To improve agonist CD40 Abs for clinical use, Osorio, Knorr, Weitzenfeld, et al. evaluated 2141-V11, an Fc-engineered anti-CD40 (with optimized FcγRIIB binding) in a phase 1 study (12 patients). To avoid systemic toxicities seen with first-generation CD40Abs, 2141-VII was given intratumorally, and was found to be safe and well tolerated, achieving a 20% ORR, with CRs in two patients (melanoma and breast cancer). Tumor regression occurred in injected and non-injected sites, with increased CD8+ T cell infiltration and tertiary lymphoid structure (TLS) formation. In a humanized CD40/FcγR mouse model, 2141-V11 also induced TLSs, local and abscopal effects, and immune memory.

Contributed by Katherine Turner

ABSTRACT: While CD40 agonism is an attractive approach for activating antigen-presenting cells and initiating antitumor responses, previous attempts have encountered limited clinical efficacy coupled with toxicity. We previously demonstrated that interactions between the antibody Fc domain and the inhibitory receptor Fc_RIIB are critical for enhanced antitumor activity. Here, we present the results of a phase 1 study on intratumoral administration of an anti-CD40 agonistic antibody (2141-V11) Fc-engineered to enhance Fc_RIIB binding. Primary endpoints included safety, maximum tolerated dose (MTD), and recommended phase 2 dose. Secondary objectives included preliminary clinical activity and correlative studies from biospecimens. 2141-V11 was well-tolerated without dose-limiting toxicities and MTD was not reached. In ten evaluable patients with metastatic cancer, the overall response rate was 20%, with complete responses in two patients (melanoma and breast carcinoma) and stable disease in six patients. 2141-V11 induced tumor regression in injected and non-injected lesions, with increased leukocyte infiltration and tertiary lymphoid structures (TLS) formation in post-treatment biopsies. In a humanized mouse model for CD40 and Fc_Rs, 2141-V11 induced TLS formation in mice bearing orthotopic breast carcinoma, correlating with local and abscopal antitumor effects, systemic immune activation, and immune memory. These findings support the safety and efficacy of 2141-V11, warranting phase 2 studies and suggesting a unique mechanism of action for this Fc-enhanced immunotherapy (NCT04059588).

Author Info: (1) (2) (3) (4) (5) (6) (7) (8) (9) (10) (11) (12)

Author Info: (1) (2) (3) (4) (5) (6) (7) (8) (9) (10) (11) (12)