347 Functional characterization of GUCY2C-TAC T cells for the treatment of colorectal cancer using preclinical models
Bibliographic record
Abstract
Background The T cell antigen coupler (TAC) is a novel chimeric receptor that facilitates the redirection of T cells to tumor cells and activates T cells by co-opting the endogenous T cell receptor complex with the goal to elicit safe and durable anti-tumor responses. TAC01-HER2, a first-in-class TAC T product targeting HER2 (ERBB2), has entered a phase I/II clinical trial in patients with HER2-positive solid tumors. Here, we present preclinical results from TAC T cells targeting guanylyl cyclase 2C (GUCY2C). GUCY2C belongs to a family of membrane-bound mucosal guanylate cyclase receptors normally expressed on the apical brush border of intestinal epithelia, a site inaccessible to T cells. In cancer, however, GUCY2C expression is frequently elevated in primary and metastatic colorectal carcinomas and is no longer confined locally, which allows for the specific targeting of tumor cells. Methods GUCY2C-TAC receptors were humanized using rational mutational changes to the nanobody framework amino acids. The resulting constructs were functionally characterized using in vitro and in vivo models. In vitro assays included T cell proliferation, repeat killing assay, and cytotoxicity via real-time microscopy co-culture assays. In vivo studies examined the anti-tumor effects in liquid and solid tumor models. Results In vitro, T cells engineered with the humanized GUCY2C-TAC receptors showed strong and antigen-specific activation when co-cultured with a variety of cancer cells ectopically and naturally expressing GUCY2C. Activation was followed by T cell proliferation and strong GUCY2C-specific anti-tumor cytotoxicity. GUCY2C-TAC T cells showed activity in a serial cytotoxicity assay, designed to test T cell fitness through chronic antigen stimulation. This assay was accompanied by complex phenotype analysis testing for T cell exhaustion, memory and activation markers. In vivo, intravenous administration of GUCY2C-TAC T cells in mice carrying GUCY2C-positive tumor xenografts led to effective tumor rejection in both liquid and solid tumor models. Conclusions In vitro and in vivo data confirm strong and specific activity of T cells engineered with humanized GUCY2C-TAC receptors. Taken together, these data support further development of GUCY2C-TAC T cells for therapeutic applications in colorectal cancer. Ethics Approval Animal studies performed for the work presented in this abstract were conducted under the Animal Utilization Protocol (AUP) # 20–10-37 and approved by the Animal Research Ethics Committee at McMaster University (Hamilton, ON, Canada).
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.001 |
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 itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".