Peter Gorer Department of Immunobiology, School of Immunology and Microbial Sciences, King's College London, Guy's Hospital, London, United Kingdom.
Institute of Medical and Biomedical Education, St. George's University of London, London, United Kingdom.
Front Immunol. 2023 Jul 3;14:1196829. doi: 10.3389/fimmu.2023.1196829. eCollection 2023.
Prostate cancer is one of the most commonly diagnosed malignancies in men with high mortality rates. Despite the recent therapeutic advances, such as immunotherapies, survival of patients with advance disease remains significantly low. Blockade of immune checkpoints has led to low response rates in these patients probably due to the immunosuppressive microenvironment and low mutation burden of prostate tumors. Combination of multiple immunotherapeutic regimes has also been unsatisfactory due to augmented adverse effects. To activate multiple immune-stimulatory pathways in the hostile prostate cancer microenvironment, we used a combination of cytotopically modified interleukin-15 (cyto-IL-15) with the stimulator of interferon genes (STING) agonist, ADU-S100.
To determine whether this combination regime could lead to both local and systemic anti-tumor effects, intratumoral administration of these agents was used in murine models of prostate cancer. Tumor growth and mouse survival were monitored, and ex vivo analyses, and RNA sequencing were performed on the tumors.
Intratumorally injected ADU-S100 and cyto-IL-15 synergized to eliminate tumors in 58-67% of mice with unilateral tumors and promoted abscopal immunity in 50% of mice with bilateral tumors treated only at one side. Moreover, this combination regime offered immunoprotection against tumor rechallenge in 83% of cured mice. The efficacy of the combination treatment was associated with a strong innate and adaptive immune activation and induction of apoptotic and necrotic cell death. Cytokines, including type I and II interferons, and cytokine signalling pathways were activated, NK and T cell mediated cytotoxicity was increased, and B cells were activated both locally and systemically. While ADU-S100 led to an ulcerative pathology at the injection site, no other adverse effects were observed.
Localised administration of a STING agonist together with cyto-IL-15 can confer significant systemic benefits and long-lasting immunity against prostate tumors while reducing immune related toxicities.
前列腺癌是男性中最常见的恶性肿瘤之一，死亡率很高。尽管最近有免疫疗法等治疗进展，但晚期疾病患者的生存率仍然很低。免疫检查点阻断在这些患者中的反应率较低，可能是由于前列腺肿瘤的免疫抑制微环境和低突变负担。由于不良反应增加，多种免疫治疗方案的联合应用也不尽如人意。为了在敌对的前列腺癌微环境中激活多种免疫刺激途径，我们使用细胞因子修饰的白细胞介素-15（细胞因子-IL-15）与干扰素基因刺激剂（STING）激动剂 ADU-S100 的组合。
为了确定这种联合方案是否能导致局部和全身抗肿瘤作用，我们在前列腺癌小鼠模型中进行了这些药物的肿瘤内给药。监测肿瘤生长和小鼠存活情况，并对肿瘤进行离体分析和 RNA 测序。
ADU-S100 和细胞因子-IL-15 的肿瘤内注射协同作用，可消除单侧肿瘤小鼠 58-67%的肿瘤，并促进仅在一侧治疗的双侧肿瘤小鼠 50%的肿瘤发生免疫治疗。此外，这种联合方案为 83%治愈小鼠提供了对肿瘤再挑战的免疫保护。联合治疗的疗效与强烈的先天和适应性免疫激活以及诱导凋亡和坏死细胞死亡有关。激活了细胞因子，包括 I 型和 II 型干扰素，以及细胞因子信号通路，增加了 NK 和 T 细胞介导的细胞毒性，并且局部和全身激活了 B 细胞。虽然 ADU-S100 导致注射部位出现溃疡性病变，但没有观察到其他不良反应。
局部施用 STING 激动剂与细胞因子-IL-15 相结合，可以在减少免疫相关毒性的同时，为前列腺肿瘤提供显著的全身益处和持久的免疫力。
