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

Alexander C. Huang, Robert J. Orlowski, Xiaowei Xu, Rosemarie Mick, Sangeeth M. George, Patrick K. Yan, Sasikanth Manne, Adam A. Kraya, Bradley Wubbenhorst, Liza Dorfman, Kurt D’Andrea, Brandon M. Wenz, Shujing Liu, Lakshmi Chilukuri, Andrew Kozlov, Mary Carberry, Lydia Giles, Melanie W. Kier, Felix Quagliarello, Suzanne McGettiganKristin Kreider, Lakshmanan Annamalai, Qing Zhao, Robin Mogg, Wei Xu, Wendy M. Blumenschein, Jennifer H. Yearley, Gerald P. Linette, Ravi K. Amaravadi, Lynn M. Schuchter, Ramin S. Herati, Bertram Bengsch, Katherine L. Nathanson, Michael D. Farwell, Giorgos C. Karakousis, E. John Wherry, Tara C. Mitchell

Research output: Contribution to journalArticlepeer-review

171 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)454-461
Number of pages8
JournalNature medicine
Volume25
Issue number3
DOIs
StatePublished - Mar 1 2019
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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