Safety, feasibility and pharmacodynamic activity of intratumoral injections of the agonist anti-CD137 (4-1BB) mAb urelumab in combination with nivolumab.

Intravenous dosing of the anti-CD137 (4-1BB) agonist monoclonal antibody urelumab is limited to 8 mg flat doses due to liver toxicity, thus reducing bioavailability. Here we explored intratumoral delivery of urelumab to increase bioavailability at the tumor, while reducing systemic exposure, in combination with systemic nivolumab (clinical trial INTRUST, NCT03792724). We delivered three 8 mg intratumoral injections of urelumab, alternating with intravenous nivolumab 240 mg every two weeks, followed by maintenance nivolumab at 480 mg every 4 weeks. Patients presenting solid tumors with known sensitivity to PD-1/PD-L1 blockade were treated in two cohorts (Cohort A: PD-1/PD-L1 blockade naive; Cohort B: progression following PD-1/PD-L1 blockade). The first six patients were treated in a safety dose-escalation cohort. We collected fresh tumor biopsies before the first three cycles and performed multiplex tissue immunofluorescence and bulk RNA-seq of these specimens. Additionally, we analyzed a comprehensive series of cytokines in sequential plasma samples. Among 31 treated patients, we observed two objective responses and a 67.7% disease control rate. Treatment was well tolerated. Serial biopsies revealed urelumab-induced increases in T lymphocyte density and CD137 expression. The increase in tumor-infiltrating CD8 T cells was associated with durable clinical benefit. RNA-seq results were consistent with such pharmacodynamic changes. We observed significant plasmatic elevations of T-cell activation cytokines. Intratumoral delivery of urelumab is feasible, safe, and induces favorable immunopharmacodynamic effects in serial biopsies and in peripheral blood. Our results support the development of tumor-targeted next-generation CD137 (4-1BB) agonists.