CSF-1R-Dependent Lethal Hepatotoxicity When Agonistic CD40 Antibody Is Given before but Not after Chemotherapy.
CSF-1R-Dependent Lethal Hepatotoxicity When Agonistic CD40 Antibody Is Given before but Not after Chemotherapy.
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DOI：
10.4049/jimmunol.1600146
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发表时间：
2016-07-01
期刊：
影响因子：
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通讯作者：
Vonderheide RH
中科院分区：
文献类型：
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作者：
Byrne KT;Leisenring NH;Bajor DL;Vonderheide RH
癌症免疫疗法在临床上的效果日益显著，尤其是对患有T细胞浸润肿瘤的患者实施免疫检查点阻断疗法。激动性CD40单克隆抗体可促进基质降解，并且与化疗联合使用时，可促进T细胞浸润以及引发针对肿瘤的从头应答，使耐药肿瘤对现有的免疫疗法变得敏感。将抗CD40与不同的治疗方法相结合是癌症免疫疗法下一阶段颇具吸引力的一种方法，目前有多项使用抗CD40组合的临床试验正在进行，但对于抗CD40的最佳治疗方案还不是很清楚。胰腺导管腺癌（PDA）通常对免疫疗法具有抗性，并且缺乏基线T细胞浸润。在此，我们利用一种源自基因工程PDA小鼠模型的肿瘤细胞系来研究抗CD40和化疗顺序的改变，以此作为一种增强化疗药物递送的方法。出乎意料的是，尽管我们之前的研究表明在化疗后使用抗CD40治疗对小鼠和PDA患者都是安全的，但我们在此报告，在化疗前不到三天使用抗CD40会导致超过一半接受治疗的C57Bl/6小鼠死亡。在化疗前两到三天使用抗CD40会导致活化的髓样细胞和巨噬细胞数量显著增加，并引发致命的肝毒性。当使用抗CSF - 1R单克隆抗体阻断巨噬细胞活化时，肝脏损伤完全消除。这些研究凸显了CD40在激活巨噬细胞和T细胞应答方面的双重性质，以及对最佳抗CD40治疗方案进行临床前研究以便安全设计临床试验的必要性。
Cancer immunotherapies are increasingly effective in the clinic, especially immune checkpoint blockade delivered to patients who have T cell-infiltrated tumors. Agonistic CD40 mAb promotes stromal degradation, and in combination with chemotherapy, drives T cell infiltration and de novo responses against tumors, rendering resistant tumors susceptible to current immunotherapies. Partnering αCD40 with different treatments is an attractive approach for the next phase of cancer immunotherapies, with a number of clinical trials using αCD40 combinations ongoing, but the optimal therapeutic regimens with αCD40 are not well understood. Pancreatic ductal adenocarcinoma (PDA) is classically resistant to immunotherapy and lacks baseline T cell infiltration. Here, we utilized a tumor cell line derived from a genetically engineered mouse model of PDA to investigate alterations in the sequence of αCD40 and chemotherapy as an approach to enhance pharmacological delivery of chemotherapy. Unexpectedly, despite our previous studies showing αCD40 treatment after chemotherapy is safe in both mice and patients with PDA, we report here that αCD40 administration less than three days in advance of chemotherapy is lethal in over half of treated C57Bl/6 mice. αCD40 treatment two or three days before chemotherapy resulted in significantly increased populations of both activated myeloid cells and macrophages, and lethal hepatotoxicity. Liver damage was fully abrogated when macrophage activation was blocked using αCSF-1R mAb. These studies highlight the dual nature of CD40 in activating both macrophages and T cell responses, and the need for preclinical investigation of optimal αCD40 treatment regimens for safe design of clinical trials.