{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T12:26:33Z","timestamp":1792067193594,"version":"4.4.0"},"reference-count":45,"publisher":"BMJ","issue":"10","license":[{"start":{"date-parts":[[2025,10,29]],"date-time":"2025-10-29T00:00:00Z","timestamp":1761696000000},"content-version":"unspecified","delay-in-days":28,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Lava Therapeutics Utrecht, NV, The Netherlands","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":[[2025,10,8]]},"published-print":{"date-parts":[[2025,10]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Despite the notable success of programmed death ligand 1 (PD-L1)\/programmed death 1 (PD-1) immune checkpoint blockade in cancer, resistance remains a substantial challenge. Combining immune checkpoint blockade with direct targeting of effector T cells to tumor cells might improve outcome for a broader spectrum of patients with cancer. Phosphoantigen-responsive V\u03b39V\u03b42-T cells are potent immune cells that play a pivotal role in tumor immunosurveillance and can coordinate downstream immune activity. Here, we explored whether a V\u03b42 bispecific T cell engager (bsTCE) directed against PD-L1 could combine lysis of PD-L1\n                      <jats:sup>+<\/jats:sup>\n                      tumor cells with PD-L1 immune checkpoint blockade.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      PD-L1 specific single domain antibodies (VHHs) were tested for binding to PD-L1 and their ability to interfere with PD-1 binding and function. One PD-L1 VHH was selected for fusion to a V\u03b42-T cell receptor specific VHH (PD-L1xV\u03b42 bsTCE) and tested for its ability to activate V\u03b39V\u03b42-T cells and lyse melanoma cell lines, as well as patient-derived renal cell carcinoma (RCC) and metastatic melanoma cells. These patient-derived tumor suspensions were also used to explore effects on CD4\n                      <jats:sup>+<\/jats:sup>\n                      and CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells and myeloid cells. Infiltration of V\u03b39V\u03b42-T cells and tumor kill was tested in a three-dimensional tumor spheroid melanoma model.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      A PD-L1xV\u03b42 bsTCE was generated and shown to block PD-1 binding resulting in the release of PD-1\n                      <jats:sup>+<\/jats:sup>\n                      cells from PD-L1 mediated inhibition. The PD-L1xV\u03b42 bsTCE also mediated robust V\u03b39V\u03b42-T cell activation, efficient lysis of RCC and melanoma cell lines and\/or patient-derived tumor cells, and infiltration of V\u03b39V\u03b42-T cells into a three-dimensional melanoma spheroid model. Of interest, exposure of co-cultures of V\u03b39V\u03b42-T cells and patient-derived tumor suspensions to the PD-L1xV\u03b42 bsTCE resulted in upregulation of activation markers on tumor-infiltrated CD4\n                      <jats:sup>+<\/jats:sup>\n                      and CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells and lysis of PD-L1\n                      <jats:sup>+<\/jats:sup>\n                      myeloid cells with a shift in the myeloid compartment from macrophage-like cells to more mature dendritic cells with costimulatory molecule expression.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>A PD-L1xV\u03b42 bsTCE was generated that acts as PD-1\/PD-L1 immune checkpoint inhibitor, enhances V\u03b39V\u03b42-T cell activation, infiltration and tumor lysis and reshapes the tumor microenvironment towards a more proinflammatory state. By targeting both PD-L1 expressing tumor and myeloid cells, it addresses key challenges of current therapies and thereby offers a promising novel therapeutic strategy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jitc-2025-012255","type":"journal-article","created":{"date-parts":[[2025,10,29]],"date-time":"2025-10-29T10:41:08Z","timestamp":1761734468000},"page":"e012255","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":7,"title":["PD-L1 directed bispecific V\u03b42-T cell engager combines lysis of PD-L1 expressing tumor cells with PD-1 immune checkpoint inhibition and modulation of the tumor immune microenvironment"],"prefix":"10.1136","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-8705-150X","authenticated-orcid":false,"given":"Lisa A","family":"King","sequence":"first","affiliation":[{"name":"Department of Medical Oncology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands"},{"name":"Cancer Centre Amsterdam, Amsterdam, The Netherlands"},{"name":"Amsterdam Institute for Infection and Immunity, Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Myrthe","family":"Veth","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands"},{"name":"Cancer Centre Amsterdam, Amsterdam, The Netherlands"},{"name":"Amsterdam Institute for Infection and Immunity, Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marieke","family":"Roos","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands"},{"name":"Cancer Centre Amsterdam, Amsterdam, The Netherlands"},{"name":"Amsterdam Institute for Infection and Immunity, Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George L","family":"Scheffer","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands"},{"name":"Cancer Centre Amsterdam, Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marko A","family":"Popovic","sequence":"additional","affiliation":[{"name":"Department of Molecular Cell Biology and Immunology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tanja D","family":"de Gruijl","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands"},{"name":"Cancer Centre Amsterdam, Amsterdam, The Netherlands"},{"name":"Amsterdam Institute for Infection and Immunity, Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hans J","family":"van der Vliet","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands"},{"name":"Cancer Centre Amsterdam, Amsterdam, The Netherlands"},{"name":"Lava Therapeutics NV, Utrecht, The 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