{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T15:10:46Z","timestamp":1788793846566,"version":"build-2803163510"},"reference-count":32,"publisher":"Oxford University Press (OUP)","issue":"7","license":[{"start":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T00:00:00Z","timestamp":1784073600000},"content-version":"vor","delay-in-days":14,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"Takeda Pharmaceuticals"},{"name":"The Royal Commission for the Exhibition of 1851"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,7,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\u03b3\u03b4 T cells are associated with favorable outcomes in many cancers likely through a mechanism of stress-directed cytotoxicity and antitumor cytokine production. V\u03b41 \u03b3\u03b4 T cells are especially promising for immunotherapy due to their broad stress recognition and resistance to activation-induced cell death. Here, we generate a CD19 engager incorporating a novel V\u03b41 binding moiety as proof-of-concept for treating CD19+ cancers, including Chronic Lymphocytic Leukemia (CLL). In vitro studies validated V\u03b41\/CD19 engager-directed cellular binding and V\u03b41 activation, where 41BB, CD25 and CD107a were upregulated on V\u03b41 T cells following co-culture with CD19+ cancer cell lines and V\u03b41\/CD19 engager treatment. Ex vivo studies demonstrated engager-mediated V\u03b41 T cell proliferation within healthy PBMC cultures that also correlated to basal V\u03b41 CD27 expression. Engager-treated PBMCs demonstrated enhanced cytotoxicity against CD19+ cell lines and primary CLL B cells, with minimal killing of healthy B cells and without inducing excessive cytokine release compared with a CD3\/CD19 engager. Phenotypic analysis suggested engager treatment encourages maturation of naive V\u03b41 T cells, where upregulation of NKG2D, DNAM-1, CD96, CD2, ICOS, and PD-1 were observed, and in culture with cancerous cells, downregulation of CD27 and CD45RA alongside granzyme-B upregulation. Blockade of such co-receptors reduced V\u03b41 cytotoxicity following engager treatment whereas co-receptor stimulation modestly enhanced V\u03b41 activation. These data suggest that V\u03b41\/CD19 engager treatment enhances anti-tumoral V\u03b41-capabilities while maintaining sufficient dependency on stress ligand availability, supporting selective targeting of malignant over healthy cells. Overall, our data support the rationale for V\u03b41-directed immunotherapies and uncovers potential mechanisms that enhance V\u03b41 cytotoxic responses against CD19+ cancers.<\/jats:p>","DOI":"10.1093\/jimmun\/vkag167","type":"journal-article","created":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T16:31:20Z","timestamp":1784133080000},"source":"Crossref","is-referenced-by-count":0,"title":["A novel V\u03b41 engager targeting CD19 enhances human V\u03b41 \u03b3\u03b4 T cell responses against CLL and CD19+ hematological malignancies"],"prefix":"10.1093","volume":"215","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-0716-5539","authenticated-orcid":false,"given":"Shefali A","family":"Bhumbra","sequence":"first","affiliation":[{"name":"Takeda Pharmaceutical Company Limited Oncology Drug Discovery Unit, , London,","place":["United Kingdom"]},{"name":"Department of Immunology and Inflammation, Imperial College London , London,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Good","sequence":"additional","affiliation":[{"name":"Takeda Pharmaceutical Company Limited Oncology Drug Discovery Unit, , London,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antara","family":"Banerjee","sequence":"additional","affiliation":[{"name":"Takeda Pharmaceutical Company Limited Oncology Drug Discovery Unit, , Boston, MA,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tyreese","family":"Hines","sequence":"additional","affiliation":[{"name":"Takeda Pharmaceutical Company Limited Oncology Drug Discovery Unit, , Boston, MA,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine J","family":"Seidl","sequence":"additional","affiliation":[{"name":"Takeda Pharmaceutical Company Limited Oncology Drug Discovery Unit, , Boston, MA,","place":["United 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