Abstract 662: Late CTLA-4 Ig treatment improves antitumor efficacy of immunotherapy

Abstract

Abstract The promising approach of combining immune checkpoint therapies such as anti-CTLA-4 and anti-PD-1 increases antitumor response and overall survival rate relative to single treatments. However, it also increases the frequency and severity of immune-related adverse events (irAEs), such as cardiotoxicity. Our previous results showed that CTLA-4 Ig (abatacept), an inhibitor of T cell costimulation through CD28, can reverse those irAEs in patients with cancer, however, its effect on the antitumor response remains unclear. In the B16F10 melanoma model, we injected mice with CTLA-4 Ig antibody when: 1) mice were first treated with anti-CTLA-4, anti-PD-1, or combination (early time point) and 2) the immunotherapy was finished (late time point). We demonstrated that CTLA-4 Ig at the early time point compromised the antitumor efficacy of the immunotherapy. In contrast, the antitumor efficacy of the immunotherapy was improved if mice were treated with CTLA-4 Ig at the late time point. We also found that the antitumor response induced by CTLA-4 Ig (late) was dependent on CD80/86. Interestingly, the frequency of ICOS+ Foxp3+ Tregs was significantly reduced by CTLA-4 Ig at the late time point. Thus, we treated B16F10 tumors in Foxp3DTR mice with anti-CTLA-4 and then with CTLA-4 Ig (late). The antitumor tumor efficacy was similar between mice treated with or without Diphtheria toxin (DT) at the late time point. This suggests that the improved antitumor efficacy of CTLA-4 Ig at the late time point was Treg dependent. Collectively, we show that CTLA-4 Ig treatment has a differential role throughout the time course of immunotherapy treatments, and this work suggests a potential combination treatment strategy with checkpoint blockade and late CTLA-4 Ig treatment. Citation Format: Stephen Mok, James P. Allison. Late CTLA-4 Ig treatment improves antitumor efficacy of immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 662.