{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T00:30:09Z","timestamp":1778805009957,"version":"3.51.4"},"reference-count":41,"publisher":"BMJ","issue":"1","license":[{"start":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T00:00:00Z","timestamp":1768521600000},"content-version":"unspecified","delay-in-days":15,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100004337","name":"F. Hoffmann-La Roche Ltd","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100004337","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2025,12,1]]},"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Cergutuzumab amunaleukin (CA) is an immunocytokine comprising an anticarcinoembryonic antigen (CEA) linked to an interleukin-2 (IL-2) variant. CA does not bind to CD25 (IL-2 receptor \u03b1) and was designed to maintain the T and natural killer (NK) cell stimulatory effect, while avoiding stimulating effects on regulatory T cells (Tregs). In mouse models, CA previously demonstrated superior tumor targeting to CEA surface expression-positive (CEA+) tumors and increased CD8+ T\u2009cells and NK cell numbers in peripheral blood and tumor tissue when compared with wild-type IL-2. We present biomarker data from the first-in-human, open-label, multicenter, phase I, dose-escalation study investigating CA in patients with metastatic\/unresectable CEA+ solid tumors (\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"clintrialgov\" xlink:href=\"NCT02004106\">NCT02004106<\/jats:ext-link>\n                      ).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Patients received ascending doses of CA intravenously weekly (qw: 6\/10\/20\u2009mg) or every 2\u2009weeks (q2w: 10\/20\/30\/40\u2009mg). Flow cytometry determined absolute numbers\/mL of CD4+ and\u2009CD8+ T\u2009cells, NK cells, macrophages\/monocytes, Tregs, and B cells and their expression of activation and proliferation markers in circulation. Sequential pretreatment and on-treatment paired tumor biopsies were studied by flow cytometry, multicolor immunohistochemistry, and bulk RNA sequencing. Antitumor activity was used for correlative studies.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Biomarker data were collected from 55\u2009patients. After treatment, peripheral blood samples showed increased proliferating NK cells, CD8+ T\u2009cells, and CD4+ T\u2009cells, without an apparent dose effect. Levels of circulating soluble CD25 increased in patients with intermediate\/high CA doses on-treatment; levels of cytokines, such as tumor necrosis factor, also increased with high CA dose levels. On-treatment tumor samples showed increases in total and proliferating CD8+ T\u2009cells as well as CD3+ perforin+ T cells but, importantly, not in Tregs. Notably, increases in the ratio of CD8+\/CD4+ T\u2009cells were more pronounced for qw than for q2w dosing, while programmed death ligand-1-positive CD14+ cells increased, particularly for the q2w schedule. Higher on-treatment circulating levels of cytokines correlated with longer progression-free survival (PFS). Apart from the positive correlation with NK cell density, no other correlations between PFS and infiltrating immune cell populations in the tumor were observed.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>CA-induced immune pharmacodynamic effects in peripheral blood and in the tumor microenvironment without preferential Treg cell activation in patients with metastatic\/unresectable CEA+ solid tumors.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Trial registration number<\/jats:title>\n                    <jats:p>\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"clintrialgov\" xlink:href=\"NCT02004106\">NCT02004106<\/jats:ext-link>\n                      ; BP28920\n                    <\/jats:p>\n                  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