Preclinical Development of T Cells Engineered to Express a T-Cell Antigen Coupler Targeting Claudin 18.2–Positive Solid Tumors
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Bibliographic record
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.
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Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.003 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.000 | 0.002 |
| Insufficient payload (model declined to judge) | 0.006 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from it