CLDN18.2 BiTE Engages Effector and Regulatory T Cells for Antitumor Immune Response in Preclinical Models of Pancreatic Cancer.

Abstract

BACKGROUND & AIMS:

BiTE (bispecific T-cell engager) immune therapy has demonstrated clinical activity in multiple tumor indications, but its influence in the tumor microenvironment remains unclear. CLDN18.2 is overexpressed in solid tumors including gastric cancer (GC) and pancreatic ductal adenocarcinoma (PDAC), both of which are characterized by the presence of immunosuppressive cells, including regulatory T cells (Tregs) and few effector T cells (Teffs).

METHODS:

We evaluated the activity of AMG 910, a CLDN18.2-targeted half-life extended (HLE) BiTE molecule, in GC and PDAC preclinical models and cocultured Tregs and Teffs in the presence of CLDN18.2-HLE-BiTE.

RESULTS:

AMG 910 induced potent, specific cytotoxicity in GC and PDAC cell lines. In GSU and SNU-620 GC xenograft models, AMG 910 engaged human CD3+ T cells with tumor cells, resulting in significant antitumor activity. AMG 910 monotherapy, in combination with a programmed death-1 (PD-1) inhibitor, suppressed tumor growth and enhanced survival in an orthotopic Panc4.14 PDAC model. Moreover, Treg infusion enhanced the antitumor efficacy of AMG 910 in the Panc4.14 model. In syngeneic KPC models of PDAC, treatment with a mouse surrogate CLDN18.2-HLE-BiTE (muCLDN18.2-HLE-BiTE) or the combination with an anti-PD-1 antibody significantly inhibited tumor growth. Tregs isolated from mice bearing KPC tumors that were treated with muCLDN18.2-HLE-BiTE showed decreased T cell suppressive activity and enhanced Teff cytotoxic activity, associated with increased production of type I cytokines and expression of Teff gene signatures.

CONCLUSIONS:

Our data suggest that BiTE molecule treatment converts Treg function from immunosuppressive to immune enhancing, leading to antitumor activity in immunologically "cold" tumors.

• Authors: Yao Xu, Juan Fu, MacKenzie Henderson, Fei Lee, Noelle Jurcak, Anja Henn, Joachim Wahl, Yingkuan Shao, Jianxin Wang, Melissa Lyman, Vanessa Funes, Birginia Espinoza, Rui Zhang, India Washington, Sophia Y Chen, Haley Zlomke, Junke Wang, Nan Niu, Pan Li, Fengxi Meng, William Burns, Matthias Friedrich, Sabine Stienen, Julie M Bailis, Lei Zheng
• Journal: Gastroenterology (Gastroenterology) Vol. 165 Issue 5 Pg. 1219-1232 (Nov 2023) ISSN: 1528-0012 [Electronic] United States
• PMID: 37507075 (Publication Type: Journal Article)
• Copyright: Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Antibodies, Bispecific
• Cell Adhesion Molecules
• CLDN18 protein, human
• Claudins

Topics

• Humans
• Animals
• Mice
• T-Lymphocytes, Regulatory (metabolism)
• Antibodies, Bispecific (genetics, pharmacology)
• Pancreatic Neoplasms (drug therapy)
• Cell Adhesion Molecules
• Carcinoma, Pancreatic Ductal (drug therapy)
• Immunity
• Tumor Microenvironment
• Claudins