期刊
NATURE MEDICINE
卷 25, 期 3, 页码 454-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41591-019-0357-y
关键词
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资金
- SPORE in Skin Cancer [P50-CA174523, P01-CA114046, T32-2T32CA009615]
- NIH/NCI Cancer Center [P30-CA016520]
- NIH [AI105343, AI108545, AI117950, AI082630, CA210944, AI114852]
- Tara Miller Foundation
- Melanoma Research Alliance
- David and Hallee Adelman Immunotherapy Research Fund
- DFG [BE5496/2-1]
- Parker Institute for Cancer Immunotherapy Bridge Scholar Award
- Merck, Inc.
Immunologic responses to anti-PD-1 therapy in melanoma patients occur rapidly with pharmacodynamic T cell responses detectable in blood by 3 weeks. It is unclear, however, whether these early blood-based observations translate to the tumor microenvironment. We conducted a study of neoadjuvant/adjuvant anti-PD-1 therapy in stage III/IV melanoma. We hypothesized that immune reinvigoration in the tumor would be detectable at 3 weeks and that this response would correlate with disease-free survival. We identified a rapid and potent anti-tumor response, with 8 of 27 patients experiencing a complete or major pathological response after a single dose of anti-PD-1, all of whom remain disease free. These rapid pathologic and clinical responses were associated with accumulation of exhausted CD8 T cells in the tumor at 3 weeks, with reinvigoration in the blood observed as early as 1 week. Transcriptional analysis demonstrated a pretreatment immune signature (neoadjuvant response signature) that was associated with clinical benefit. In contrast, patients with disease recurrence displayed mechanisms of resistance including immune suppression, mutational escape, and/or tumor evolution. Neoadjuvant anti-PD-1 treatment is effective in high-risk resectable stage III/IV melanoma. Pathological response and immunological analyses after a single neoadjuvant dose can be used to predict clinical outcome and to dissect underlying mechanisms in checkpoint blockade.
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