Although co-stimulation of T cells with agonist antibodies targeting 4-1BB (CD137) improves antitumor immune responses in preclinical studies, clinical success has been limited by on-target, off-tumor activity. Here, we report the development of a tumor-anchored ɑ4-1BB agonist (ɑ4-1BB-LAIR), which consists of a ɑ4-1BB antibody fused to the collagen-binding protein LAIR. While combination treatment with an antitumor antibody (TA99) shows only modest efficacy, simultaneous depletion of CD4+ T cells boosts cure rates to over 90% of mice. Mechanistically, this synergy depends on ɑCD4 eliminating tumor draining lymph node regulatory T cells, resulting in priming and activation of CD8+ T cells which then infiltrate the tumor microenvironment. The cytotoxic program of these newly primed CD8+ T cells is then supported by the combined effect of TA99 and ɑ4-1BB-LAIR. The combination of TA99 and ɑ4-1BB-LAIR with a clinically approved ɑCTLA-4 antibody known for enhancing T cell priming results in equivalent cure rates, which validates the mechanistic principle, while the addition of ɑCTLA-4 also generates robust immunological memory against secondary tumor rechallenge. Thus, our study establishes the proof of principle for a clinically translatable cancer immunotherapy.

尽管在临床前研究中，T 细胞与靶向 4-1BB (CD137) 的激动剂抗体共同刺激可改善抗肿瘤免疫反应，但临床成功却受到靶向、脱肿瘤活性的限制。在此，我们报告了肿瘤锚定的 ɑ4-1BB 激动剂（ɑ4-1BB-LAIR）的开发，该激动剂由与胶原结合蛋白 LAIR 融合的 ɑ4-1BB 抗体组成。虽然与抗肿瘤抗体 (TA99) 的联合治疗仅显示出有限的疗效，但同时消除 CD4+ T 细胞可提高小鼠 90% 以上的治愈率。从机制上讲，这种协同作用取决于ɑCD4消除肿瘤引流淋巴结调节性T细胞，导致CD8+ T细胞的启动和激活，然后渗透肿瘤微环境。这些新启动的 CD8+ T 细胞的细胞毒性程序随后得到 TA99 和 ɑ4-1BB-LAIR 的联合作用的支持。 TA99 和 ɑ4-1BB-LAIR 与临床批准的 ɑCTLA-4 抗体（已知可增强 T 细胞启动）的组合可产生相同的治愈率，这验证了机制原理，而 ɑCTLA-4 的添加还产生了针对继发性的强大免疫记忆。肿瘤再挑战。因此，我们的研究为临床可转化的癌症免疫疗法建立了原理证明。