{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T10:21:24Z","timestamp":1793701284410,"version":"4.5.1"},"reference-count":25,"publisher":"American Society of Hematology","issue":"1","license":[{"start":{"date-parts":[[2023,10,12]],"date-time":"2023-10-12T00:00:00Z","timestamp":1697068800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2024,1,4]]},"abstract":"<jats:sec>\n                    <jats:title>Abstract<\/jats:title>\n                    <jats:p>Bruton tyrosine kinase inhibitors (BTKis) that target B-cell receptor signaling have led to a paradigm shift in chronic lymphocytic leukemia (CLL) treatment. BTKis have been shown to reduce abnormally high CLL-associated T-cell counts and the expression of immune checkpoint receptors concomitantly with tumor reduction. However, the impact of BTKi therapy on T-cell function has not been fully characterized. Here, we performed longitudinal immunophenotypic and functional analysis of pretreatment and on-treatment (6 and 12 months) peripheral blood samples from patients in the phase 3 E1912 trial comparing ibrutinib-rituximab with fludarabine, cyclophosphamide, and rituximab (FCR). Intriguingly, we report that despite reduced overall T-cell counts; higher numbers of T cells, including effector CD8+ subsets at baseline and at the 6-month time point, associated with no infections; and favorable progression-free survival in the ibrutinib-rituximab arm. Assays demonstrated enhanced anti-CLL T-cell killing function during ibrutinib-rituximab treatment, including a switch from predominantly CD4+ T-cell:CLL immune synapses at baseline to increased CD8+ lytic synapses on-therapy. Conversely, in the FCR arm, higher T-cell numbers correlated with adverse clinical responses and showed no functional improvement. We further demonstrate the potential of exploiting rejuvenated T-cell cytotoxicity during ibrutinib-rituximab treatment, using the bispecific antibody glofitamab, supporting combination immunotherapy approaches.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1182\/blood.2023020554","type":"journal-article","created":{"date-parts":[[2023,10,12]],"date-time":"2023-10-12T16:01:20Z","timestamp":1697126480000},"page":"57-63","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":25,"title":["Ibrutinib-based therapy reinvigorates CD8+ T cells compared to chemoimmunotherapy: immune monitoring from the E1912 trial"],"prefix":"10.1182","volume":"143","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-5818-8663","authenticated-orcid":false,"given":"Despoina","family":"Papazoglou","sequence":"first","affiliation":[{"name":"1School of Cancer and Pharmaceutical Sciences, Faculty of Life Sciences & Medicine, King's College London, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin Victoria","family":"Wang","sequence":"additional","affiliation":[{"name":"2Department of Data Science, Dana-Farber Cancer Institute, Boston, MA"},{"name":"3Department of Biostatistics, Harvard TH Chan School of Public Health, Boston, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tait D.","family":"Shanafelt","sequence":"additional","affiliation":[{"name":"4School of Medicine, Stanford University, Stanford, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Connie E.","family":"Lesnick","sequence":"additional","affiliation":[{"name":"5Department of Immunology, Mayo Clinic, Rochester, MN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikolaos","family":"Ioannou","sequence":"additional","affiliation":[{"name":"1School of Cancer and Pharmaceutical Sciences, Faculty of Life Sciences & Medicine, King's College London, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6163-4590","authenticated-orcid":false,"given":"Giulia","family":"De Rossi","sequence":"additional","affiliation":[{"name":"6Institute of Ophthalmology, University College London, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sylvia","family":"Herter","sequence":"additional","affiliation":[{"name":"7Discovery Oncology, Roche Innovation Center Z\u00fcrich, Schlieren, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina","family":"Bacac","sequence":"additional","affiliation":[{"name":"7Discovery Oncology, Roche Innovation Center Z\u00fcrich, Schlieren, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Klein","sequence":"additional","affiliation":[{"name":"7Discovery Oncology, Roche Innovation Center Z\u00fcrich, Schlieren, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin S.","family":"Tallman","sequence":"additional","affiliation":[{"name":"8Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5951-5055","authenticated-orcid":false,"given":"Neil E.","family":"Kay","sequence":"additional","affiliation":[{"name":"5Department of Immunology, Mayo Clinic, Rochester, MN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0452-0420","authenticated-orcid":false,"given":"Alan G.","family":"Ramsay","sequence":"additional","affiliation":[{"name":"1School of Cancer and Pharmaceutical Sciences, Faculty of Life Sciences & Medicine, King's College London, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"234","reference":[{"issue":"5","key":"2024010416272707700_bib1","doi-asserted-by":"crossref","first-page":"432","DOI":"10.1056\/NEJMoa1817073","article-title":"Ibrutinib-rituximab or chemoimmunotherapy for chronic lymphocytic leukemia","volume":"381","author":"Shanafelt","year":"2019","journal-title":"N\u00a0Engl J Med"},{"issue":"2","key":"2024010416272707700_bib2","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1182\/blood.2021014960","article-title":"Long-term outcomes for ibrutinib-rituximab and chemoimmunotherapy in CLL: updated results of the E1912 Trial","volume":"140","author":"Shanafelt","year":"2022","journal-title":"Blood"},{"issue":"1","key":"2024010416272707700_bib3","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1182\/bloodadvances.2020003423","article-title":"Overcoming resistance to targeted therapies in chronic lymphocytic leukemia","volume":"5","author":"Sk\u00e5nland","year":"2021","journal-title":"Blood Adv"},{"issue":"1","key":"2024010416272707700_bib4","doi-asserted-by":"crossref","first-page":"68","DOI":"10.3390\/ijms21010068","article-title":"Harnessing the effects of BTKi on T cells for effective immunotherapy against CLL","volume":"21","author":"Mhibik","year":"2019","journal-title":"Int J Mol Sci"},{"issue":"26","key":"2024010416272707700_bib5","doi-asserted-by":"crossref","first-page":"3419","DOI":"10.1182\/blood-2017-02-765685","article-title":"Pembrolizumab in patients with CLL and Richter transformation or with relapsed CLL","volume":"129","author":"Ding","year":"2017","journal-title":"Blood"},{"issue":"2","key":"2024010416272707700_bib6","doi-asserted-by":"crossref","first-page":"e67","DOI":"10.1016\/S2352-3026(18)30217-5","article-title":"Safety and activity of ibrutinib in combination with nivolumab in patients with relapsed non-Hodgkin lymphoma or chronic lymphocytic leukaemia: a phase 1\/2a study","volume":"6","author":"Younes","year":"2019","journal-title":"Lancet Haematol"},{"issue":"3","key":"2024010416272707700_bib7","doi-asserted-by":"crossref","first-page":"562","DOI":"10.3324\/haematol.2016.151100","article-title":"T\u00a0cells in chronic lymphocytic leukemia display dysregulated expression of immune checkpoints and activation markers","volume":"102","author":"Palma","year":"2017","journal-title":"Haematologica"},{"issue":"8","key":"2024010416272707700_bib8","doi-asserted-by":"crossref","first-page":"2012","DOI":"10.1038\/s41375-020-0873-2","article-title":"T-cells in chronic lymphocytic leukemia: guardians or drivers\u00a0of\u00a0disease?","volume":"34","author":"Roessner","year":"2020","journal-title":"Leukemia"},{"issue":"8","key":"2024010416272707700_bib9","doi-asserted-by":"crossref","first-page":"3052","DOI":"10.1172\/JCI89756","article-title":"Ibrutinib treatment improves T cell number and function in CLL 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