CD27 agonist antibodies mediate clinical responses through intratumoral stimulation in B-cell malignancies: multicenter RiVa trial

Abstract

Purpose: Varlilumab is a CD27 agonist antibody, delivering a T-cell costimulation. Preclinical studies show 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 (B-NHL). Patient and Methods: This multicenter phase IIa trial recruited patients with relapsed or refractory CD20+ B-NHL. Patients were randomized to Arm A or B. All received rituximab on Day 1 of Cycles1-6, 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 collecting pre-treatment and on-treatment (after varlilumab in Arm A and before varlilumab in Arm B). The primary objective was to assess safety and anti-tumor 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 pre-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 non-response. Conclusions: Rituximab and varlilumab show modest activity. However, CD27 agonist antibodies may elicit meaningful anti-tumor responses when tumors express sufficient intratumoral targets and exhibit existing immune priming.