The DOI matches its Crossref record; 75 of the 76 references it cites were found in a registry or an index.
Tumor and Microenvironment Evolution during Immunotherapy with Nivolumab
Open accessAbstract
The mechanisms by which immune checkpoint blockade modulates tumor evolution during therapy are unclear. We assessed genomic changes in tumors from 68 patients with advanced melanoma, who progressed on ipilimumab or were ipilimumab-naive, before and after nivolumab initiation (CA209-038 study). Tumors were analyzed by whole-exome, transcriptome, and/or T cell receptor (TCR) sequencing. In responding patients, mutation and neoantigen load were reduced from baseline, and analysis of intratumoral heterogeneity during therapy demonstrated differential clonal evolution within tumors and putative selection against neoantigenic mutations on-therapy. Transcriptome analyses before and during nivolumab therapy revealed increases in distinct immune cell subsets, activation of specific transcriptional networks, and upregulation of immune checkpoint genes that were more pronounced in patients with response. Temporal changes in intratumoral TCR repertoire revealed expansion of T cell clones in the setting of neoantigen loss. Comprehensive genomic profiling data in this study provide insight into nivolumab's mechanism of action.
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Metadata
- Authors
- Riaz, N., Havel, J. J., Makarov, V., Desrichard, A., Urba, W. J., Sims, J. S., Hodi, F. S., Martín-Algarra, S., Mandal, R., Sharfman, W. H., Bhatia, S., Hwu, W.-J., Gajewski, T. F., Slingluff, C. L., Chowell, D., Kendall, S. M., Chang, H., Shah, R., Kuo, F., Morris, L. G. T., Sidhom, J.-W., Schneck, J. P., Horak, C. E., Weinhold, N., & Chan, T. A.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- Providence Portland Medical Center (US)
- Dana-Farber Cancer Institute (US)
- Johns Hopkins University (US)
- University of Washington (US)
- The University of Texas MD Anderson Cancer Center (US)
- University of Chicago (US)
- University of Virginia Medical Center (US)
- Bristol-Myers Squibb (United States) (US)
- Corresponding author
- Weinhold, Nils
- Chan, Timothy A.
- ORCID
- Riaz, Nadeem
- Havel, Jonathan J.
- Makarov, Vladimir
- Desrichard, Alexis
- Urba, Walter J.
- Hodi, F. Stephen
- Mandal, Rajarsi
- Sharfman, William H.
- Bhatia, Shailender
- Hwu, Wen-Jen
- Gajewski, Thomas F.
- Slingluff, Craig L.
- Chowell, Diego
- Kendall, Sviatoslav M.
- Chang, Han
- Shah, Rachna
- Kuo, Fengshen
- Morris, Luc G.T.
- Sidhom, John-William
- Schneck, Jonathan P.
- Weinhold, Nils
- Chan, Timothy A.
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2017-11
- Volume
- 171
- Issue
- 4
- Pages
- 934-949.e16
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC5685550
- OpenAlex
- W2761575992
- Cited by
- 2,401
- References
- 76
- Citations by year
- 2026: 205 · 2025: 264 · 2024: 365 · 2023: 365 · 2022: 334 · 2021: 333 · 2020: 242 · 2019: 173 · 2018: 105 · 2017: 10
- FWCI
- 63.48
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Bristol-Myers Squibb
- Pershing Square Sohn Cancer Research Foundation
- PaineWebber Chair
- Stand Up 2 Cancer
- Memorial Sloan Kettering Cancer Center (5P30 CA008748-50)
- STARR Cancer Consortium
- Abraxis
- Amgen
- Bionomics
- EMD Serono
- Immune Design
- Immunogen
- Merck
- NantKwest
- OncoSec
- Incyte
- Ono
- Genentech
- Seattle Genetics
- GlaxoSmithKline
- MedImmune
- NexImmune
- Polynoma
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- nivolumab, immune checkpoint blockade, melanoma, tumor evolution, intratumoral heterogeneity, neoantigens, clonal evolution, T cell receptor repertoire, immune cell transcriptome, immune checkpoint genes, ipilimumab, tumor mutational burden, treatment response
- MeSH terms
- Nivolumab, Antibodies, Monoclonal, Antineoplastic Agents, Humans, Immunotherapy, Melanoma, T-Lymphocytes, Genome-Wide Association Study, Tumor Microenvironment, Transcriptome, Programmed Cell Death 1 Receptor
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