Post-immunotherapy CTLA-4 Ig treatment improves antitumor efficacy

• Published in: Proceedings of the National Academy of Sciences - PNAS 2024-07, Vol.121 (27), p.e2404661121
• Main Authors: Mok, Stephen, Ağaç Çobanoğlu, Didem, Liu, Huey, Mancuso, James J, Allison, James P
• Format: Article
• Language: English
• Subjects: Abatacept - pharmacology; Abatacept - therapeutic use; Animal models; Animals; Anticancer properties; Antitumor activity; Biological Sciences; CD28 antigen; CD8 antigen; CD8-Positive T-Lymphocytes - immunology; Cell culture; Cell fusion; Cell Line, Tumor; CTLA-4 Antigen - antagonists & inhibitors; CTLA-4 Antigen - immunology; CTLA-4 protein; Cytotoxicity; Effectiveness; Female; Fusion protein; Heart diseases; Humans; Immune checkpoint; Immune Checkpoint Inhibitors - pharmacology; Immune Checkpoint Inhibitors - therapeutic use; Immunoglobulins; Immunotherapy; Immunotherapy - methods; Lymphocytes; Lymphocytes T; Mice; Mice, Inbred C57BL; Myocarditis; Neoplasms - drug therapy; Neoplasms - immunology; Neoplasms - therapy; PD-1 protein; Programmed Cell Death 1 Receptor - antagonists & inhibitors; Programmed Cell Death 1 Receptor - immunology; T-Lymphocytes, Regulatory - immunology
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.2404661121

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.