靶向BCMA CAR-T治療RRMM的局限性及優化策略

劉匯洪 王立茹

【摘要】 嵌合抗原受體T細胞（CAR-T）免疫療法快速發展，為多發性骨髓瘤（MM）治療帶來新的曙光，尤其B細胞成熟抗原（BCMA）作為迄今為止最成功的靶標，靶向BCMA CAR-T療法可以使MM的癥狀獲得持久且深度的緩解，在復發難治性多發性骨髓瘤（RRMM）治療中取得突破性進展。但由于抗原逃逸、CAR-T衰竭等因素，多數患者仍會進展或復發，靶向BCMA CAR-T治療后復發或難治患者的后續治療缺乏標準方案。同時，復雜、昂貴且耗時的個性化CAR-T制造流程也限制其臨床療效的發揮。針對此現狀，該綜述總結了靶向BCMA CAR-T治療的局限性及其機制，同時結合MM治療領域新進展，提出改善進展或RRMM患者結局的潛在優化治療策略。

【關鍵詞】 B細胞成熟抗原 CAR-T療法 復發難治性多發性骨髓瘤 耐藥性

Current Limitations and Potential Strategies of BCMA-targeted CAR-T Therapy in Relapsed Refractory Multiple Myeloma/LIU Huihong， WANG Liru. //Medical Innovation of China， 2024， 21（15）： -188

[Abstract] The rapid development of chimeric antigen receptor T cell （CAR-T） immunotherapy has brought new light to the treatment of multiple myeloma （MM）， among which B cell mature antigen is one of the most popular and successful target. BCMA-targeted CAR-T therapy has demonstrated deep and durable remissions of myeloma symptoms， a breakthrough in the treatment of relapsed refractory multiple myeloma （RRMM）. However， due to antigen escape， CAR-T failure and other factors， most patients will still progress or relapse， and there is a lack of standard follow-up therapies for RRMM patients after BCMA-targeted CAR-T therapy. Furthermore， the complex， expensive and time-consuming manufacturing process of personalized CAR-T also limits its clinical efficacy and application. In view of the above challenges， this review summarizes the limitations and mechanisms of BCMA-targeted CAR-T therapy， combined with the latest advances in the field of MM therapy， and proposes potential optimal treatment strategies to further improve progression or outcomes in RRMM patients.

[Key words] B cell mature antigen CAR-T therapy Relapsed refractory multiple myeloma Resistance

First-author's address： The Eighth Clinical Medical College of Capital Medical University， Beijing 100038， China

doi：10.3969/j.issn.1674-4985.2024.15.043

多發性骨髓瘤（multiple myeloma，MM）是血液系統第二大常見腫瘤，占血液腫瘤的18%，其特征是骨髓中克隆性漿細胞異常增生，分泌過多單克隆免疫球蛋白或其片段（M蛋白），最終導致終末器官損害。MM目前仍無法治愈，隨著治療手段不斷進展，MM患者總生存期顯著改善，但復發難治仍不可避免，且預后極差[1]。令人鼓舞的是，靶向BCMA CAR-T療法在RRMM中展現出較傳統療法更好的有效性和緩解率，然而如何克服此療法的潛在問題，減少治療后再復發、病情進展[2]，一直是研究熱點，本文圍繞靶向BCMA CAR-T療法的局限性及潛在優化策略綜述。

1 靶向BCMA CAR-T療法

BCMA作為MM CAR-T治療最成功的靶點，目前全球范圍內兩種靶向BCMA CAR-T產品

idecabtagene vicleucel（ide-cel）和ciltacabtagene autoleucel

（cilta-cel）已獲美國食品和藥物管理局（FDA）批準用于治療既往經過四線及以上治療的RRMM患者，已有結果證明其在RRMM患者中顯著有效和持久的臨床應答。……