A first-in-human Phase I clinical trial demonstrated promising efficacy of an Fc-optimized CD40 agonistic antibody (2141.V11) delivered via intratumoral injection in 12 metastatic cancer patients. Half of treated patients exhibited tumor shrinkage, including complete remission in melanoma and breast cancer cases, with tumor regression observed at noninjected sites, indicating systemic immune activation. The findings published in Cancer Cell suggest potential for novel immunotherapeutics overcoming past toxicities associated with CD40 agonists.