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.
Author Info: (1) Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030. (2) Department of Immunology, The University of Texas MD Anderson Cancer Center,
Author Info: (1) Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030. (2) Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030. (3) Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030. (4) Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030. Parker Institute for Cancer Immunotherapy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030. (5) Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030. Parker Institute for Cancer Immunotherapy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030.
