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

Nature Medicine
Alexander C HuangTara C Mitchell

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-ris...Continue Reading

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Methods Mentioned

BETA
biopsy
surgical resection
exome sequencing
biopsies
blood draw
Assay
genotyping

Clinical Trials Mentioned

NCT02434354

Software Mentioned

NetMHCcons
Integrative Genomics Viewer
ggplot2
nCounter
MuTect2
NanoString
R package pheatmap
SPSS
Variant Effect Predictor
MuTect

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