Eradication of Canine Diffuse Large B-Cell Lymphoma in a Murine Xenograft Model with CD47 Blockade and Anti-CD20.
Eradication of Canine Diffuse Large B-Cell Lymphoma in a Murine Xenograft Model with CD47 Blockade and Anti-CD20.
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DOI：
10.1158/2326-6066.cir-16-0105
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发表时间：
2016-12
影响因子：
10.1
通讯作者：
Modiano JF
中科院分区：
文献类型：
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作者：
Weiskopf K;Anderson KL;Ito D;Schnorr PJ;Tomiyasu H;Ring AM;Bloink K;Efe J;Rue S;Lowery D;Barkal A;Prohaska S;McKenna KM;Cornax I;O'Brien TD;O'Sullivan MG;Weissman IL;Modiano JF
癌症免疫疗法有很大的希望，但它们在兽医环境中的潜力尚未得到充分认识。犬淋巴瘤是犬最常见的肿瘤之一，与人类疾病有显著的相似性。在这项研究中，我们研究了CD 47阻断与抗CD 20被动免疫治疗犬淋巴瘤的组合。CD 47/SIRPα轴是调节巨噬细胞活化的免疫检查点。在人类中，CD 47在癌细胞上表达，并能够逃避吞噬作用。CD 47阻断疗法目前正在各种人类癌症的临床试验中进行研究。我们发现犬CD 47/SIRPα轴在生化和功能上是保守的。我们在体外鉴定了拮抗犬CD 47并刺激犬癌细胞吞噬作用的高亲和力SIRPα变体。当作为Fc融合蛋白进行测试时，这些治疗剂在犬淋巴瘤的小鼠异种移植模型中表现出单药疗效。由于CD 47阻断和肿瘤特异性抗体之间的强大协同作用已被证明用于人类癌症，我们评估了CD 47阻断与1 E4-cIgGB（一种针对CD 20的犬特异性抗体）的组合。1 E4-cIgGB单药治疗犬淋巴瘤有较好的疗效。然而，当与CD 47阻断疗法结合时，观察到增强的反应，导致体外和体内协同作用，并在100%的携带犬淋巴瘤的小鼠中引起治愈。我们的研究结果支持在兽医环境中进一步测试单独的CD 47阻断疗法和与CD 20抗体的组合。
Cancer immunotherapies hold much promise, but their potential in veterinary settings has not yet been fully appreciated. Canine lymphomas are among the most common tumors of dogs and bear remarkable similarity to human disease. In this study, we examined the combination of CD47 blockade with anti-CD20 passive immunotherapy for canine lymphoma. The CD47/SIRPα axis is an immune checkpoint that regulates macrophage activation. In humans, CD47 is expressed on cancer cells and enables evasion from phagocytosis. CD47-blocking therapies are now under investigation in clinical trials for a variety of human cancers. We found the canine CD47/SIRPα axis to be conserved biochemically and functionally. We identified high-affinity SIRPα variants that antagonize canine CD47 and stimulate phagocytosis of canine cancer cells in vitro. When tested as Fc fusion proteins, these therapeutic agents exhibited single-agent efficacy in a mouse xenograft model of canine lymphoma. Since robust synergy between CD47 blockade and tumor-specific antibodies has been demonstrated for human cancer, we evaluated the combination of CD47-blockade with 1E4-cIgGB, a canine-specific antibody to CD20. 1E4-cIgGB could elicit a therapeutic response against canine lymphoma in vivo as a single agent. However, augmented responses were observed when combined with CD47-blocking therapies, resulting in synergy in vitro and in vivo and eliciting cures in 100% of mice bearing canine lymphoma. Our findings support further testing of CD47-blocking therapies alone and in combination with CD20 antibodies in the veterinary setting.