IL-15 synergizes with CD40 agonist antibodies to induce durable immunity against bladder cancer.
IL-15 synergizes with CD40 agonist antibodies to induce durable immunity against bladder cancer.
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IL-15 与 CD40 激动剂抗体协同作用，诱导针对膀胱癌的持久免疫力。
DOI：
10.1101/2023.01.30.526266
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Knorr,DavidA
中科院分区：
文献类型：
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作者：
Wong,JeffreyL;Smith,Patrick;Angulo-Lozano,Juan;Ranti,Daniel;Bochner,BernardH;Sfakianos,JohnP;Horowitz,Amir;Ravetch,JeffreyV;Knorr,DavidA
CD40是一种中央共刺激受体，参与多种癌症(包括膀胱癌)的高效抗肿瘤免疫反应。尽管有强大的临床前理论基础，但针对CD40途径的治疗性激动型抗体的全身应用已显示出剂量限制性毒性，临床活性最低，强调了优化CD40靶向治疗方法的重要需要，包括合理的联合治疗策略。在这里，我们描述了内源性IL-15途径在原位膀胱肿瘤CD40激动剂治疗活性中的作用，通过上调转移性IL-15/IL-15Rα表面复合体，特别是通过交叉呈递常规的1型DC(树突状细胞)，以及相关的激活的CD8T细胞的浓缩。在膀胱癌患者样本中，我们确定DC是IL-15的主要来源，尽管它们在基线水平缺乏高水平的IL-15Rα。使用人源化的免疫活性原位膀胱肿瘤模型，我们证明了通过联合抗CD40激动剂抗体和外源性IL-15，包括目前正在临床开发的用于治疗膀胱癌的完全人类Fc优化的抗体2141-V11，能够在治疗上增强这种相互作用。总之，这些数据揭示了IL-15在介导膀胱癌抗肿瘤CD40激动剂反应中的重要作用，并为联合使用FC优化的抗CD40激动剂抗体和针对IL-15途径的药物提供了关键的概念证明。这些数据支持正在进行的临床研究的扩展，评估抗CD40激动剂抗体和基于IL-15的方法，以开发这些有希望的治疗方法的组合，用于治疗膀胱癌患者。
CD40 is a central costimulatory receptor implicated in productive antitumor immune responses across multiple cancers, including bladder cancer. Despite strong preclinical rationale, systemic administration of therapeutic agonistic antibodies targeting the CD40 pathway has demonstrated dose-limiting toxicities with minimal clinical activity, emphasizing an important need for optimized CD40-targeted approaches, including rational combination therapy strategies. Here, we describe a role for the endogenous IL-15 pathway in contributing to the therapeutic activity of CD40 agonism in orthotopic bladder tumors, with upregulation of transpresented IL-15/IL-15Rα surface complexes, particularly by cross-presenting conventional type 1 DCs (Dendritic Cells), and associated enrichment of activated CD8 T cells. In bladder cancer patient samples, we identify DCs as the primary source of IL-15, although they lack high levels of IL-15Rα at baseline. Using humanized immunocompetent orthotopic bladder tumor models, we demonstrate the ability to therapeutically augment this interaction through combined treatment with anti-CD40 agonist antibodies and exogenous IL-15, including the fully-human Fc-optimized antibody 2141-V11 currently in clinical development for the treatment of bladder cancer. Collectively, these data reveal an important role for IL-15 in mediating antitumor CD40 agonist responses in bladder cancer and provide key proof-of-concept for combined use of Fc-optimized anti-CD40 agonist antibodies and agents targeting the IL-15 pathway. These data support expansion of ongoing clinical studies evaluating anti-CD40 agonist antibodies and IL-15-based approaches to develop combinations of these promising therapeutics for the treatment of patients with bladder cancer.