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CLDN18.2 BiTE Engages Effector and Regulatory T Cells for Antitumor Immune Response in Preclinical Models of
Yao Xu1, Juan Fu2, MacKenzie Henderson3
1The Sidney Kimmel Comprehensive Cancer Center and Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland; The Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, Maryland; The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, Maryland.
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.
Insights
Bispecific T-cell engager (BiTE) therapy targets CLDN18.2 in gastric and pancreatic cancers. This therapy converts immunosuppressive regulatory T cells (Tregs) into immune-enhancing cells, promoting antitumor activity.
Area of Science:
- Immunology
- Oncology
- Cancer Immunotherapy
Background:
- Bispecific T-cell engager (BiTE) immunotherapy shows promise but its effect on the tumor microenvironment is unclear.
- Claudin 18.2 (CLDN18.2) is overexpressed in gastric cancer (GC) and pancreatic ductal adenocarcinoma (PDAC), tumors often characterized by immunosuppressive cells like regulatory T cells (Tregs).
Purpose of the Study:
- To evaluate the activity of AMG 910, a CLDN18.2-targeted half-life extended (HLE) BiTE molecule, in preclinical models of GC and PDAC.
- To investigate the impact of CLDN18.2-HLE-BiTE on T cell populations, specifically Tregs and effector T cells (Teffs), within the tumor microenvironment.
Main Methods:
- Assessed AMG 910 cytotoxicity in GC and PDAC cell lines.
- Evaluated AMG 910 antitumor activity in GC xenograft and PDAC orthotopic/syngeneic models.
- Co-cultured Tregs and Teffs with CLDN18.2-HLE-BiTE and analyzed T cell function and cytokine production.
Main Results:
- AMG 910 demonstrated potent, specific cytotoxicity against GC and PDAC cells.
- AMG 910 treatment resulted in significant antitumor activity in preclinical models, with enhanced efficacy when combined with PD-1 inhibition.
- BiTE treatment modulated Treg function, decreasing suppressive activity and enhancing Teff cytotoxic activity, accompanied by increased type I cytokine production.
Conclusions:
- BiTE molecule treatment can reprogram Tregs from an immunosuppressive to an immune-enhancing phenotype.
- This Treg modulation contributes to antitumor activity, even in immunologically "cold" tumors like GC and PDAC.
- CLDN18.2-targeted BiTE therapy holds potential for treating solid tumors by overcoming the immunosuppressive tumor microenvironment.
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