First-in-human study with intratumoral administration of a CD40 agonistic antibody, ADC-1013, in advanced solid malignancies
First-in-human study with intratumoral administration of a CD40 agonistic antibody, ADC-1013, in advanced solid malignancies
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DOI：
10.1002/ijc.32141
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发表时间：
2019-09-01
影响因子：
6.4
通讯作者：
Ullenhag, Gustav J.
中科院分区：
文献类型：
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作者：
Irenaeus, Sandra M. M.;Nielsen, Dorte;Ullenhag, Gustav J.
激动性CD 40抗体激活树突状细胞，并且可以扩增和激活肿瘤特异性T细胞。我们的目的是评估CD 40激动性抗体ADC-1013在临床环境中的作用，包括肿瘤内给药，因为临床前研究表明肿瘤内给药优于静脉内给药。在已接受既定治疗的晚期实体瘤患者中进行了一项I期、开放标签、多中心研究。采用改良的3 + 3剂量递增（每隔一周给药一次）。用ADC-1013肿瘤内（剂量从22.5 μ g/kg至400 μ g/kg）或静脉内（剂量为75 μ g/kg）治疗23名患者。在hCD 40 tg小鼠模型中进一步验证了在患者中观察到的药效学效应。不良事件大多为不良事件通用术语标准（CTCAE）1级或2级和一过性。与在浅表转移中接受注射的患者相比，在深部转移中接受注射的患者中血清浓度ADC-1013和细胞因子释放（MCP-1、TNF α和IL-6）更明显。用ADC-1013处理导致24小时后外周血中B细胞水平显著降低，而剩余的B细胞显著增加其细胞表面活化标志物CD 86的表达。在hCD 40 tg小鼠中证明了抗原呈递细胞的活化和随后的T细胞活化。此外，在该小鼠模型中，ADC-1013治疗与PD-1抑制剂协同作用。ADC-1013的首次人体研究的结果表明，ADC-1013在临床相关剂量下肿瘤内给药至浅表病变中耐受良好，并与药效学反应相关。
Agonistic CD40 antibodies activate dendritic cells and can expand and activate tumor-specific T cells. Our purpose was to assess the CD40 agonistic antibody ADC-1013 in the clinical setting including intratumoral administration since preclinical studies have indicated that intratumoral is better than intravenous administration. A Phase I, open label, multicenter study was conducted in patients with advanced solid tumors who had received established treatments. A modified 3 + 3 dose-escalation was applied (every other week dosing). Twenty-three patients were treated with ADC-1013 intratumorally (dosing from 22.5 mu g/kg up to 400 mu g/kg) or intravenously (dosing at 75 mu g/kg). The pharmacodynamic effects observed in the patients were further verified in an hCD40tg mouse model. Adverse events were mostly Common Terminology Criteria for Adverse Events (CTCAE) Grades 1 or 2 and transient. The serum concentration ADC-1013 and cytokine release (MCP-1, TNF alpha and IL-6) were more pronounced in patients receiving injections in deep metastases compared to patients receiving injections in superficial metastases. Treatment with ADC-1013 resulted in a marked decrease in B cell levels in peripheral blood after 24 h while remaining B cells significantly increased their expression of the cell surface activation marker CD86. Activation of antigen-presenting cells and subsequent activation of T cells were demonstrated in hCD40tg mice. Moreover, ADC-1013 treatment in this mouse model acted synergistically with a PD-1 inhibitor. The results from the first-in-human study of ADC-1013 indicate that intratumoral administration of ADC-1013 into superficial lesions is well tolerated at clinically relevant doses and associated with pharmacodynamic responses.