肿瘤细胞治疗研究
英文原题：PD1-IL2v expands and induces effector CD8(+) TILs, but not Tregs, in the BCG treated orthotopic non-muscle invasive bladder cancer model.
膀胱内联合应用BCG与murinized PD1-IL2v选择性增加细胞毒性CD8+ TIL数量，而不增加Tregs，并改善膀胱癌临床前模型中小鼠的生存。这些发现支持探索eciskafusp alfa膀胱内给药用于高危NMIBC患者的临床应用的合理性。BCG与eciskafusp alfa的联合方案可作为对BCG无应答的NMIBC患者的二线治疗加以部署。
系统免疫检查点抑制剂与标准治疗膀胱内卡介苗（BCG）疗法联合用于非肌层浸润性膀胱癌（NMIBC）已显示出增强BCG治疗效果的潜力。然而，疾病复发、进展和免疫相关毒性等挑战仍是重大障碍。此外，BCG的作用机制涉及广泛的非特异性免疫激活。虽然这能招募旁观者CD8+和NK细胞，但也会引发Tregs的不期望扩增，最终可能削弱治疗效果。我们旨在探索一种靶向方法的可行性，该方法旨在克服膀胱内肿瘤耐药性并选择性增强CD8+ TILs的扩增和效应功能。
我们在NMIBC的临床前小鼠模型中测试了膀胱内给予BCG联合murinized PD1-IL2v，后者是一种同时在同一细胞上顺式靶向PD-1和IL-2Rβγ的融合蛋白。
BCG单药治疗和与鼠源化PD1-IL2v联合治疗均改善了动物生存。值得注意的是，与BCG单药治疗相比，BCG与鼠源化PD1-IL2v的膀胱内联合治疗显著增加了具有多能细胞毒性效应表型的CD8+ TIL数量，并避免了Treg扩增。此外，在患者来源的肿瘤中，我们观察到CD8⁺ TIL的频率（18%）高于Treg（5%），其中60%的CD8+ TIL表面表达PD-1，代表PD1-IL2v（又名eciskafusp alfa）的潜在靶点。
BACKGROUND: The combination of systemic immune checkpoint inhibitors with standard of care intravesical Bacillus Calmette-Guerin (BCG) therapy for non-muscle invasive bladder cancer (NMIBC) has shown potential in enhancing BCG therapeutic effects. However, challenges such as disease recurrence, progression, and immune-related toxicities remain a significant hurdle. Furthermore, the mechanism of action of BCG involves broad, non-specific immune activation. While this recruits bystander CD8+ and NK cells, it also triggers the undesired expansion of Tregs, which may ultimately hamper therapeutic efficacy. We aimed to explore the feasibility of a targeted approach designed to overcome intravesical tumor resistance and selectively enhance the expansion and effector functions of CD8+ TILs. METHODS: We tested intravesical administration of BCG with murinized PD1-IL2v, a fusion protein that simultaneously targets PD-1 and IL-2Rβγ in cis on the same cell, in a preclinical mouse model of NMIBC. RESULTS: Both BCG monotherapy and co-treatment with a murinized PD1-IL2v improved animal survival. Notably, the intravesical combination of BCG and murinized PD1-IL2v significantly increased the number of CD8+ TILs with polyfunctional cytotoxic effector phenotype and avoided Treg expansion in contrast to BCG monotherapy. In addition, in patient-derived tumors, we observed a higher frequency of CD8⁺ TILs (18%) compared to Tregs (5%), with 60% of the CD8+ TILs expressing PD-1 on their surface, representing a potential target for PD1-IL2v, alias eciskafusp alfa. CONCLUSIONS: The intravesical combination of BCG with murinized PD1-IL2v selectively increases the number of cytotoxic CD8+ TILs, but not Tregs, and improves the survival of the mice in the preclinical model of bladder cancer model. These findings support the rationale for exploring the clinical use of eciskafusp alfa for intravesical administration in high-risk NMIBC patients. The combination of BCG and eciskafusp alfa could be deployable as a second line of treatment for NMIBC patients unresponsive to BCG.
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