{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T05:12:14Z","timestamp":1789017134017,"version":"build-2803163510"},"reference-count":37,"publisher":"BMJ","issue":"3","license":[{"start":{"date-parts":[[2024,3,22]],"date-time":"2024-03-22T00:00:00Z","timestamp":1711065600000},"content-version":"unspecified","delay-in-days":21,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009857","name":"Regeneron Pharmaceuticals","doi-asserted-by":"publisher","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"10.13039\/100009857","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2024,2,20]]},"published-print":{"date-parts":[[2024,3]]},"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Patients with relapsed\/refractory B-cell non-Hodgkin lymphoma (R\/R B-NHL) have a significant need for effective treatment options. Odronextamab is an Fc-silenced, human, CD20\u00d7CD3 bispecific antibody that targets CD20-expressing cells via T-cell-mediated cytotoxicity independent of T-cell\/major histocompatibility complex interaction. Phase I results in patients with R\/R B-NHL demonstrated that odronextamab monotherapy could achieve deep and durable responses with a generally manageable safety profile (ELM-1;<jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"clintrialgov\" xlink:href=\"NCT02290951\">NCT02290951<\/jats:ext-link>). As part of a biomarker analysis of the same study, we investigated potential biomarkers and mechanisms of resistance to odronextamab.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Patients with R\/R B-NHL enrolled in ELM-1 received one time per week doses of intravenous odronextamab for 4\u00d721\u2009day cycles, then doses every 2 weeks thereafter. Patient tumor biopsies were obtained at baseline, on-treatment, and at progression. Immune cell markers were analyzed by immunohistochemistry, flow cytometry, single-cell RNA sequencing, and whole genome sequencing.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Baseline tumor biopsies showed that almost all patients had high proportions of B cells that expressed the CD20 target antigen, whereas expression of other B-cell surface antigens (CD19, CD22, CD79b) was more variable. Responses to odronextamab in patients with diffuse large B-cell lymphoma were not related to the relative level of baseline CD20 expression, cell of origin, or high-risk molecular subtype. A potential link was observed between greater tumor programmed cell death-ligand 1 expression and increased likelihood of response to odronextamab. Similarly, a trend was observed between clinical response and increased levels of CD8 T cells and regulatory T cells at baseline. We also identified an on-treatment pharmacodynamic shift in intratumoral immune cell subsets. Finally, loss of CD20 expression through inactivating gene mutations was identified as a potential mechanism of resistance in patients who were treated with odronextamab until progression, as highlighted in two detailed patient cases reported here.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>This biomarker analysis expands on clinical findings of odronextamab in patients with R\/R B-NHL, providing verification of the suitability of CD20 as a therapeutic target, as well as evidence for potential mechanisms of action and resistance.<\/jats:p><\/jats:sec>","DOI":"10.1136\/jitc-2023-008338","type":"journal-article","created":{"date-parts":[[2024,6,2]],"date-time":"2024-06-02T10:38:49Z","timestamp":1717324729000},"page":"e008338","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":28,"title":["Molecular assessment of intratumoral immune cell subsets and potential mechanisms of resistance to odronextamab, a CD20\u00d7CD3 bispecific antibody, in patients with relapsed\/refractory B-cell non-Hodgkin lymphoma"],"prefix":"10.1136","volume":"12","clinical-trial-number":[{"clinical-trial-number":"nct02290951","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct02290951","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct02651662","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct05685173","registry":"10.18810\/clinical-trials-gov"}],"author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-3839-6791","authenticated-orcid":false,"given":"Jurriaan","family":"Brouwer-Visser","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathalie","family":"Fiaschi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raquel P","family":"Deering","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kamil J","family":"Cygan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Darius","family":"Scott","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Se","family":"Jeong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lauren","family":"Boucher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Namita T","family":"Gupta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suraj","family":"Gupta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina","family":"Adler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Max S","family":"Topp","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rajat","family":"Bannerji","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johannes","family":"Duell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ranjana H","family":"Advani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dina M","family":"Flink","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aafia","family":"Chaudhry","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gavin","family":"Thurston","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Srikanth R","family":"Ambati","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vladimir","family":"Jankovic","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2024,3,21]]},"reference":[{"key":"2024060203084702000_12.3.e008338.2","doi-asserted-by":"crossref","DOI":"10.1186\/s12885-023-10546-6","article-title":"Clinical outcomes in patients relapsed\/refractory after \u22652 prior lines of therapy for follicular lymphoma: a systematic literature review and meta-analysis","volume":"23","author":"Kanters","year":"2023","journal-title":"BMC Cancer"},{"key":"2024060203084702000_12.3.e008338.3","doi-asserted-by":"crossref","first-page":"935","DOI":"10.1007\/s40265-023-01894-5","article-title":"Glofitamab: first 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Results of a second, prespecified analysis of the phase 2 study ELM-2 confirm high rates of durable complete response with odronextamab in patients with relapsed\/refractory (R\/R) follicular lymphoma (FL) with extended follow-up. Poster presentation of abstract 3041 at the American Society of Hematology (ASH) annual meeting, December 2023.","DOI":"10.1182\/blood-2023-181650"},{"key":"2024060203084702000_12.3.e008338.8","doi-asserted-by":"crossref","unstructured":"Ayyappan S , Kim WS , Kim TM , et al . Final analysis of the phase 2 ELM-2 study: odronextamab in patients with relapsed\/refractory diffuse large B-cell lymphoma (DLBCL). 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