen. Lenalidomide maintained the in vitro effector functions of CD23.CAR T cells effector functions in terms of antigen-specific cytotoxicity, cytokine release and proliferation. Overall, lenalidomide preserved functional CAR T-CLL cell immune synapses. In a Rag2γ-based xenograft model of CLL, we demonstrated that, when combined with low-dose lenalidomide, CD23.CAR T cells efficiently migrated to leukemic sites and delayed disease progression when compared to CD23.CAR T cells given with rhIL-2. These observations underline the therapeutic potential of this novel CAR-based combination strategy in CLL.
嵌合抗原受体 (CAR)-修饰的 T 细胞是治疗慢性淋巴细胞白血病 (CLL) 的一种新兴治疗工具。然而，在 CLL 患者中，众所周知的 T 细胞缺陷和肿瘤微环境 (TME) 的抑制特性会阻碍 CAR T 细胞的疗效。我们探索了一种将 CAR 与来那度胺相结合的新方法，来那度胺是一种免疫调节药物，可调节 CLL TME 的免疫抑制活性。我们对来自 CLL 患者的 T 细胞进行了基因工程改造，使其表达针对 CD23 的 CAR，CD23 是一种很有前途的靶抗原。来那度胺维持了 CD23.CAR T 细胞在体外的效应功能，包括抗原特异性细胞毒性、细胞因子释放和增殖。总体而言，来那度胺保留了功能性 CAR T-CLL 细胞免疫突触。在基于 Rag2γ 的 CLL 异种移植模型中，我们证明了与低剂量来那度胺联合使用时，与给予 rhIL-2 的 CD23.CAR T 细胞相比，CD23.CAR T 细胞能够更有效地迁移到白血病部位，并延迟疾病进展。这些观察结果强调了这种新型基于 CAR 的联合策略在 CLL 中的治疗潜力。
