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Lookup NU author(s): Dr Wendy Osborne
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©2025 American Association for Cancer Research. PURPOSE: Varlilumab is a CD27 agonist antibody, delivering a T-cell costimulation. Preclinical studies show that agonistic CD27 antibodies can activate intratumoral T cells to release chemokines and cytokines to augment macrophage-dependent tumor killing induced by CD20 antibodies, i.e., rituximab, in B-cell lymphoma. This clinical trial evaluated the safety and efficacy of rituximab and varlilumab in patients with previously treated B-cell non-Hodgkin lymphoma. PATIENTS AND METHODS: This multicenter phase IIa trial recruited patients with relapsed or refractory CD20+ B-cell non-Hodgkin lymphoma. Patients were randomized to arm A or B. All patients received rituximab on day 1 of cycles 1 to 6 and varlilumab on day 2 (arm A) or day 8 (arm B) of cycle 1 and day 2 of cycles 3 and 5. Tumor biopsies were collected before treatment and on-treatment (after varlilumab in arm A and before varlilumab in arm B). The primary objective was to assess safety and antitumor activity. RESULTS: Twenty-seven participants were evaluable, with modest overall response and disease control rates of 15.4% (4/27) and 38.8% (8/27), respectively. Intratumoral bulk RNA sequencing analysis demonstrated that adding varlilumab to rituximab enhanced CD4+ T-cell infiltration and increased T- and innate-cell signatures; inflamed tumor signatures were observed before treatment in responders. Single-cell analysis further showed that higher levels of CD27-expressing T and NK cells, along with activated γδ T-cell signatures, were associated with response, whereas CD27-expressing B cells correlated with nonresponse. CONCLUSIONS: Rituximab and varlilumab show modest activity. However, CD27 agonist antibodies may elicit meaningful antitumor responses when tumors express sufficient intratumoral targets and exhibit existing immune priming.
Author(s): Buermann LE, Stanton L, Rose-Zerilli MJJ, Thorne K, Coleman A, Turaj AH, Caddy J, Wignall C, Keyworth N, Konn Z, McKay P, Osborne W, Linton K, Medd P, Lown R, Davies AJ, Johnson PWM, Al-Shamkhani A, Cragg MS, Collins GP, Keler T, Yellin M, Gentles AJ, Griffiths G, Lim SH
Publication type: Article
Publication status: Published
Journal: Clinical Cancer Research
Year: 2025
Volume: 31
Issue: 22
Pages: 4664-4679
Print publication date: 15/11/2025
Online publication date: 14/11/2025
Acceptance date: 02/09/2025
ISSN (print): 1078-0432
ISSN (electronic): 1557-3265
Publisher: American Association for Cancer Research
URL: https://doi.org/10.1158/1078-0432.CCR-25-2029
DOI: 10.1158/1078-0432.CCR-25-2029
PubMed id: 40920567
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