Post- immunotherapy CTLA-4 Ig treatment improves antitumor efficacy

• 成果类型: Article
• 署名作者: Mok, Stephen; Cobanoglu, Didem Agac; Liu, Huey; Mancuso, James J.; Allison, James P.
• 署名单位: University of Texas System; UTMD Anderson Cancer Center; University of Texas System; UTMD Anderson Cancer Center
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-12099
• DOI: 10.1073/pnas.2404661121
• 发表日期: 2024-07-02
• 关键词: regulatory t; pd-1 blockade; anti-ctla-4; cells; cd28; ipilimumab; effector; survival; therapy

摘要

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.