{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T20:28:18Z","timestamp":1792787298653,"version":"4.5.0"},"reference-count":38,"publisher":"BMJ","issue":"1","license":[{"start":{"date-parts":[[2025,1,9]],"date-time":"2025-01-09T00:00:00Z","timestamp":1736380800000},"content-version":"unspecified","delay-in-days":8,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"Shattuck Labs","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2024,12,18]]},"published-print":{"date-parts":[[2025,1]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      SL-172154 is a hexameric fusion protein adjoining the extracellular domain of SIRP\u03b1 to the extracellular domain of CD40L via an inert IgG\n                      <jats:sub>4<\/jats:sub>\n                      -derived Fc domain. In preclinical studies, a murine equivalent SIRP\u03b1-Fc-CD40L fusion protein provided superior antitumor immunity in comparison to CD47- and CD40-targeted antibodies. A first-in-human phase I trial of SL-172154 was conducted in patients with platinum-resistant ovarian cancer.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>SL-172154 was administered intravenously at 0.1, 0.3, 1.0, 3.0, and 10.0\u2009mg\/kg. Dose escalation followed a modified toxicity probability interval-2 design. Objectives included evaluation of safety, dose-limiting toxicity, recommended phase II dose, pharmacokinetic (PK) and pharmacodynamic (PD) parameters, and antitumor activity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      27 patients (median age 66 years (range, 33\u201385); median of 4 prior systemic therapies (range, 2\u20139)) with ovarian (70%), fallopian tube (15%), or primary peritoneal (15%) cancer received SL-172154. Treatment-emergent adverse events (TEAEs) were reported for 27 patients (100%), with 24 (88.9%) having a drug-related TEAE and infusion-related reactions being the most common. 12 patients (44.4%) had grade 3\/4 TEAEs, and half of these patients (22.2%) had a drug-related grade 3\/4 TEAE. There were no fatal adverse events, and no TEAEs led to drug discontinuation. SL-172154 C\n                      <jats:sub>max<\/jats:sub>\n                      and area under the curve increased with dose with greater than proportional exposure noted at 3.0 and 10.0\u2009mg\/kg. CD47 and CD40 target engagement on CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cells and B cells, respectively, approached 100% by 3.0\u2009mg\/kg. Dose-dependent responses in multiple cytokines (eg, interleukin 12 (IL-12), IP-10) approached a plateau at \u22653.0\u2009mg\/kg. Paired tumor biopsies demonstrated a shift in macrophages from an M2- to an M1-dominant phenotype and increased infiltration of CD8 T cells. PK\/PD modeling showed near maximal margination of B cells and a dose-dependent production of IL-12 nearing a plateau at &gt;3.0\u2009mg\/kg. The best response was stable disease in 6\/27 (22%) patients.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>SL-172154 was tolerable as monotherapy and induced, dose-dependent, and cyclical immune cell activation, increases in multiple serum cytokines, and trafficking of CD40-positive B cells and monocytes following each infusion. The safety, PK, and PD activity support 3.0\u2009mg\/kg as a safe and pharmacologically active dose.<\/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=\"NCT04406623\">NCT04406623<\/jats:ext-link>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jitc-2024-010565","type":"journal-article","created":{"date-parts":[[2025,1,11]],"date-time":"2025-01-11T23:45:15Z","timestamp":1736639115000},"page":"e010565","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":25,"title":["First-in-human phase I trial of the bispecific CD47 inhibitor and CD40 agonist Fc-fusion protein, SL-172154 in patients with platinum-resistant ovarian 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