@article{089474be1e574c38932d70a11c6d7c5e,
title = "A single dose of neoadjuvant PD-1 blockade predicts clinical outcomes in resectable melanoma",
abstract = "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.",
author = "Huang, {Alexander C.} and Orlowski, {Robert J.} and Xiaowei Xu and Rosemarie Mick and George, {Sangeeth M.} and Yan, {Patrick K.} and Sasikanth Manne and Kraya, {Adam A.} and Bradley Wubbenhorst and Liza Dorfman and Kurt D{\textquoteright}Andrea and Wenz, {Brandon M.} and Shujing Liu and Lakshmi Chilukuri and Andrew Kozlov and Mary Carberry and Lydia Giles and Kier, {Melanie W.} and Felix Quagliarello and Suzanne McGettigan and Kristin Kreider and Lakshmanan Annamalai and Qing Zhao and Robin Mogg and Wei Xu and Blumenschein, {Wendy M.} and Yearley, {Jennifer H.} and Linette, {Gerald P.} and Amaravadi, {Ravi K.} and Schuchter, {Lynn M.} and Herati, {Ramin S.} and Bertram Bengsch and Nathanson, {Katherine L.} and Farwell, {Michael D.} and Karakousis, {Giorgos C.} and Wherry, {E. John} and Mitchell, {Tara C.}",
note = "Funding Information: Clinical and correlative studies were supported in part by the SPORE in Skin Cancer: P50-CA174523 (X.X., K.L.N., L.M.S., R.K.A., R.M., G.C.K.), P01-CA114046 (X.X.), T32-2T32CA009615 (A.C.H.); the NIH/NCI Cancer Center Support Grant P30-CA016520 (R.K.A., K.L.N., L.M.S., R.M.), and NIH grants AI105343, AI108545, AI117950, AI082630, CA210944 (E.J.W.), and AI114852 (R.S.H.); the Tara Miller Foundation (A.C.H.); the Melanoma Research Alliance (E.J.W.); the David and Hallee Adelman Immunotherapy Research Fund (E.J.W.); the Heisenberg program BE5496/2-1 of the DFG (B.B.); and the Parker Institute for Cancer Immunotherapy Bridge Scholar Award (A.C.H.). Merck, Inc. supplied drugs and supported clinical and translational aspects of this study. The Human Immunology Core and the Tumor Tissue and Biospecimen Bank of the University of Pennsylvania (supported by P30-CA016520) assisted in tissue collection, processing, and storage. Publisher Copyright: {\textcopyright} 2019, The Author(s), under exclusive licence to Springer Nature America, Inc.",
year = "2019",
month = mar,
day = "1",
doi = "10.1038/s41591-019-0357-y",
language = "English (US)",
volume = "25",
pages = "454--461",
journal = "Nature Medicine",
issn = "1078-8956",
publisher = "Nature Publishing Group",
number = "3",
}