دورية أكاديمية
A single dose of neoadjuvant PD-1 blockade predicts clinical outcomes in resectable melanoma.
| العنوان: | A single dose of neoadjuvant PD-1 blockade predicts clinical outcomes in resectable melanoma. |
|---|---|
| المؤلفون: | Huang AC; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. alexander.huang@uphs.upenn.edu.; Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. alexander.huang@uphs.upenn.edu.; Parker Institute for Cancer Immunotherapy at University of Pennsylvania, Philadelphia, PA, USA. alexander.huang@uphs.upenn.edu.; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. alexander.huang@uphs.upenn.edu., Orlowski RJ; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.; Merck & Co., Inc., Kenilworth, NJ, USA., Xu X; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Mick R; Parker Institute for Cancer Immunotherapy at University of Pennsylvania, Philadelphia, PA, USA.; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.; Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., George SM; Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.; Bristol-Myers Squibb, Lawrenceville, NJ, USA., Yan PK; Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.; Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Manne S; Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.; Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Kraya AA; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Wubbenhorst B; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Dorfman L; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., D'Andrea K; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Wenz BM; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Liu S; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Chilukuri L; Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.; Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Kozlov A; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.; Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Carberry M; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Giles L; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Kier MW; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Quagliarello F; Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.; Stem Cell Technologies, Vancouver, British Columbia, Canada., McGettigan S; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Kreider K; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Annamalai L; Merck Research Laboratories, Kenilworth, NJ, USA., Zhao Q; Merck Research Laboratories, Kenilworth, NJ, USA., Mogg R; Merck Research Laboratories, Kenilworth, NJ, USA.; Bill & Melinda Gates Medical Research Institute, Cambridge, MA, USA., Xu W; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Blumenschein WM; Merck Research Laboratories, Kenilworth, NJ, USA., Yearley JH; Merck Research Laboratories, Kenilworth, NJ, USA., Linette GP; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.; Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.; Parker Institute for Cancer Immunotherapy at University of Pennsylvania, Philadelphia, PA, USA.; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Amaravadi RK; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Schuchter LM; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Herati RS; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.; Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Bengsch B; Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.; Department of Medicine II, Gastroenterology, Hepatology, Endocrinology, and Infectious Diseases, University Medical Center Freiburg, Freiburg, Germany., Nathanson KL; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.; Parker Institute for Cancer Immunotherapy at University of Pennsylvania, Philadelphia, PA, USA.; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Farwell MD; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.; Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Karakousis GC; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.; Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Wherry EJ; Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. wherry@pennmedicine.upenn.edu.; Parker Institute for Cancer Immunotherapy at University of Pennsylvania, Philadelphia, PA, USA. wherry@pennmedicine.upenn.edu.; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. wherry@pennmedicine.upenn.edu.; Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. wherry@pennmedicine.upenn.edu., Mitchell TC; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. tara.mitchell@uphs.upenn.edu.; Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. tara.mitchell@uphs.upenn.edu. |
| المصدر: | Nature medicine [Nat Med] 2019 Mar; Vol. 25 (3), pp. 454-461. Date of Electronic Publication: 2019 Feb 25. |
| نوع المنشور: | Clinical Trial, Phase I; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: Nature Publishing Company Country of Publication: United States NLM ID: 9502015 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1546-170X (Electronic) Linking ISSN: 10788956 NLM ISO Abbreviation: Nat Med Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: New York Ny : Nature Publishing Company Original Publication: New York, NY : Nature Pub. Co., [1995- |
| مواضيع طبية MeSH: | Dermatologic Surgical Procedures*, Antibodies, Monoclonal, Humanized/*therapeutic use , Antineoplastic Agents, Immunological/*therapeutic use , Melanoma/*drug therapy , Skin Neoplasms/*drug therapy, Adult ; Aged ; Aged, 80 and over ; CD8-Positive T-Lymphocytes ; Chemotherapy, Adjuvant ; Female ; Gene Expression Profiling ; Humans ; Kaplan-Meier Estimate ; Male ; Melanoma/pathology ; Middle Aged ; Neoadjuvant Therapy ; Neoplasm Staging ; Proportional Hazards Models ; Skin Neoplasms/pathology ; Transcriptome ; Tumor Escape |
| مستخلص: | 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. |
| التعليقات: | Comment in: Nat Rev Clin Oncol. 2019 May;16(5):272. doi: 10.1038/s41571-019-0196-2. (PMID: 30837713) |
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| معلومات مُعتمدة: | P01 AI108545 United States AI NIAID NIH HHS; K08 AI114852 United States AI NIAID NIH HHS; P01 CA114046 United States CA NCI NIH HHS; P01 CA210944 United States CA NCI NIH HHS; T32 CA009615 United States CA NCI NIH HHS; R01 AI105343 United States AI NIAID NIH HHS; U19 AI082630 United States AI NIAID NIH HHS; P50 CA174523 United States CA NCI NIH HHS; P30 CA016520 United States CA NCI NIH HHS; U19 AI117950 United States AI NIAID NIH HHS |
| المشرفين على المادة: | 0 (Antibodies, Monoclonal, Humanized) 0 (Antineoplastic Agents, Immunological) DPT0O3T46P (pembrolizumab) |
| تواريخ الأحداث: | Date Created: 20190227 Date Completed: 20190513 Latest Revision: 20240719 |
| رمز التحديث: | 20240719 |
| مُعرف محوري في PubMed: | PMC6699626 |
| DOI: | 10.1038/s41591-019-0357-y |
| PMID: | 30804515 |
| قاعدة البيانات: | MEDLINE |
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