CD27 Agonist Antibodies Mediate Clinical Responses through Intratumoral Stimulation in B-cell Malignancies: Multicent...

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.