Fc-optimized CD40 Agonistic Antibody Induces Tertiary Lymphoid Structures and Systemic Antitumor Immunity in Metastatic Cancer Patients

CD40 agonistic antibodies are an attractive strategy to activate antigen-presenting cells (APC) and initiate antitumor immune responses. However, previous attempts to agonize this pathway have failed due to significant toxicity and poor on-target activity. We previously demonstrated that interactions between the antibody Fc domain and the inhibitory receptor FcgRIIB are critical for enhanced antitumor activity. Here, we present the results of a phase 1 study on intratumoral (IT) administration of an anti-CD40 agonistic antibody (2141-V11), Fc-engineered to enhance FcgRIIB binding (NCT04059588). We found that 2141-V11 was well-tolerated without dose-limiting toxicities. Among eleven evaluable metastatic cancer patients, six experienced tumor reduction, including two complete responses in melanoma and breast cancer. 2141-V11 induced regression in both injected and non-injected lesions, which correlated with systemic immune cell activation, robust tumor immune infiltration and formation of tertiary lymphoid structures (TLS) in complete responders. In several tumor models using mice humanized for CD40 and FcgRs, 2141-V11 induced de novo TLS formation in injected tumors, correlating with local and abscopal antitumor effects, systemic immune activation, and sustained antitumor immune memory. These findings demonstrate that IT 2141-V11 is safe and promotes effective and systemic antitumor immune responses in a subset of patients, supporting ongoing phase 2 studies and suggesting a unique mechanism of action for this Fc-enhanced immunotherapy.