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201 Development of GUCY2C-TAC T cells for the treatment of colorectal cancer
  1. Tania Benatar,
  2. Ling Wang,
  3. Thanyashanthi Nitya-Nootan,
  4. Heather MacGregor,
  5. Suzanna Prosser,
  6. Philbert IP,
  7. Prabha Lal,
  8. Stacey Xu,
  9. Laura Shaver,
  10. Sadhak Sengupta,
  11. Christopher Helsen and
  12. Andreas Bader
  1. Triumvira Immunologics, Inc., Hamilton, ON, Canada


Background The T cell antigen coupler (TAC) is a novel, proprietary chimeric receptor that facilitates the re-direction 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 the development of a new TAC T product targeting guanylyl cyclase 2C (GUCY2C) to treat colorectal cancer. GUCY2C belongs to a family of membrane-bound mucosal guanylate cyclase receptors and is selectively expressed on the apical brush border of intestinal epithelia, a site inaccessible to T cells. In cancer, however, GUCY2C is frequently overexpressed in primary and metastatic colorectal carcinomas and, thus, a preferred antigen for the specific targeting of tumor cells via TAC T cells.

Methods GUCY2C-TAC receptor functionality was characterized using a variety of in vitro and in vivo assays. In vitro assays were based on flow cytometric analysis of TAC surface staining, CD69 upregulation and T cell proliferation. Cytotoxicity was assessed via real-time microscopy co-culture assays. In vivo studies examined the anti-tumor effect of TAC-engineered T-cells against established GUCY2C-expressing tumor xenografts.

Results The GUCY2C-TAC receptor showed strong surface expression and specific activation when co-cultured with a variety of cancer cells expressing GUCY2C in vitro. Upregulation of the activation-induced CD69 marker was comparable with levels induced by activated control TAC T cells. Proliferation of GUCY2C-TAC T cells was induced by co-culture with naturally expressing GUCY2C target cell lines as well as GUCY2C-engineered cell lines. In vitro cytotoxicity assay demonstrated a strong anti-GUCY2C response and killing of GUCY2C-expressing target cell lines. No increases in T cell activation, proliferation and no cytotoxicity were observed in non-transduced T cells and GUCY2C-TAC T cells co-cultured with GUCY2C-negative target cells, indicating that the T cell response is specific to the GUCY2C antigen. Intravenous administration of GUCY2C-TAC T cells in mice carrying GUCY2C -positive tumor xenografts led to a sustained anti-tumor response.

Conclusions The in vitro and in vivo data confirm strong and specific activity of GUCY2C-targeted TAC T cells against GUCY2C-expressing tumor models and highlight the versatility of the TAC platform for therapeutic applications in solid tumors.

Ethics Approval AUP number 20–10–37, approved by McMaster University’s Animal Research Ethics Board.

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