Increasing FcγR Binding Activity May Enhance Anti-CTLA4 Efficacy

Immune checkpoint blockade with anti-CTLA4 antibodies relieves inhibition of effector T cells to promote antitumor immune responses. In addition, recent preclinical data has suggested that anti-CTLA4 may also deplete regulatory T cells (Treg) via antibody-dependent cell-mediated cytotoxicity (ADCC), but the effects on Tregs are not well understood. Vargas, Furness, and colleagues investigated the role of Treg depletion in anti-CTLA4–mediated antitumor immunity in vivo using a mouse model expressing human Fc-gamma receptors (FcγR) treated with anti-CTLA4 monoclonal antibodies. CTLA4 was highly expressed by tumor-infiltrating Treg cells, and treatment with anti-CTLA4 antibodies induced FcγR-dependent cytotoxicity in vitro and depleted intratumoral Tregs in vivo. This resulted in an increase in the ratio of intratumoral T effector cells to Tregs, thereby enhancing antitumor immunity. In mouse models of fibrosarcoma or colon carcinoma, anti-CTLA4 alone was insufficient to produce a robust antitumor immune response, whereas CTLA4 blockade with an antibody with enhanced affinity for activating FcγRs produced durable tumor regression. However, this effect was not observed in a B16 melanoma model, suggesting that it may be relevant only to inflamed tumors with abundant expression of FcγR-expressing innate effector cells. In patients with advanced melanoma, a single nucleotide polymorphism in the FcγR-activating receptor CD16a (CD16a-V158F) that resulted in an increased affinity for IgG was associated with an increased response to treatment with the anti-CTLA4 antibody ipilimumab in inflamed tumors. Taken together, these findings suggest that enhancing the FcγR binding activity of anti-CTLA4 antibodies may result in superior efficacy, depleting intratumoral Tregs to improve the antitumor activity.

Vargas FA, Furness AJ, Litchfield K, Joshi K, Rosenthal R, Ghorani E, et al. Fc effector function contributes to the activity of human anti-CTLA-4 antibodies. Cancer Cell 2018;33:649–63.e4.

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