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A single dose of neoadjuvant PD-1 blockade predicts clinical outcomes in resectable melanoma.

Huang, Alexander C; Orlowski, Robert J; Xu, Xiaowei; Mick, Rosemarie; George, Sangeeth M; Yan, Patrick K; Manne, Sasikanth; Kraya, Adam A; Wubbenhorst, Bradley; Dorfman, Liza; D'Andrea, Kurt; Wenz, Brandon M; Liu, Shujing; Chilukuri, Lakshmi; Kozlov, Andrew; Carberry, Mary; Giles, Lydia; Kier, Melanie W; Quagliarello, Felix; McGettigan, Suzanne; Kreider, Kristin; Annamalai, Lakshmanan; Zhao, Qing; Mogg, Robin; Xu, Wei; Blumenschein, Wendy M; Yearley, Jennifer H; Linette, Gerald P; Amaravadi, Ravi K; Schuchter, Lynn M; Herati, Ramin S; Bengsch, Bertram; Nathanson, Katherine L; Farwell, Michael D; Karakousis, Giorgos C; Wherry, E John; Mitchell, Tara C.
Nat Med; 25(3): 454-461, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30804515
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.
Selo DaSilva