Post-immunotherapy Ctla-4 IG Treatment Improves Antitumor Efficacy

Authors

Stephen Mok
Didem Ağaç Çobanoğlu
Huey Liu
James J Mancuso
James P Allison

Publication Date

7-2-2024

Journal

Proceedings of the National Academy of Sciences of the United States of America

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.

Keywords

Animals, Mice, Immunotherapy, CTLA-4 Antigen, Immune Checkpoint Inhibitors, CD8-Positive T-Lymphocytes, T-Lymphocytes, Regulatory, Cell Line, Tumor, Abatacept, Female, Humans, Mice, Inbred C57BL, Neoplasms, Programmed Cell Death 1 Receptor

Comments

Supplementary Materials

PMID: 38923991