{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,31]],"date-time":"2026-01-31T03:16:22Z","timestamp":1769829382123,"version":"3.49.0"},"reference-count":50,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2025,7,10]],"date-time":"2025-07-10T00:00:00Z","timestamp":1752105600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004622","name":"Dutch Cancer Society","doi-asserted-by":"crossref","award":["#13077"],"award-info":[{"award-number":["#13077"]}],"id":[{"id":"10.13039\/501100004622","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Maurits en Anna de Kock Stichting","award":["#90032230 2023-10"],"award-info":[{"award-number":["#90032230 2023-10"]}]},{"DOI":"10.13039\/100016060","name":"De Cock-Hadders","doi-asserted-by":"publisher","award":["#2025-20"],"award-info":[{"award-number":["#2025-20"]}],"id":[{"id":"10.13039\/100016060","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background\/Objectives: The physiological activation of cytotoxic CD8pos T cells (CTLs) relies on the engagement of the TCR\/CD3 complex with cognate peptide-HLA class I (pHLA-I) on target cells, triggering cell lysis with appropriate cytokine release and minimized off-target toxicity. In contrast, current immunotherapies for CD19-expressing hematological malignancies, such as chimeric antigen receptor (CAR) T cells and bispecific T cell engagers (BiTEs), bypass TCR\/pHLA interactions, resulting in CTL hyperactivation and excessive cytokine release, which frequently cause severe immune-related adverse events (irAEs). Thus, there is a pressing need for T cell-based therapies that preserve physiological activation while maintaining antitumor efficacy. Methods: To address this, we developed CD19-ReTARGTPR, a novel fusion protein consisting of the immunodominant cytomegalovirus (CMV) pp65-derived peptide TPRVTGGAM (TPR) covalently presented by a soluble HLA-B*07:02\/\u03b22-microglobulin complex fused to a high-affinity CD19-targeting Fab antibody fragment. The treatment of CD19-expressing cancer cells with CD19-ReTARGTPR makes them recognizable for pre-existing anti-CMVpp65 CTLs via physiological TCR-pHLA engagement. Results: Our preclinical data demonstrate that CD19-ReTARGTPR efficiently redirects anti-CMV CTLs to eliminate CD19-expressing cancer cells, including both established cell lines and primary chronic lymphocytic leukemia (CLL) cells. Unlike CD19-directed CAR T cells or the CD19\/CD3 BiTE blinatumomab, CD19-ReTARGTPR mediated robust cytotoxic activity without triggering supraphysiological cytokine release. Importantly, this approach retained efficacy even against cancer cells with low CD19 expression. Conclusions: In summary, we provide a robust proof-of-concept study and show that CD19-ReTARGTPR offers a promising alternative strategy for T cell redirection, enabling the selective and effective killing of CD19-expressing malignancies while minimizing cytokine-driven toxicities through physiological CTL activation pathways.<\/jats:p>","DOI":"10.3390\/cancers17142300","type":"journal-article","created":{"date-parts":[[2025,7,10]],"date-time":"2025-07-10T15:36:58Z","timestamp":1752161818000},"page":"2300","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["CD19-ReTARGTPR: A Novel Fusion Protein for Physiological Engagement of Anti-CMV Cytotoxic T Cells Against CD19-Expressing Malignancies"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8221-1180","authenticated-orcid":false,"given":"Anne Paulien","family":"van Wijngaarden","sequence":"first","affiliation":[{"name":"University of Groningen, Laboratory for Translational Surgical Oncology, Department of Surgery, University Medical Center Groningen, 9713 GZ Groningen, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4772-9889","authenticated-orcid":false,"given":"Isabel","family":"Britsch","sequence":"additional","affiliation":[{"name":"University of Groningen, Laboratory for Translational Surgical Oncology, Department of Surgery, University Medical Center Groningen, 9713 GZ Groningen, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthias","family":"Peipp","sequence":"additional","affiliation":[{"name":"Department of Stem Cell Transplantation and Immunotherapy, Christian-Albrechts-Universit\u00e4t zu Kiel, Arnold-Heller Strasse 3, 24105 Kiel, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0613-7150","authenticated-orcid":false,"given":"Douwe Freerk","family":"Samplonius","sequence":"additional","affiliation":[{"name":"University of Groningen, Laboratory for Translational Surgical Oncology, Department of Surgery, University Medical Center Groningen, 9713 GZ Groningen, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7004-3995","authenticated-orcid":false,"given":"Wijnand","family":"Helfrich","sequence":"additional","affiliation":[{"name":"University of Groningen, Laboratory for Translational Surgical Oncology, Department of Surgery, University Medical Center Groningen, 9713 GZ Groningen, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1016\/j.htct.2023.06.006","article-title":"All about blinatumomab: The bispecific T cell engager immunotherapy for B cell acute lymphoblastic leukemia","volume":"46","author":"Mirfakhraie","year":"2024","journal-title":"Hematol. 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