Long-term outcomes of a phase I study of agonist CD40 antibody and CTLA-4 blockade in patients with metastatic melanoma.
Long-term outcomes of a phase I study of agonist CD40 antibody and CTLA-4 blockade in patients with metastatic melanoma.
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DOI：
10.1080/2162402x.2018.1468956
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发表时间：
2018
期刊：
影响因子：
7.2
通讯作者：
Vonderheide RH
中科院分区：
文献类型：
--
作者：
Bajor DL;Mick R;Riese MJ;Huang AC;Sullivan B;Richman LP;Torigian DA;George SM;Stelekati E;Chen F;Melenhorst JJ;Lacey SF;Xu X;Wherry EJ;Gangadhar TC;Amaravadi RK;Schuchter LM;Vonderheide RH
我们报告了在转移性黑色素瘤患者中观察到的激动剂CD 40单克隆抗体（mAb）和阻断CTLA-4 mAb的I期试验的长期临床结局和免疫应答。入组了24例既往未接受过检查点阻断治疗的患者。激动性CD 40 mAb CP-870，893和CTLA-4阻断性mAb曲美木单抗分别每3周和12周伴随给药，分为4种剂量组合。两名患者发生剂量限制性3级免疫介导的结肠炎，导致最大耐受剂量（MTD）的定义。其他免疫介导的毒性包括葡萄膜炎（n = 1）、垂体炎（n = 1）、甲状腺功能减退症（n = 2）和3级细胞因子释放综合征（CRS）（n = 1）。估计的MTD为0.2mg/kg CP-870，893和10 mg/kg曲美木单抗。在22例可评价患者中，客观缓解率（ORR）为27.3%：2例患者（9.1%）完全缓解（CR），4例患者（18.2%）部分缓解（PR）。中位随访45个月，中位无进展生存期（PFS）为3.2个月（95% CI，1.3-5.1个月），中位总生存期（OS）为23.6个月（95% CI，11.7-35.5个月）。9名患者为长期存活者（> 3年），其中8名随后接受了其他治疗，包括PD-1 mAb、手术或放射治疗。基线可溶性CD 25升高与OS缩短相关。在免疫学上，治疗与T细胞活化和肿瘤T细胞浸润增加的证据相关，而无需治疗性PD-1/PD-L1阻断。这些结果提示了PD-1以外的免疫激活和癌症免疫治疗的机会。
We report long-term clinical outcomes and immune responses observed from a phase 1 trial of agonist CD40 monoclonal antibody (mAb) and blocking CTLA-4 mAb in patients with metastatic melanoma. Twenty-four patients previously untreated with checkpoint blockade were enrolled. The agonistic CD40 mAb CP-870,893 and the CTLA-4 blocking mAb tremelimumab were dosed concomitantly every 3 weeks and 12 weeks, respectively, across four dose combinations. Two patients developed dose-limiting grade 3 immune-mediated colitis that led to the definition of the maximum tolerated dose (MTD). Other immune-mediated toxicity included uveitis (n = 1), hypophysitis (n = 1), hypothyroidism (n = 2), and grade 3 cytokine release syndrome (CRS) (n = 1). The estimated MTD was 0.2 mg/kg of CP-870,893 and 10 mg/kg of tremelimumab. In 22 evaluable patients, the objective response rate (ORR) was 27.3%: two patients (9.1%) had complete responses (CR) and four (18.2%) patients had partial responses (PR). With a median follow-up of 45 months, the median progression-free survival (PFS) was 3.2 months (95% CI, 1.3–5.1 months) and median overall survival (OS) was 23.6 months (95% CI, 11.7–35.5 months). Nine patients are long-term survivors (> 3 years), 8 of whom subsequently received other therapy including PD-1 mAb, surgery, or radiation therapy. Elevated baseline soluble CD25 was associated with shorter OS. Immunologically, treatment was associated with evidence of T cell activation and increased tumor T cell infiltration that was accomplished without therapeutic PD-1/PD-L1 blockade. These results suggest opportunities for immune activation and cancer immunotherapy beyond PD-1.