A single dose of neoadjuvant PD-1 blockade predicts clinical outcomes in resectable melanoma.
Alexander C HuangRobert J OrlowskiXiaowei XuRosemarie MickSangeeth M GeorgePatrick K YanSasikanth ManneAdam A KrayaBradley WubbenhorstLiza DorfmanKurt D'AndreaBrandon M WenzShujing LiuLakshmi ChilukuriAndrew KozlovMary CarberryLydia GilesMelanie W KierFelix QuagliarelloSuzanne McGettiganKristin KreiderLakshmanan AnnamalaiQing ZhaoRobin MoggWei XuWendy M BlumenscheinJennifer H YearleyGerald P LinetteRavi K AmaravadiLynn M SchuchterRamin S HeratiBertram BengschKatherine L NathansonMichael D FarwellGiorgos C KarakousisE John WherryTara C MitchellPublished in: Nature medicine (2019)
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.
Keyphrases
- locally advanced
- rectal cancer
- lymph node
- end stage renal disease
- free survival
- neoadjuvant chemotherapy
- ejection fraction
- newly diagnosed
- chronic kidney disease
- stem cells
- early stage
- prognostic factors
- magnetic resonance imaging
- clinical trial
- patient reported outcomes
- computed tomography
- skin cancer
- bone marrow
- gestational age
- cell proliferation
- preterm birth
- loop mediated isothermal amplification
- basal cell carcinoma
- data analysis