CTLA-4 Ig attenuates ICB-related AEs in mice by inhibiting T cell costimulation via CD28, yet its effects on antitumor immunity are unknown. Mok et al. administered CTLA-4 Ig in mice either concomitantly with ICB or following ICB. Across multiple tumor models, co-treatment blunted antitumor efficacy, yet post-treatment enhanced tumor control. CTLA-4 Ig did not alter the functionality of APCs, nor the frequency, exhaustion, or cytotoxicity of i.t. CD8+ T cells, but significantly reduced the frequency of i.t. Tregs. These results suggest that appropriately timed CTLA-4 Ig may reduce AEs, without compromising ICB efficacy, and further drive antitumor immunity.
Contributed by Morgan Janes
ABSTRACT: Immune checkpoint therapies (ICT) improve overall survival of patients with cancer but may cause immune-related adverse events (irAEs) such as myocarditis. Cytotoxic T lymphocyte-associated antigen 4 immunoglobulin fusion protein (CTLA-4 Ig), an inhibitor of T cell costimulation through CD28, reverses irAEs in animal models. However, concerns exist about potentially compromising antitumor response of ICT. In mouse tumor models, we administered CTLA-4 Ig 1) concomitantly with ICT or 2) after ICT completion. Concomitant treatment reduced antitumor efficacy, while post-ICT administration improved efficacy without affecting frequency and function of CD8 T cells. The improved response was independent of the ICT used, whether CTLA-4 or PD-1 blockade. The frequency of Tregs was significantly decreased with CTLA-4 Ig. The resulting increased CD8/Treg ratio potentially underlies the enhanced efficacy of ICT followed by CTLA-4 Ig. This paradoxical mechanism shows that a CTLA-4 Ig regimen shown to reduce irAE severity does not compromise antitumor efficacy.
