Preclinical Development of T Cells Engineered to Express a T-Cell Antigen Coupler Targeting Claudin 18.2-Positive
Stacey X Xu1, Ling Wang1, Philbert Ip1
1Triumvira Immunologics, Inc., headquartered in Austin, Texas, with research facilities in Hamilton, Canada.
Abstract:
The T-cell antigen coupler (TAC) is a chimeric receptor that facilitates tumor antigen-specific activation of T cells by co-opting the endogenous T-cell receptor complex in the absence of tonic signaling. Previous data demonstrate that the TAC affords T cells with the ability to induce durable and safe antitumor responses in preclinical models of hematologic and solid tumors. In this study, we describe the preclinical pharmacology and safety of an autologous Claudin 18.2 (CLDN18.2)-directed TAC T-cell therapy, TAC01-CLDN18.2, in preparation for a phase I/II clinical study in subjects with CLDN18.2-positive solid tumors. Following a screen of putative TAC constructs, the specificity, activity, and cytotoxicity of TAC T cells expressing the final CLDN18.2-TAC receptor were evaluated in vitro and in vivo using gastric, gastroesophageal, and pancreatic tumor models as well as human cells derived from normal tissues. CLDN18.2-specific activity and cytotoxicity of CLDN18.2-TAC T cells were observed in coculture with various 2D tumor cultures naturally expressing CLDN18.2 as well as tumor spheroids. These effects occurred in models with low antigen levels and were positively associated with increasing CLDN18.2 expression. CLDN18.2-TAC T cells effectively eradicated established tumor xenografts in mice in the absence of observed off-target or on-target/off-tumor effects, elicited durable efficacy in recursive killing and tumor rechallenge experiments, and remained unreactive in coculture with human cells representing vital organs. Thus, the data demonstrate that CLDN18.2-TAC T cells can induce a specific and long-lasting antitumor response in various CLDN18.2-positive solid tumor models without notable TAC-dependent toxicities, supporting the clinical development of TAC01-CLDN18.2.
Insights
T-cell antigen coupler (TAC) therapy targeting Claudin 18.2 (CLDN18.2) demonstrated potent and durable antitumor activity in preclinical models. This novel immunotherapy showed specific cancer cell killing without significant off-target toxicities, supporting clinical trials.
Area of Science:
- Immunology
- Oncology
- Biotechnology
Background:
- T-cell antigen coupler (TAC) therapy leverages T cells for targeted tumor destruction.
- Previous studies show TAC efficacy in preclinical hematologic and solid tumor models.
- Claudin 18.2 (CLDN18.2) is a target antigen for solid tumors.
Purpose of the Study:
- To describe the preclinical pharmacology and safety of TAC01-CLDN18.2, an autologous CLDN18.2-directed TAC T-cell therapy.
- To prepare for a Phase I/II clinical study in patients with CLDN18.2-positive solid tumors.
Main Methods:
- Screening of TAC constructs for specificity and activity.
- In vitro and in vivo evaluation of CLDN18.2-TAC T cells using gastric, gastroesophageal, and pancreatic tumor models.
- Assessment of cytotoxicity against normal human cells and efficacy in xenograft models.
Main Results:
- CLDN18.2-TAC T cells exhibited specific activity and cytotoxicity against CLDN18.2-expressing tumor cells, including spheroids and low-antigen models.
- Established tumor xenografts were eradicated in mice with durable efficacy observed in rechallenge experiments.
- No off-target or on-target/off-tumor toxicities were noted, with T cells remaining unreactive to normal human tissues.
Conclusions:
- CLDN18.2-TAC T cells induce specific, long-lasting antitumor responses in CLDN18.2-positive solid tumor models.
- The therapy demonstrated a favorable safety profile with no significant TAC-dependent toxicities.
- These findings support the clinical development of TAC01-CLDN18.2 for solid tumors.
