Long-term outcomes of a phase I study of agonist CD40 antibody and CTLA-4 blockade in patients with metastatic melanoma

被引:88
作者
Bajor, David L. [1 ,2 ]
Mick, Rosemarie [1 ,3 ,4 ,5 ]
Riese, Matthew J. [1 ,2 ]
Huang, Alex C. [1 ,2 ]
Sullivan, Brendan [1 ]
Richman, Lee P. [1 ]
Torigian, Drew A. [1 ,8 ]
George, Sangeeth M. [9 ,10 ]
Stelekati, Erietta [9 ,10 ]
Chen, Fang [1 ]
Melenhorst, J. Joseph [1 ]
Lacey, Simon F. [1 ]
Xu, Xiaowei [1 ,6 ,7 ]
Wherry, E. John [1 ,9 ,10 ]
Gangadhar, Tara C. [1 ,2 ]
Amaravadi, Ravi K. [1 ,2 ]
Schuchter, Lynn M. [1 ,2 ]
Vonderheide, Robert H. [1 ,2 ,10 ]
机构
[1] Univ Penn, Abramson Canc Ctr, Perelman Sch Med, Philadelphia, PA 19104 USA
[2] Univ Penn, Dept Med, Perelman Sch Med, Philadelphia, PA 19104 USA
[3] Univ Penn, Perelman Sch Med, Dept Biostat, Philadelphia, PA 19104 USA
[4] Univ Penn, Perelman Sch Med, Dept Epidemiol, Philadelphia, PA 19104 USA
[5] Univ Penn, Perelman Sch Med, Dept Informat, Philadelphia, PA 19104 USA
[6] Univ Penn, Dept Pathol, Perelman Sch Med, Philadelphia, PA 19104 USA
[7] Univ Penn, Perelman Sch Med, Dept Lab Med, Philadelphia, PA 19104 USA
[8] Univ Penn, Dept Radiol, Perelman Sch Med, Philadelphia, PA 19104 USA
[9] Univ Penn, Dept Microbiol, Perelman Sch Med, Philadelphia, PA 19104 USA
[10] Univ Penn, Perelman Sch Med, Inst Immunol, Philadelphia, PA 19104 USA
关键词
CD40; CTLA4; melanoma; CANCER-THERAPY; PANCREATIC-CARCINOMA; MONOCLONAL-ANTIBODY; IMMUNE MODULATION; DENDRITIC CELL; CLINICAL-TRIAL; CP-870,893; RESPONSES; TREMELIMUMAB; COMBINATION;
D O I
10.1080/2162402X.2018.1468956
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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.
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页数:11
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