PO.CL06.01 · 临床研究
cGAS-STING通路激动剂联合免疫检查点抑制剂增强化疗在小鼠骨肉瘤模型中的疗效
cGAS-STING pathway agonist plus immune checkpoint inhibitor augments chemotherapy effectiveness in murine osteosarcoma models
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
骨肉瘤（OS）是最常见的儿童骨癌，其标准治疗包括新辅助化疗、手术和辅助化疗。已识别出若干总生存的预后因素，包括原发手术时肿瘤坏死率>95%（化疗敏感性的替代指标）以及诊断时肿瘤内炎性免疫浸润的程度。我们假设增加OS中的免疫浸润将改善肿瘤对化疗的敏感性和总生存。我们团队研究了通过瘤内递送ADU-S100（一种强效STING激动剂）激活OS中cGAS-STING通路的影响，涵盖小鼠和犬OS。ADU-S100可提高治疗肿瘤中促炎细胞因子和趋化因子的水平，包括肿瘤坏死因子-α、干扰素-β、白细胞介素-6、CCL5和CXCL10。此外，还观察到活化的巨噬细胞、T细胞和B细胞浸润增加。我们假设将ADU-S100 STING激动剂与化疗联用可改善我们OS模型的疗效。由于我们已证明STING激动剂招募T细胞进入肿瘤的作用，我们还纳入了免疫检查点抑制剂（ICI）治疗（抗PD1和抗CTLA4）。我们使用同基因小鼠OS细胞系F420在C57BL/6小鼠中建立胫骨内肿瘤。肿瘤可触及后，将小鼠队列用ADU-S100治疗，随后给予卡铂和ICI，并将疗效与单药和双药对照队列进行比较。ADU-S100 + 卡铂（犬OS的标准化疗）或ADU-S100 + 卡铂 + ICI相较于任何单药治疗均显著延长（P<0.05）中位生存。在ADU-S100 + 卡铂基础上加用ICI似乎可进一步延长应答小鼠的生存。在肿瘤攻击后第40天，ADU-S100 + 卡铂 + ICI治疗的小鼠中46%持续保持疾病控制，而ADU-S100 + 卡铂治疗队列为9%（P=0.035）。正在进行的研究包括将ADU-S100 + ICI与多柔比星、顺铂和甲氨蝶呤（人类OS标准化疗药物）联用，以及探究决定应答与非应答小鼠机制的研究。
查看英文原文 English abstract
Osteosarcoma (OS) is the most prevalent pediatric bone cancer, and standard of care treatment includes neoadjuvant chemotherapy, surgery, and adjuvant chemotherapy. Several prognostic factors for overall survival have been identified, including >95% tumor necrosis at the time of primary surgery (surrogate of chemotherapy sensitivity) and the degree of inflammatory immune infiltrates in the tumor at diagnosis. We hypothesize that increasing the immune infiltrates in OS will improve tumor sensitivity to chemotherapy and overall survival. Our group has studied the impact of activating the cGAS-STING pathway in OS via intratumoral delivery of ADU-S100 - a potent STING agonist - in both murine and canine OS. ADU-S100 increases levels of pro-inflammatory cytokines and chemokines, including Tumor Necrosis Factor-alpha, Interferon-beta, Interleukin-6, CCL5 and CXCL10 in the treated tumors. In addition, increased activated macrophage, T-, and B-cell infiltrates are observed. We hypothesized that combining the ADU-S100 STING agonist with chemotherapy could improve outcomes in our models of OS. As we have shown the effects of STING agonist to recruit T-cells into the tumor, we also incorporated immune checkpoint inhibitor (ICI) treatment (anti-PD1 and anti-CTLA4). We used the syngeneic murine OS cell line F420 to establish intratibial tumors in C57BL/6 mice. Once tumors were palpable, cohorts of mice were treated with ADU-S100 followed by carboplatin and ICI, comparing outcomes to the monotherapy and dual therapy control cohorts. ADU-S100 + carboplatin (standard OS chemotherapy in canines) or ADU-S100 + carboplatin + ICI significantly increases (P<0.05) median survival compared to any of the treatments given as monotherapy. The addition of ICI to ADU-S100 + carboplatin appears to further extend the survival in responder mice. At day 40 post-tumor challenge, 46% of the ADU-S100 + carboplatin + ICI treated mice continue with disease control compared to 9% in the ADU-S100 + carboplatin treated cohort (P=0.035). Ongoing studies include combining ADU-S100 + ICI with doxorubicin, cisplatin, and methotrexate (standard of care chemotherapy agents given for OS in humans) and investigations of the mechanisms determining responder versus non-responder mice.
利益披露 Disclosure
M. L. Mendiola, None..
M. Doucet, None.
E. E. Resch,
Merck & Co Employment.
B. H. Ladle, None.