Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, California.
Judy and Bernard Briskin Center for Multiple Myeloma, City of Hope, Duarte, California.
Clin Cancer Res. 2018 Jan 1;24(1):106-119. doi: 10.1158/1078-0432.CCR-17-0344. Epub 2017 Oct 23.
Multiple myeloma remains an incurable malignancy of plasma cells despite considerable advances in treatment. The purpose of the study was to develop novel chimeric antigen receptors (CAR) for the treatment of multiple myeloma and explore combinatorial therapy using CAR T cells and immunomodulatory drugs such as lenalidomide for increasing treatment efficacy. We redirected central memory T cells to express second-generation CAR-specific for CS1 and adoptively transferred them into multiple myeloma tumor-bearing mice to test their anti-multiple myeloma activity. CS1 CAR T cells were transduced and expanded in the presence of lenalidomide The phenotype and effector function of CS1 CAR T cells treated with and without lenalidomide were compared. Finally, CS1 CAR T cells and lenalidomide were administered to treat multiple myeloma-bearing mice as combinatorial therapy. CS1 CAR T cells exhibited efficient antitumor activity when adoptively transferred into mice. Mechanistic studies indicated that the addition of lenalidomide during CS1 CAR T-cell expansion enhanced the immune functions of CS1 CAR T cells, including cytotoxicity, memory maintenance, Th1 cytokine production, and immune synapse formation. Furthermore, lenalidomide enhanced the antitumor activity and persistence of adoptively transferred CS1 CAR T cells The study demonstrates that lenalidomide improves the anti-multiple myeloma properties of CS1-directed CAR T cells and provides a basis for a planned clinical trial using the combination of lenalidomide with engineered T cells against CS1 in relapsed myeloma. .
尽管在治疗方面取得了相当大的进展，但多发性骨髓瘤仍然是一种无法治愈的浆细胞瘤恶性肿瘤。本研究旨在开发用于治疗多发性骨髓瘤的新型嵌合抗原受体（CAR），并探索使用 CAR T 细胞和免疫调节药物（如来那度胺）的联合治疗方法，以提高治疗效果。我们将中央记忆 T 细胞重定向表达第二代针对 CS1 的 CAR，并将其过继转移到多发性骨髓瘤肿瘤荷瘤小鼠中，以测试其抗多发性骨髓瘤活性。CS1 CAR T 细胞在来那度胺存在的情况下进行转导和扩增，比较了用和没用来那度胺处理的 CS1 CAR T 细胞的表型和效应功能。最后，用 CS1 CAR T 细胞和来那度胺进行组合治疗，以治疗多发性骨髓瘤荷瘤小鼠。当过继转移到小鼠中时，CS1 CAR T 细胞表现出有效的抗肿瘤活性。机制研究表明，在 CS1 CAR T 细胞扩增期间添加来那度胺增强了 CS1 CAR T 细胞的免疫功能，包括细胞毒性、记忆维持、Th1 细胞因子产生和免疫突触形成。此外，来那度胺增强了过继转移的 CS1 CAR T 细胞的抗肿瘤活性和持久性。该研究表明，来那度胺改善了 CS1 定向 CAR T 细胞的抗多发性骨髓瘤特性，并为计划在复发性骨髓瘤中使用来那度胺联合针对 CS1 的工程化 T 细胞的临床试验提供了依据。
