{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,18]],"date-time":"2026-07-18T15:05:03Z","timestamp":1784387103261,"version":"3.55.0"},"posted":{"date-parts":[[2026,7,15]]},"group-title":"Immunology","reference-count":52,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T00:00:00Z","timestamp":1784073600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"name":"Hoffman LaRoche, Inc.","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]},{"DOI":"10.13039\/100005601","name":"CLL Global Research Foundation","doi-asserted-by":"crossref","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"10.13039\/100005601","id-type":"DOI","asserted-by":"crossref"}]},{"name":"the UT MD Anderson Cancer Center Moon Shot Program","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]},{"name":"Rosemary and Daniel J. Harrison III Philantropic fund"},{"name":"NIH\/NCI"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,7,15]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  CD19-4-1BBL is a bispecific antibody fusion protein that targets CD19 and costimulates 4-1BB on T cells and other immune cells. Its antitumor activity has been reported in B-cell non-Hodgkin lymphoma with emphasis on its T-cell mediated cytotoxic activity. Its effect on other 4-1BB expressing immune cells is unexplored. Here, we investigated the molecular mechanisms and the antileukemic effect of CD19-4-1BBL in chronic lymphocytic leukemia (CLL), a B-cell malignancy profoundly marked by the immunosuppressive activity of myeloid-derived suppressor cells, tumor-associated macrophages and CD4\n                  <jats:sup>+<\/jats:sup>\n                  regulatory T cells. We demonstrated that CD19-4-1BBL simultaneously mitigates the immunosuppressive phenotype and transcriptome machinery of these cells and promotes antitumor CD8\n                  <jats:sup>+<\/jats:sup>\n                  T-cell immunity. Finally, in a preclinical, patient-derived xenograft model of CLL, we observed a favourable survival impact, especially in mice transplanted with immune cells from patients with high-risk\/progressive leukemia. Our findings provide evidence that the CD19-4-1BBL treatment is a multifaceted, immune-based strategy that should be clinically explored in patients with chronic lymphocytic leukemia.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>KEY POINTS<\/jats:title>\n                  <jats:list list-type=\"bullet\">\n                    <jats:list-item>\n                      <jats:p>\n                        CD19-4-1BBL sharpens the myeloid cell transcriptome and stimulates diverse memory CD8\n                        <jats:sup>+<\/jats:sup>\n                        T cell clonotypic responses.\n                      <\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>CD19-4-1BBL costimulation can be therapeutically exploited in high-risk chronic lymphocytic leukemia.<\/jats:p>\n                    <\/jats:list-item>\n                  <\/jats:list>\n                <\/jats:sec>","DOI":"10.64898\/2026.07.09.737515","type":"posted-content","created":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T21:25:23Z","timestamp":1784150723000},"source":"Crossref","is-referenced-by-count":0,"title":["The CD19-4-1BBL antibody fusion protein unleashes the immune system against high-risk chronic lymphocytic leukemia"],"prefix":"10.64898","author":[{"given":"Priyanka","family":"Khare","sequence":"first","affiliation":[{"name":"Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ronghua","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Ivan","sequence":"additional","affiliation":[{"name":"Department of Experimental Therapeutics, The University of Texas MD 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USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Navid","family":"Sobhani","sequence":"additional","affiliation":[{"name":"Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harry","family":"Polasek","sequence":"additional","affiliation":[{"name":"Department of Veterinary Medicine and Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vanessa Behrana","family":"Jensen","sequence":"additional","affiliation":[{"name":"Department of Veterinary Medicine and Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen","family":"Clise-Dwyer","sequence":"additional","affiliation":[{"name":"Department of Hematopoietic Biology and Malignancy, The University of Texas MD Anderson Cancer 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