肿瘤内免疫疗法采用 TLR7/8 激动剂 MEDI9197 调节肿瘤微环境，与其他免疫疗法联合使用时可增强其活性。

BACKGROUND: Immune checkpoint blockade (ICB) promotes adaptive immunity and tumor regression in some cancer patients. However, in patients with immunologically "cold" tumors, tumor-resident innate immune cell activation may be required to prime an adaptive immune response and so exploit the full potential of ICB. Whilst Toll-like receptor (TLR) agonists have been used topically to successfully treat some superficial skin tumors, systemic TLR agonists have not been well-tolerated. METHODS: The response of human immune cells to TLR7 and 8 agonism was measured in primary human immune cell assays. MEDI9197 (3M-052) was designed as a novel lipophilic TLR7/8 agonist that is retained at the injection site, limiting systemic exposure. Retention of the TLR7/8 agonist at the site of injection was demonstrated using quantitative whole-body autoradiography, HPLC-UV, and MALDI mass spectrometry imaging. Pharmacodynamic changes on T cells from TLR7/8 agonist treated B16-OVA tumors was assessed by histology, quantitative real time PCR, and flow cytometry. Combination activity of TLR7/8 agonism with immunotherapies was assessed in vitro by human DC-T cell MLR assay, and in vivo using multiple syngeneic mouse tumor models. RESULTS: Targeting both TLR7 and 8 triggers an innate and adaptive immune response in primary human immune cells, exemplified by secretion of IFNα, IL-12 and IFNγ. In contrast, a STING or a TLR9 agonist primarily induces release of IFNα. We demonstrate that the TLR7/8 agonist, MEDI9197, is retained at the sight of injection with limited systemic exposure. This localized TLR7/8 agonism leads to Th1 polarization, enrichment and activation of natural killer (NK) and CD8 T cells, and inhibition of tumor growth in multiple syngeneic models. The anti-tumor activity of this TLR7/8 agonist is enhanced when combined with T cell-targeted immunotherapies in pre-clinical models. CONCLUSION: Localized TLR7/8 agonism can enhance recruitment and activation of immune cells in tumors and polarize anti-tumor immunity towards a Th1 response. Moreover, we demonstrate that the anti-tumor effects of this TLR7/8 agonist can be enhanced through combination with checkpoint inhibitors and co-stimulatory agonists.

背景：免疫检查点阻断（ICB）可促进某些癌症患者的适应性免疫和肿瘤消退。然而，在免疫“冷”肿瘤患者中，可能需要肿瘤驻留固有免疫细胞的激活来启动适应性免疫反应，从而充分发挥 ICB 的潜力。虽然 Toll 样受体（TLR）激动剂已被用于成功治疗一些浅表皮肤肿瘤，但全身 TLR 激动剂的耐受性并不理想。

方法：在原代人免疫细胞测定中测量了人免疫细胞对 TLR7 和 8 激动剂的反应。MEDI9197（3M-052）被设计为一种新型亲脂 TLR7/8 激动剂，可在注射部位保留，限制全身暴露。使用定量全身放射性自显影、HPLC-UV 和 MALDI 质谱成像证明 TLR7/8 激动剂在注射部位的保留。通过组织学、定量实时 PCR 和流式细胞术评估 TLR7/8 激动剂处理的 B16-OVA 肿瘤中 T 细胞的药效变化。通过人 DC-T 细胞 MLR 测定和多种同基因小鼠肿瘤模型在体内评估 TLR7/8 激动剂与免疫疗法的组合活性。

结果：靶向 TLR7 和 8 都会在原代人免疫细胞中引发先天和适应性免疫反应，表现为 IFNα、IL-12 和 IFNγ 的分泌。相比之下，STING 或 TLR9 激动剂主要诱导 IFNα 的释放。我们证明 TLR7/8 激动剂 MEDI9197 在注射部位保留，全身暴露有限。这种局部 TLR7/8 激动可导致 Th1 极化、自然杀伤（NK）和 CD8 T 细胞的富集和激活，并抑制多种同基因模型中的肿瘤生长。在临床前模型中，该 TLR7/8 激动剂与 T 细胞靶向免疫疗法联合使用可增强其抗肿瘤活性。

结论：局部 TLR7/8 激动可增强肿瘤中免疫细胞的募集和激活，并将抗肿瘤免疫向 Th1 反应极化。此外，我们证明这种 TLR7/8 激动剂的抗肿瘤作用可以通过与检查点抑制剂和共刺激激动剂联合增强。