Bajor David L, Mick Rosemarie, Riese Matthew J, Huang Alex C, Sullivan Brendan, Richman Lee P, Torigian Drew A, George Sangeeth M, Stelekati Erietta, Chen Fang, Melenhorst J Joseph, Lacey Simon F, Xu Xiaowei, Wherry E John, Gangadhar Tara C, Amaravadi Ravi K, Schuchter Lynn M, Vonderheide Robert H
Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA.
Departments of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA.
Oncoimmunology. 2018 Aug 20;7(10):e1468956. doi: 10.1080/2162402X.2018.1468956. eCollection 2018.
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.
我们报告了在转移性黑色素瘤患者中进行的激动剂CD40单克隆抗体（mAb）和阻断性CTLA-4 mAb 1期试验观察到的长期临床结果和免疫反应。招募了24名先前未接受过检查点阻断治疗的患者。激动性CD40 mAb CP-870,893和CTLA-4阻断性mAb曲美木单抗分别每3周和12周给药一次，共有四种剂量组合。两名患者出现剂量限制性3级免疫介导的结肠炎，这导致了最大耐受剂量（MTD）的确定。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（n = 2）和3级细胞因子释放综合征（CRS）（n = 1）。估计的MTD为CP-870,893 0.2 mg/kg和曲美木单抗10 mg/kg。在22例可评估患者中，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例患者为长期存活者（>3年），其中8例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CD25升高与较短的OS相关。在免疫学上，治疗与T细胞活化证据和肿瘤T细胞浸润增加相关，这是在没有治疗性PD-1/PD-L1阻断的情况下实现的。这些结果表明了超越PD-1的免疫激活和癌症免疫治疗的机会。
