Background: HER2 overexpression is well established as a therapeutic target in breast cancer and can be seen in a variety of gastrointestinal malignancies, notably in gastroesophageal cancer where positivity ranges from 4.4% to 53.4%. The recent approval of HER2-targeted therapies to treat gastroesophageal adenocarcinomas has validated HER2 as an actionable target in these diseases. Recent data also support the emerging role of HER2 directed therapy in colorectal cancer, among other solid tumors. Although patient outcomes have improved, this remains an area of significant unmet medical need. The T cell antigen coupler (TAC) technology is a novel approach to modifying a patient’s own T cells, allowing them to recognize and treat HER2+ solid tumors. The TAC receptor is composed of a HER2-binding domain, similar to a traditional chimeric antigen receptor (CAR) T cell, however unlike CAR T cells, it uses the signaling pathway of the natural T cell receptor (TCR) to avoid off target toxicity. This novel “TAC receptor” is hypothesized to deliver a targeted anti-cancer T cell response with a much-improved safety profile as compared with traditional CAR T cells such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome events (ICANS). In this ongoing clinical trial (NCT04727151), subjects undergo leukapheresis, bridging therapy (if needed) while TAC T cells are engineered, lymphodepletion chemotherapy (LDC), and finally TAC01-HER2 infusion. Methods: The Phase 1 dose escalation study is underway to investigate the safety and tolerability of TAC01-HER2 in adult subjects with HER2+ solid tumors (1+, 2+ or 3+) who have progressed after ≥2 lines of therapy at dose levels 0.3, 0.8, 3, and 8 x 10⁶ cells/kg. Dose limiting toxicities (DLTs) are assessed up to day 28. A Phase 2 will further evaluate the safety, efficacy, and pharmacokinetics of the optimal TAC01-HER2 dose in various HER2+ tumors. As of 19 August 2022, 8 subjects have been treated at Dose Levels (DL) 1 and 2, with no observed DLTs, CRS, or ICANS. Five subjects had 11 serious adverse events, all unrelated to TAC01-HER2 treatment. A majority of adverse events were related to LDC and/or the underlying disease. At DL 2, a partial response was observed in a subject with refractory metastatic gastric adenocarcinoma (3+ HER2) on day 29, with a 36.5% reduction in measurable disease. Two additional subjects at DL 2 had stable disease, one with refractory gall bladder cancer (3+ HER2) and one with refractory colorectal cancer (2+ HER2) with no change in tumor measurements compared to baseline. Dose escalation of TAC01-HER2 is ongoing, with the first subject being treated at DL 3. These results in a heavily pre-treated gastrointestinal cancer population show manageable safety and promising efficacy with a novel T cell therapy that may have broad clinical applicability in HER+ cancers. Clinical trial information: NCT04727151.