共 30 条
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.
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机构:
Univ Penn, Abramson Canc Ctr, Perelman Sch Med, Philadelphia, PA 19104 USA
Univ Penn, Dept Med, Perelman Sch Med, Philadelphia, PA 19104 USA Univ Penn, Abramson Canc Ctr, Perelman Sch Med, Philadelphia, PA 19104 USA

Mick, Rosemarie
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h-index: 0
机构:
Univ Penn, Abramson Canc Ctr, Perelman Sch Med, Philadelphia, PA 19104 USA
Univ Penn, Perelman Sch Med, Dept Biostat, Philadelphia, PA 19104 USA
Univ Penn, Perelman Sch Med, Dept Epidemiol, Philadelphia, PA 19104 USA
Univ Penn, Perelman Sch Med, Dept Informat, Philadelphia, PA 19104 USA Univ Penn, Abramson Canc Ctr, Perelman Sch Med, Philadelphia, PA 19104 USA

Riese, Matthew J.
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h-index: 0
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Univ Penn, Abramson Canc Ctr, Perelman Sch Med, Philadelphia, PA 19104 USA
Univ Penn, Dept Med, Perelman Sch Med, Philadelphia, PA 19104 USA Univ Penn, Abramson Canc Ctr, Perelman Sch Med, Philadelphia, PA 19104 USA

Huang, Alex C.
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h-index: 0
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Univ Penn, Abramson Canc Ctr, Perelman Sch Med, Philadelphia, PA 19104 USA
Univ Penn, Dept Med, Perelman Sch Med, Philadelphia, PA 19104 USA Univ Penn, Abramson Canc Ctr, Perelman Sch Med, Philadelphia, PA 19104 USA

Sullivan, Brendan
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Univ Penn, Abramson Canc Ctr, Perelman Sch Med, Philadelphia, PA 19104 USA Univ Penn, Abramson Canc Ctr, Perelman Sch Med, Philadelphia, PA 19104 USA

Richman, Lee P.
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h-index: 0
机构:
Univ Penn, Abramson Canc Ctr, Perelman Sch Med, Philadelphia, PA 19104 USA Univ Penn, Abramson Canc Ctr, Perelman Sch Med, Philadelphia, PA 19104 USA

Torigian, Drew A.
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h-index: 0
机构:
Univ Penn, Abramson Canc Ctr, Perelman Sch Med, Philadelphia, PA 19104 USA
Univ Penn, Dept Radiol, Perelman Sch Med, Philadelphia, PA 19104 USA Univ Penn, Abramson Canc Ctr, Perelman Sch Med, Philadelphia, PA 19104 USA

George, Sangeeth M.
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h-index: 0
机构:
Univ Penn, Dept Microbiol, Perelman Sch Med, Philadelphia, PA 19104 USA
Univ Penn, Perelman Sch Med, Inst Immunol, Philadelphia, PA 19104 USA Univ Penn, Abramson Canc Ctr, Perelman Sch Med, Philadelphia, PA 19104 USA

Stelekati, Erietta
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Univ Penn, Dept Microbiol, Perelman Sch Med, Philadelphia, PA 19104 USA
Univ Penn, Perelman Sch Med, Inst Immunol, Philadelphia, PA 19104 USA Univ Penn, Abramson Canc Ctr, Perelman Sch Med, Philadelphia, PA 19104 USA

Chen, Fang
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Univ Penn, Abramson Canc Ctr, Perelman Sch Med, Philadelphia, PA 19104 USA Univ Penn, Abramson Canc Ctr, Perelman Sch Med, Philadelphia, PA 19104 USA

Melenhorst, J. Joseph
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Univ Penn, Abramson Canc Ctr, Perelman Sch Med, Philadelphia, PA 19104 USA Univ Penn, Abramson Canc Ctr, Perelman Sch Med, Philadelphia, PA 19104 USA

Lacey, Simon F.
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Univ Penn, Abramson Canc Ctr, Perelman Sch Med, Philadelphia, PA 19104 USA Univ Penn, Abramson Canc Ctr, Perelman Sch Med, Philadelphia, PA 19104 USA

Xu, Xiaowei
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机构:
Univ Penn, Abramson Canc Ctr, Perelman Sch Med, Philadelphia, PA 19104 USA
Univ Penn, Dept Pathol, Perelman Sch Med, Philadelphia, PA 19104 USA
Univ Penn, Perelman Sch Med, Dept Lab Med, Philadelphia, PA 19104 USA Univ Penn, Abramson Canc Ctr, Perelman Sch Med, Philadelphia, PA 19104 USA

Wherry, E. John
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Univ Penn, Abramson Canc Ctr, Perelman Sch Med, Philadelphia, PA 19104 USA
Univ Penn, Dept Microbiol, Perelman Sch Med, Philadelphia, PA 19104 USA
Univ Penn, Perelman Sch Med, Inst Immunol, Philadelphia, PA 19104 USA Univ Penn, Abramson Canc Ctr, Perelman Sch Med, Philadelphia, PA 19104 USA

Gangadhar, Tara C.
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Univ Penn, Abramson Canc Ctr, Perelman Sch Med, Philadelphia, PA 19104 USA
Univ Penn, Dept Med, Perelman Sch Med, Philadelphia, PA 19104 USA Univ Penn, Abramson Canc Ctr, Perelman Sch Med, Philadelphia, PA 19104 USA

Amaravadi, Ravi K.
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Univ Penn, Abramson Canc Ctr, Perelman Sch Med, Philadelphia, PA 19104 USA
Univ Penn, Dept Med, Perelman Sch Med, Philadelphia, PA 19104 USA Univ Penn, Abramson Canc Ctr, Perelman Sch Med, Philadelphia, PA 19104 USA

Schuchter, Lynn M.
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h-index: 0
机构:
Univ Penn, Abramson Canc Ctr, Perelman Sch Med, Philadelphia, PA 19104 USA
Univ Penn, Dept Med, Perelman Sch Med, Philadelphia, PA 19104 USA Univ Penn, Abramson Canc Ctr, Perelman Sch Med, Philadelphia, PA 19104 USA

Vonderheide, Robert H.
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h-index: 0
机构:
Univ Penn, Abramson Canc Ctr, Perelman Sch Med, Philadelphia, PA 19104 USA
Univ Penn, Dept Med, Perelman Sch Med, Philadelphia, PA 19104 USA
Univ Penn, Perelman Sch Med, Inst Immunol, Philadelphia, PA 19104 USA Univ Penn, Abramson Canc Ctr, Perelman Sch Med, Philadelphia, PA 19104 USA
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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共 30 条
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Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA
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Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA
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Torigian, Drew A.
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Mick, Rosemarie
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Univ Penn, Perelman Sch Med, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA

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Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA
Univ Penn, Perelman Sch Med, Dept Med, Philadelphia, PA 19104 USA Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA

Schuchter, Lynn M.
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Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA
Univ Penn, Abramson Family Canc Res Inst, Philadelphia, PA 19104 USA
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Kalos, Michael
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Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA
Univ Penn, Perelman Sch Med, Dept Pathol, Philadelphia, PA 19104 USA Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA

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Univ Penn, Abramson Family Canc Res Inst, Sch Med, Philadelphia, PA 19104 USA
Univ Penn, Abramson Canc Ctr, Sch Med, Philadelphia, PA 19104 USA
Univ Penn, Div Hematol Oncol, Sch Med, Dept Med, Philadelphia, PA 19104 USA Univ Penn, Abramson Family Canc Res Inst, Sch Med, Philadelphia, PA 19104 USA
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Leiden Univ, Med Ctr, Dept Immunohematol & Blood Transfus, NL-2300 RC Leiden, Netherlands Leiden Univ, Med Ctr, Dept Immunohematol & Blood Transfus, NL-2300 RC Leiden, Netherlands

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Leiden Univ, Med Ctr, Dept Immunohematol & Blood Transfus, NL-2300 RC Leiden, Netherlands Leiden Univ, Med Ctr, Dept Immunohematol & Blood Transfus, NL-2300 RC Leiden, Netherlands

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Leiden Univ, Med Ctr, Dept Immunohematol & Blood Transfus, NL-2300 RC Leiden, Netherlands
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YALE UNIV,SCH MED,HOWARD HUGHES MED INST,IMMUNOBIOL SECT,NEW HAVEN,CT 06510 YALE UNIV,SCH MED,HOWARD HUGHES MED INST,IMMUNOBIOL SECT,NEW HAVEN,CT 06510