Post- immunotherapy CTLA-4 Ig treatment improves antitumor efficacy

Immune checkpoint therapies (ICT) improve overall survival of patients with cancer but may cause immune - related adverse events (irAEs) such as myocarditis. Cytotoxic T lymphocyteassociated 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.