肿瘤细胞治疗研究
英文原题：Intravesical mesothelin-based CAR T cells targeting MUC16 effectively control bladder cancer in preclinical models.
这些发现共同证实 MUC16 是一个治疗候选靶点，并验证膀胱内给药可作为 T 细胞免疫疗法用于治疗器官局限性膀胱癌的平台。
膀胱癌（BCa）管理主要依赖膀胱内治疗，但其疗效受毒性和复发限制。CAR T细胞疗法虽已在血液系统恶性肿瘤中显示前景，但用于实体瘤时受到肿瘤归巢能力差以及靶向肿瘤同时损伤正常组织等毒性的限制。本研究鉴定并验证了MUC16作为BCa中具有临床意义的靶点，并发现其在对现有疗法难治的肿瘤中表达富集。我们构建了第二代间皮素基础CAR（MSLN-28z），并在多种BCa细胞系及患者来源肿瘤类器官中证实其具有强劲活性。在BCa异种移植模型中，与静脉输注相比，膀胱内给予MSLN-28z CAR T细胞可更有效控制肿瘤，同时减少全身T细胞植入。膀胱内过继转移可使局部抗肿瘤疗效与潜在全身毒性相分离；这一特点也见于数种具有靶向肿瘤同时损伤正常组织活性的T细胞免疫疗法。总之，这些发现支持MUC16作为治疗候选靶点，并验证膀胱内递送可作为器官局限性BCa中T细胞免疫疗法的平台。
Intravesical therapies are the mainstay of bladder cancer (BCa) management, but their efficacy is limited by toxicities and recurrences. While CAR T cell therapy has shown promise in hematologic malignancies, its application in solid tumors is limited by poor trafficking and on-target off-tumor toxicities. Here, we identify and validate MUC16 as a clinically relevant target for BCa, noting enriched expression in tumors recalcitrant to existing therapies. We engineered a second-generation mesothelin-based CAR (MSLN-28z) and demonstrated robust activity across multiple BCa cell lines and patient-derived tumor organoids. Intravesical delivery of MSLN-28z CAR T cells in xenograft BCa models conferred superior tumor control compared with intravenous transfer, while attenuating systemic T cell engraftment. Intravesical adoptive transfer uncouples local antitumor efficacy from potential systemic toxicity-a feature conserved across several T cell immunotherapies with on-target off-tumor activity. Collectively, these findings substantiate MUC16 as a therapeutic candidate and validate intravesical delivery as a platform for T cell immunotherapies in the management of organ-confined BCa.
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