CD27 Agonist Antibodies Mediate Clinical Responses through Intratumoral Stimulation in B-cell Malignancies: Multicenter RiVa Trial

作者：Lara E. Buermann, Louise Stanton, Matthew J.J. Rose-Zerilli, Kerensa I. Thorne, Adam Coleman, Anna H. Turaj, Joshua Caddy, Christopher Wignall, Nicole Keyworth, Zoë J. Konn, Pam McKay, Wendy Osborne, Kim Linton, Patrick G. Medd, Robert N. Lown, Andrew John Davies, Peter Johnson, Aymen Al‐Shamkhani, Mark Steven Cragg, Graham P. Collins, Tibor Keler, Michael Jay Yellin, Andrew J. Gentles, Gareth Owen Griffiths, Sean H. Lim · 发表于：Clinical Cancer Research · 年份：2025 · DOI：10.1158/1078-0432.ccr-25-2029 · 被引用次数：1 · 研究领域：CAR-T cell therapy research、Lymphoma Diagnosis and Treatment、Cancer Immunotherapy and Biomarkers

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 s...