{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T07:48:49Z","timestamp":1782719329614,"version":"3.54.5"},"reference-count":62,"publisher":"BMJ","issue":"6","license":[{"start":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T00:00:00Z","timestamp":1782432000000},"content-version":"unspecified","delay-in-days":25,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"LAVA therapeutics NV","award":["NA"],"award-info":[{"award-number":["NA"]}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2026,6,11]]},"published-print":{"date-parts":[[2026,6]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>V\u03b39V\u03b42-T cells form a conserved T-cell subset known for its potent intrinsic antitumor activity and versatility in recognizing diverse cancer types independently of the major histocompatibility complex. Previously, we reported the preclinical activity of a bispecific T-cell engager (bsTCE) specific for both CD1d and the V\u03b42-TCR that engaged both V\u03b39V\u03b42-T and type 1 natural killer T cells to CD1d-expressing hematological malignancies, including multiple myeloma (MM) and acute myeloid leukemia (AML). Here, we evaluated whether various standard-of-care drugs for patients with MM and AML\/myelodysplastic syndromes (MDS) affected the in vitro antitumor activity of CD1d-V\u03b42 bsTCE-activated V\u03b39V\u03b42-T cells.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>MM and AML\/MDS standard-of-care drugs were tested for antagonistic, additive, or synergistic effects on CD1d-V\u03b42 bsTCE-induced and V\u03b39V\u03b42-T cell-mediated tumor cell lysis. Based on observed synergy, the immunomodulatory drug (IMiD) lenalidomide was studied in more detail, exploring effects on V\u03b39V\u03b42-T cell proliferation, phenotype, cytokine profile, and cytolytic activity, as well as its mechanism of action, using healthy donor peripheral blood mononuclear cells (PBMC) and MDS patient PBMC and bone marrow samples.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Lenalidomide exerted synergistic activity on CD1d-V\u03b42 bsTCE-triggered V\u03b39V\u03b42-T cell antitumor activity and was found to substantially enhance CD1d-V\u03b42 bsTCE-induced V\u03b39V\u03b42-T cell activation, degranulation, T\n                      <jats:sub>h<\/jats:sub>\n                      1-type cytokine secretion, and expansion. Stimulatory effects of lenalidomide on V\u03b39V\u03b42-T cell effector functions were mediated via enhanced intracellular CD28 phosphorylation, activation of Notch signaling, and interleukin-2 release. Importantly, lenalidomide facilitated otherwise absent proliferation of V\u03b39V\u03b42-T cells with oncolytic potential in response to CD1d-V\u03b42 bsTCE exposure in MDS patient-derived bone marrow samples.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Our findings provide a rationale to explore the combination of CD1d-V\u03b42 bsTCE and the IMiD lenalidomide in patients with CD1d-expressing hematological malignancies.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jitc-2025-013127","type":"journal-article","created":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T07:35:16Z","timestamp":1782718516000},"page":"e013127","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["Lenalidomide boosts CD1d-V\u03b42 bispecific antibody-engaged V\u03b39V\u03b42-T cell effector functions via CD28, Notch signaling and IL-2 release"],"prefix":"10.1136","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6121-4211","authenticated-orcid":false,"given":"Milon","family":"de Jong","sequence":"first","affiliation":[{"name":"Department of Medical Oncology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands"},{"name":"Cancer Center Amsterdam, Cancer Biology and Immunology, 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 Center Amsterdam, Cancer Biology and Immunology, Amsterdam, The Netherlands"},{"name":"Amsterdam Institute for Infection and Immunity, Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tereza","family":"Brachtlov\u00e1","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands"},{"name":"Cancer Center Amsterdam, Cancer Biology and Immunology, Amsterdam, The Netherlands"},{"name":"Amsterdam Institute for Infection and Immunity, Amsterdam, The Netherlands"},{"name":"ORCA Therapeutics, \u2018s-Hertogenbosch, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-8705-150X","authenticated-orcid":false,"given":"Lisa A","family":"King","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands"},{"name":"Cancer Center Amsterdam, Cancer Biology and Immunology, Amsterdam, The Netherlands"},{"name":"Amsterdam Institute for Infection and Immunity, Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6924-7798","authenticated-orcid":false,"given":"Jos\u00e9","family":"Saura-Esteller","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands"},{"name":"Cancer Center Amsterdam, Cancer Biology and Immunology, Amsterdam, The Netherlands"},{"name":"Amsterdam Institute for Infection and Immunity, Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tamara M","family":"Bechler","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands"},{"name":"Cancer Center Amsterdam, Cancer Biology and Immunology, Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pauline M","family":"van Helden","sequence":"additional","affiliation":[{"name":"LAVA Therapeutics, Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Canan","family":"Alhan","sequence":"additional","affiliation":[{"name":"Cancer Center Amsterdam, Cancer Biology and Immunology, Amsterdam, The Netherlands"},{"name":"Department of Hematology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4729-8863","authenticated-orcid":false,"given":"Roeland","family":"Lameris","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands"},{"name":"Cancer Center Amsterdam, Cancer Biology and Immunology, Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tanja D","family":"de Gruijl","sequence":"additional","affiliation":[{"name":"Department 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