{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T12:10:16Z","timestamp":1784635816987,"version":"3.55.0"},"reference-count":54,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2024,5,20]],"date-time":"2024-05-20T00:00:00Z","timestamp":1716163200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,7,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>High-dose (HD) IL-2 was the first immuno-oncology agent approved for treating advanced renal cell carcinoma and metastatic melanoma, but its use was limited because of substantial toxicities. Multiple next-generation IL-2 agents are being developed to improve tolerability. However, a knowledge gap still exists for the genomic markers that define the target pharmacology for HD IL-2 itself. In this retrospective observational study, we collected PBMC samples from 23 patients with metastatic renal cell carcinoma who were treated with HD IL-2 between 2009 and 2015. We previously reported the results of flow cytometry analyses. In this study, we report the results of our RNA-sequencing immunogenomic survey, which was performed on bulk PBMC samples from immediately before (day 1), during (day 3), and after treatment (day 5) in cycle 1 and\/or cycle 2 of the first course of HD IL-2. As part of a detailed analysis of immunogenomic response to HD IL-2 treatment, we analyzed the changes in individual genes and immune gene signatures. By day 3, most lymphoid cell types had transiently decreased, whereas myeloid transcripts increased. Although most genes and\/or signatures generally returned to pretreatment expression levels by day 5, certain ones representative of B cell, NK cell, and T cell proliferation and effector functions continued to increase, along with B cell (but not T cell) oligoclonal expansion. Regulatory T cells progressively expanded during and after treatment. They showed strong negative correlation with myeloid effector cells. This detailed RNA-sequencing immunogenomic survey of IL-2 pharmacology complements results of prior flow cytometry analyses. These data provide valuable pharmacological context for assessing PBMC gene expression data from patients dosed with IL-2\u2013related compounds that are currently in development.<\/jats:p>","DOI":"10.4049\/jimmunol.2300736","type":"journal-article","created":{"date-parts":[[2024,5,20]],"date-time":"2024-05-20T13:26:31Z","timestamp":1716211591000},"page":"29-39","source":"Crossref","is-referenced-by-count":3,"title":["The Immunogenomic Landscape of Peripheral High-Dose IL-2 Pharmacodynamics in Patients with Metastatic Renal Cell Carcinoma: A Benchmark for Next-Generation IL-2\u2013Based Immunotherapies"],"prefix":"10.1093","volume":"213","author":[{"given":"Kirk D","family":"Beebe","sequence":"first","affiliation":[{"name":"GeneCentric Therapeutics, Inc. , Durham, NC"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joel R","family":"Eisner","sequence":"additional","affiliation":[{"name":"GeneCentric Therapeutics, Inc. , Durham, NC"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1287-1906","authenticated-orcid":false,"given":"John","family":"Guo","sequence":"additional","affiliation":[{"name":"GeneCentric Therapeutics, Inc. , Durham, NC"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4539-0172","authenticated-orcid":false,"given":"Yoichiro","family":"Shibata","sequence":"additional","affiliation":[{"name":"GeneCentric Therapeutics, Inc. , Durham, NC"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2453-7227","authenticated-orcid":false,"given":"James M","family":"Davison","sequence":"additional","affiliation":[{"name":"GeneCentric Therapeutics, Inc. , Durham, NC"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Josh","family":"Uronis","sequence":"additional","affiliation":[{"name":"GeneCentric Therapeutics, Inc. , Durham, NC"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9189-983X","authenticated-orcid":false,"given":"Carol","family":"Farhangfar","sequence":"additional","affiliation":[{"name":"Levine Cancer Institute, Atrium Health , Charlotte, NC"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-2663-053X","authenticated-orcid":false,"given":"Farhang","family":"Farhangfar","sequence":"additional","affiliation":[{"name":"Levine Cancer Institute, Atrium Health , Charlotte, NC"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jill","family":"Mooney","sequence":"additional","affiliation":[{"name":"Synthorx \u2013 A Sanofi Company , La Jolla, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael V","family":"Milburn","sequence":"additional","affiliation":[{"name":"GeneCentric Therapeutics, Inc. , Durham, NC"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6559-8312","authenticated-orcid":false,"given":"Richard L","family":"White","sequence":"additional","affiliation":[{"name":"Levine Cancer Institute, Atrium Health , Charlotte, NC"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Asim","family":"Amin","sequence":"additional","affiliation":[{"name":"Levine Cancer Institute, Atrium Health , Charlotte, NC"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6446-2085","authenticated-orcid":false,"given":"Marcos E","family":"Milla","sequence":"additional","affiliation":[{"name":"Synthorx \u2013 A Sanofi Company , La Jolla, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4230-8356","authenticated-orcid":false,"given":"David M","family":"Foureau","sequence":"additional","affiliation":[{"name":"Levine Cancer Institute, Atrium Health , Charlotte, NC"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2024,5,20]]},"reference":[{"key":"2025012305101585900_r1","doi-asserted-by":"crossref","first-page":"884","DOI":"10.1084\/jem.157.3.884","article-title":"Lymphokine-activated killer cell phenomenon. 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