Even with the prolific clinical use of next-generation cancer therapeutics, many tumors remain unresponsive or become refractory to therapy, creating a medical need. In cancer, DCs are indispensable for T cell activation, so there is a restriction on cytotoxic T cell immunity if DCs are not present in sufficient numbers in the tumor and draining lymph nodes to take up and present relevant cancer antigens. To address this bottleneck, we developed a therapeutic based on albumin fused with FMS-related tyrosine kinase 3 ligand (Alb-Flt3L) that demonstrated superior pharmacokinetic properties compared with Flt3L, including significantly longer half-life, accumulation in tumors and lymph nodes, and cross-presenting-DC expansion following a single injection. We demonstrated that Alb-Flt3L, in combination with standard-of-care chemotherapy and radiation therapy, serves as an in situ vaccination strategy capable of engendering polyclonal tumor neoantigen–specific immunity spontaneously. In addition, Alb-Flt3L–mediated tumor control synergized with immune checkpoint blockade delivered as anti–PD-L1. The mechanism of action of Alb-Flt3L treatment revealed a dependency on Batf3, type I IFNs, and plasmacytoid DCs. Finally, the ability of Alb-Flt3L to expand human DCs was explored in humanized mice. We observed significant expansion of human cross-presenting-DC subsets, supporting the notion that Alb-Flt3L could be used clinically to modulate human DC populations in future cancer therapeutic regimens.

中文翻译：

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通过组织靶向 cDC1 扩增进行原位疫苗接种可增强放化疗和免疫治疗的免疫原性

即使下一代癌症疗法在临床上得到大量使用，许多肿瘤仍然没有反应或对治疗变得难治，从而产生了医疗需求。在癌症中，DC对于T细胞的激活是不可或缺的，因此，如果肿瘤和引流淋巴结中没有足够数量的DC来摄取和呈递相关的癌症抗原，那么细胞毒性T细胞免疫就会受到限制。为了解决这一瓶颈，我们开发了一种基于与 FMS 相关酪氨酸激酶 3 配体融合的白蛋白 (Alb-Flt3L) 的治疗药物，与 Flt3L 相比，该药物表现出更优异的药代动力学特性，包括显着更长的半衰期、在肿瘤和淋巴结中的积累，以及单次注射后交叉呈现 DC 扩展。我们证明，Alb-Flt3L 与标准护理化疗和放射治疗相结合，作为一种原位疫苗接种策略，能够自发产生多克隆肿瘤新抗原特异性免疫。此外，Alb-Flt3L 介导的肿瘤控制与抗 PD-L1 形式的免疫检查点阻断具有协同作用。Alb-Flt3L 治疗的作用机制揭示了对 Batf3、I 型 IFN 和浆细胞样 DC 的依赖性。最后，在人源化小鼠中探索了 Alb-Flt3L 扩增人类 DC 的能力。我们观察到人类交叉呈递 DC 亚群的显着扩展，支持了 Alb-Flt3L 可在临床上用于在未来癌症治疗方案中调节人类 DC 群体的观点。