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

DOI

10.1073/pnas.2404661121

PMID

38923991

PMCID

PMC11228532

PubMedCentral® Posted Date

June 2024

PubMedCentral® Full Text Version

Post-print

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

Published Open-Access

yes

Recommended Citation

Mok, Stephen; Ağaç Çobanoğlu, Didem; Liu, Huey; et al., "Post-immunotherapy Ctla-4 IG Treatment Improves Antitumor Efficacy" (2024). Faculty, Staff and Student Publications. 120.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/120