To overcome some of the limitations and increase the clinical benefit of anti-CTLA-4 therapy, Chand et al. studied Fc-enhanced antibodies in preclinical models, and botensilimab in a clinical setting. Consistent with mouse models, botensilimab enhanced FcγR-dependent T cell responses and peripheral T cell activation, reduced the frequency of intratumoral (but not peripheral) Tregs, activated myeloid cells (including APCs), and upregulated genes associated with T cell-inflamed TMEs, independent of FcγRIIIA allele status. Favorable TME remodeling was also observed in patients with multiple treatment-refractory cancers, including those that progressed on prior anti-PD-1/PD-L1 or anti-CTLA-4 therapy.
Contributed by Ute Burkhardt
ABSTRACT: Conventional immune checkpoint inhibitors (ICI) targeting CTLA-4 elicit durable survival, but primarily in patients with immune-inflamed tumors. Although the mechanisms underlying response to anti-CTLA-4 remain poorly understood, Fc-gamma receptor (FcγR) IIIA co-engagement appears critical for activity, potentially explaining the modest clinical benefits of approved anti-CTLA-4 antibodies. We demonstrate that anti-CTLA-4 engineered for enhanced FcγR affinity leverages FcγR-dependent mechanisms to potentiate T cell responsiveness, reduce intratumoral Tregs, and enhance antigen presenting cell activation. Fc-enhanced anti-CTLA-4 promoted superior efficacy in mouse models and remodeled innate and adaptive immunity versus conventional anti-CTLA-4. These findings extend to patients treated with botensilimab, an Fc-enhanced anti-CTLA-4 antibody, with clinical activity across multiple poorly immunogenic and ICI treatment-refractory cancers. Efficacy was independent of tumor neoantigen burden or FcγRIIIA genotype. However, FcγRIIA and FcγRIIIA expression emerged as potential response biomarkers. These data highlight the therapeutic potential of Fc-enhanced anti-CTLA-4 antibodies in cancers unresponsive to conventional ICI therapy.
Author Info: (1) Agenus (United States), Lexington, MA, United States. (2) Agenus, Lexington, MA, United States. (3) Agenus (United States), Lexington, MA, United States. (4) Agenus (United Sta
Author Info: (1) Agenus (United States), Lexington, MA, United States. (2) Agenus, Lexington, MA, United States. (3) Agenus (United States), Lexington, MA, United States. (4) Agenus (United States), Lexington, MA, United States. (5) Agenus (United States), Lexington, MA, United States. (6) Agenus (United States), Lexington, MA, United States. (7) Agenus (United States), Lexington, MA, United States. (8) Agenus (United States), Lexington, MA, United States. (9) Agenus (United States), Lexington, MA, United States. (10) Agenus (United States), Lexington, MA, United States. (11) Agenus (United States), Lexington, MA, United States. (12) Agenus (United States), Lexington, MA, United States. (13) Agenus (United States), Lexington, MA, United States. (14) Agenus (United States), Lexington, MA, United States. (15) Agenus (United States), Lexington, MA, United States. (16) Agenus (United States), Lexington, MA, United States. (17) Agenus (United States), Lexington, MA, United States. (18) Translational Genomics Research Institute, Phoenix, AZ, United States. (19) TGEN, Phoenix, Arizona, United States. (20) Agenus (United States), Lexington, MA, United States. (21) Agenus (United States), Lexington, MA, United States. (22) Agenus Inc., Lexington, MA, United States. (23) Agenus (United States), Lexington, MA, United States. (24) Agenus (United States), Lexington, MA, United States. (25) Agenus Inc., Lexington, MA, United States. (26) Agenus Inc, Lexington, MA, United States. (27) Agenus (United States), Lexington, MA, United States. (28) GlaxoSmithKline (United States), Collegeville, PA, United States. (29) Agenus (United States), Lexington, MA, United States. (30) Agenus (United States), Cambridge, United Kingdom. (31) Agenus (United States), Lexington, MA, United States. (32) Agenus (United States), Cambridge, United Kingdom. (33) Agenus (United States), Cambridge, United Kingdom. (34) Agenus (United States), Lexington, MA, United States. (35) Agenus (United States), Lexington, MA, United States. (36) Agenus Inc., Lexington, MA, United States. (37) Agenus Inc., Lexington, MA, United States. (38) Translational Genomics Research Institute, Phoenix, United States. (39) Anglia Ruskin University, Cambridge, United Kingdom. (40) Dartmouth Health and The Geisel Medical School at Dartmouth, Lebanon, NO, United States. (41) Agenus Inc., Lexington, MA, United States. (42) Agenus Inc., Lexington, MA, United States. (43) Agenus (United States), Lexington, MA, United States.
