ABSTRACT

Background
The T cell antigen coupler (TAC) is a novel, proprietary 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 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.

Materials and 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 TACengineered 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. The 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 cocultured 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.

Conclusion
The in vitro and in vivo data confirm a 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.

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ABSTRACT

Background
The T cell antigen coupler (TAC) is a novel, proprietary 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. The subject of this presentation is a new TAC T product, TAC01-CLDN18.2, targeting claudin 18.2 (CLDN18.2) to treat gastric cancer. CLDN18.2 belongs to a family of claudin tight junction proteins and is naturally restricted to the epithelia of normal stomachs. In gastric cancer cells, CLDN18.2 expression can go awry, is no longer confined to tight junctions, and is, thus, targetable by CLDN18.2-TAC T cells.

Materials and Methods
CLDN18.2-TAC T cells were evaluated using a variety of in vitro and in vivo assays. In vitro assays were based on flow cytometric analysis of T cell proliferation and surface activation marker expression. Cytotoxicity was assessed via real-time microscopy-based co-culture assays. In vivo studies examined the anti-tumor effect of CLDN18.2-TAC T cells against established solid CLDN18.2-expressing tumors.

Results
CLDN18.2-TAC T cells showed specific anti-tumor cytotoxicity in CLDN18.2-expressing gastric spheroid models as well as 2Dco-cultures with tumor cells expressing endogenous CLDN18.2. In contrast, CLDN18.2-TAC T cells lacked activity when cultured with CLDN18.2-negative cells derived from normal human tissues. While CLDN18.2-TAC T cells also cross-reacted with murine CLDN18.2, mice showed no signs of toxicity, suggesting that CLDN18.2-TAC T cells do not induce off-tumor effects. The in vitro repeat killing assay demonstrated strong and persistent anti-tumor activity of CLDN18.2-TAC T cells against CLDN18.2-expressing target cells. Lastly, treatment with CLDN18.2-TAC T cells in MHC DKO mice bearing CLDN18.2-positive tumors led to complete and sustained tumor clearance, even after a secondary tumor re-challenge, indicating long-term persistence of TAC cells up to 56 days after initial dosing.

Conclusion
The in vitro and in vivo data con􀈈rm strong and specific activity of CLDN18.2-targeted TAC T cells against CLDN18.2-expressing solid tumor models and highlight the versatility of the TAC platform for therapeutic applications in solid tumors.

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“There’s sort of 2 big groups of HER2 solid tumors: there’s the breast cancer population, and there’s everybody else. The reality in breast cancers is there’s a myriad of effective treatments: cytotoxics, antibody-drug conjugates, combinations, monoclonal antibodies, and targeted therapies. And those have had much less benefit in other HER2-positive malignancies… HER2 therapy has not been as effective in GI malignancies and other malignancies as it has been in breast cancer.”

While commercially available treatment options have shown efficacy in treating HER2-positive solid tumors in patients with breast cancer, these same treatments have been less effective in treating patients with HER2-positive solid tumors in other types of cancers, such as gastrointestinal (GI) malignancies.

Benjamin L. Schlechter, MD, instructor, medicine, Harvard Medical School, and Dana-Farber Cancer Institute, recently presented data from the ongoing phase 1/2 TACTIC-2 clinical trial (NCT04727151) of TAC01-HER2, an investigational HER2-targeted T-cell antigen coupler (TAC) T-cell therapy intended to address unmet needs for patients with HER2-positive solid tumors, at the European Society for Medical Oncology (ESMO) Congress 2022, taking place September 9-13, in Paris, France, and virtually.

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Introduction:

• 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 a safe and durable anti‑tumor response. In preclinical models of cancer, TAC‑engineered T cells effectively eradicate tumor cells in vitro and in vivo without TAC‑related toxicities.
• TACTIC‑2 (NCT04727151) is an open‑label, multicenter phase I/II study that aims to establish safety, maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), pharmacokinetic profile, and efficacy of TAC01‑HER2 in patients with HER2‑positive solid tumors (i.e. breast, lung, pancreatic, colorectal, gastric, endometrial, ovarian, and others) whom have progressed on prior anti‑cancer therapies.
• We present a clinical update from Cohorts 1 & 2 (8 participants) that highlights safety and efficacy data; the study further elucidates potential therapeutic impact to patients with HER2 overexpressed solid tumors.

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Christopher W. Helsen, Tania Benatar, Thanyashanthi Nitya-Nootan, Heather McGregor, Philbert Ip, Prabha Lal, Stacey Xu, Laura Shaver, Suzy Prosser, Sadhak Sengupta, Andreas G. Bader. Triumvira Immunologics, 9433 Bee Caves Rd Building 1, Suite 240, Austin, TX 78733, USA (Headquarters), 270 Longwood Road South, Hamilton, Ontario L8P 0A6, Canada (Research Division)

Abstract
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 a safe and durable anti-tumor response.

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