BMS-986178

OX40 is a costimulatory molecule that belongs to the tumor necrosis factor receptor (TNFR) superfamily. OX40 agonist‐based combinations are emerging as promising candidates for novel cancer immunotherapy. Clinical trials have shown that OX40 agonist antibodies could lead to better results in cancer patients. Using a hybridoma platform and three different types of immunization strategies, namely recombinant protein, DNA, and overexpressing cells, we identified a chimeric anti‐OX40 antibody (mAb035‐hIgG1 from DNA immunization) that shows excellent binding specificity, and slightly stronger activation of human memory CD4+ T cells and similar potent antitumor activity compared with BMS 986178, an anti‐OX40 antibody currently being evaluated for the treatment of solid tumors. This paper further systematically investigates the antigen‐specific immune response, the number of binders, epitope bins, and functional activities of antibodies among different immunization strategies. Interestingly, we found that different immunization strategies affect the biological activity of monoclonal antibodies.

This phase I/IIa study (NCT02737475) evaluated the safety and activity of BMS-986178, a fully human OX40 agonist IgG1 mAb, ± nivolumab and/or ipilimumab in patients with advanced solid tumors.

Patients (with non–small cell lung, renal cell, bladder, other advanced cancers) received BMS-986178 (20–320 mg) ± nivolumab (240–480 mg) and/or ipilimumab (1–3 mg/kg). The primary endpoint was safety. Additional endpoints included immunogenicity, pharmacodynamics, pharmacokinetics, and antitumor activity per RECIST version 1.1.

Twenty patients received BMS-986178 monotherapy, and 145 received combination therapy in various regimens (including two patients receiving nivolumab monotherapy). With a follow-up of 1.1 to 103.6 weeks, the most common (≥5%) treatment-related adverse events (TRAEs) included fatigue, pruritus, rash, pyrexia, diarrhea, and infusion-related reactions. Overall, grade 3–4 TRAEs occurred in one of 20 patients (5%) receiving BMS-986178 monotherapy, six of 79 (8%) receiving BMS-986178 plus nivolumab, zero of two receiving nivolumab monotherapy, six of 41 (15%) receiving BMS-986178 plus ipilimumab, and three of 23 (13%) receiving BMS-986178 plus nivolumab plus ipilimumab. No deaths occurred. No dose-limiting toxicities were observed with monotherapy, and the MTD was not reached in either the monotherapy or the combination escalation cohorts. No objective responses were seen with BMS-986178 alone; objective response rates ranged from 0% to 13% across combination therapy cohorts.

In this study, BMS-986178 ± nivolumab and/or ipilimumab appeared to have a manageable safety profile, but no clear efficacy signal was observed above that expected for nivolumab and/or ipilimumab.