{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T01:52:02Z","timestamp":1793238722367,"version":"4.5.0"},"reference-count":70,"publisher":"BMJ","issue":"4","license":[{"start":{"date-parts":[[2025,4,10]],"date-time":"2025-04-10T00:00:00Z","timestamp":1744243200000},"content-version":"unspecified","delay-in-days":9,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100032339","name":"BioNTech","doi-asserted-by":"crossref","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"10.13039\/100032339","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100032702","name":"Genmab","doi-asserted-by":"crossref","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"10.13039\/100032702","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2025,3,24]]},"published-print":{"date-parts":[[2025,4]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Next-generation cancer immunotherapies aim to improve patient outcomes by combining inhibitory signal blockade with targeted T-cell costimulation in tumor and lymphoid tissues. Acasunlimab (DuoBody-PD-L1\u00d74-1BB) is an investigational, bispecific antibody designed to elicit an antitumor immune response via conditional 4-1BB activation strictly dependent on simultaneous programmed death-ligand 1 (PD-L1) binding. Since 4-1BB is coexpressed with programmed cell death protein-1 (PD-1) on CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells, PD-1 blockade and simultaneous costimulation through 4-1BB may synergistically enhance T-cell effector functions. We hypothesized that combining acasunlimab with PD-1 blockade to fully disrupt PD-1 interactions with both PD-L1 and PD-L2 would amplify the depth and duration of antitumor immunity.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>The effect of acasunlimab and pembrolizumab combination was analyzed in vitro using functional immune cell assays, including mixed-lymphocyte reactions and antigen-specific T-cell proliferation and cytotoxicity assays. The antitumor activity of the combination was tested in vivo in (1) MC38, MB49, Pan02, and B16F10 syngeneic tumor models using acasunlimab and anti-PD-1 mouse-surrogate antibodies; and (2) triple knock-in mice expressing the human targets using an acasunlimab chimeric antibody (chi-acasunlimab) and pembrolizumab. The mechanism of action of the combination was investigated in the MC38 syngeneic model through immunohistochemistry, flow cytometry, and bulk RNA sequencing.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      The combination reinvigorated dysfunctional T cells in vitro, while also potentiating T-cell expansion, interleukin (IL)-2 and interferon gamma secretion and cytotoxic activity. In vivo, the combination of chi-acasunlimab and pembrolizumab or mouse-surrogate antibodies potentiated antitumor activity and survival in the humanized knock-in and multiple syngeneic mouse models, leading to durable complete tumor regressions in the MC38 model consistent with therapeutic synergy. Mechanistically, the combination enhanced clonal expansion of tumor-specific CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells in tumor-draining lymph nodes and increased the density of proliferating and cytotoxic CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells in the tumor microenvironment. It also potentiated the IL-2 signaling pathway, increasing the proportion of granzyme B (GZMB\n                      <jats:sup>+<\/jats:sup>\n                      ) stem-like CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells thought to have superior effector function.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      These preclinical results demonstrate that conditional 4-1BB stimulation combined with complete PD-1 blockade enhances antitumor immunity through complementary mechanisms. The acasunlimab and pembrolizumab combination is being evaluated in Phase 2 (\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"clintrialgov\" xlink:href=\"NCT05117242\">NCT05117242<\/jats:ext-link>\n                      ) and pivotal Phase 3 (\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"clintrialgov\" xlink:href=\"NCT06635824\">NCT06635824<\/jats:ext-link>\n                      ) trials in patients with metastatic non-small cell lung cancer after checkpoint inhibitor therapy failure.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jitc-2024-011377","type":"journal-article","created":{"date-parts":[[2025,4,11]],"date-time":"2025-04-11T02:00:16Z","timestamp":1744336816000},"page":"e011377","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":17,"title":["Acasunlimab, an Fc-inert PD-L1\u00d74-1BB bispecific antibody, combined with PD-1 blockade potentiates antitumor immunity via complementary immune modulatory effects"],"prefix":"10.1136","volume":"13","clinical-trial-number":[{"clinical-trial-number":"nct05117242","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct06635824","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct06635824","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct03917381","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct04937153","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct05117242","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct06635824","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct05117242","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct06635824","registry":"10.18810\/clinical-trials-gov"}],"author":[{"given":"Michela","family":"Capello","sequence":"first","affiliation":[{"name":"Genmab BV, Utrecht, 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