A phase 1/2 study evaluating the safety and efficacy of autologous TAC T cells in subjects with claudin 18.2+ advanced solid tumors.

e14519 Background: The purpose of this study is to determine the safety of autologous TAC T cell administration to subjects with claudin 18.2+ advanced solid tumors. Claudin18.2 (CLDN18.2) is a tight junction protein found in gastric epithelial cells. It can become abnormally expressed in gastric cancer and other solid tumors, rendering it a candidate for targeted therapy. The T cell antigen coupler (TAC) technology modifies T cells ex vivo , allowing cytotoxicity of tumor cells by co-opting the natural T cell receptor. TAC T cells demonstrate a safer profile than chimeric antigen receptor T cells. TAC01-CLDN18.2 is an autologous T-cell product comprising T cells expressing CLDN18.2 TAC. Methods: In this first-in-human study (NCT05862324), subjects undergo leukapheresis (bridging anticancer therapy during cell manufacturing is allowed). Prior to TAC01-CLDN18.2 infusion, subjects undergo lymphodepletion chemotherapy. In Phase I, TAC01-CLDN18.2 is being administered at increasing doses (3 cohorts) in adult subjects with ≥2 lines of prior therapy (1 for subjects with pancreatic ductal adenocarcinoma (PDAC)) using the classic 3+3 dose escalation study design. CLDN18.2 expression levels are determined centrally using a validated clinical trial assay. Dose-limiting toxicities (DLTs) are assessed for up to 28 days after the infusion. A second dose may be administered according to preidentified clinical and safety criteria. In Phase II, dose expansion groups will evaluate the efficacy, safety, and pharmacokinetics of the optimal TAC01-CLDN18.2 dose, with the option of redosing. Indications will include gastric and esophageal adenocarcinoma (group A), PDAC (group B) and ovarian and non-small cell lung cancer (group C) in subjects with < 4 lines of prior therapy. Results: The first two dose cohorts of Phase I have been completed, and the third cohort has been deemed safe by the Data and Safety Monitoring Committee, with no reported dose-limiting toxicities (DLT). One subject experienced two Grade 3 treatment-related adverse events (TRAEs): gastritis and gastric hemorrhage (both resolving within 4 days). Three subjects experienced CRS (one Grade 2 and two Grade 1). One subject in cohort 2 experienced a grade 1 neurotoxicity, which resolved the same day without intervention. Eight subjects reported a total of 18 serious adverse events, with 5 related to TAC01-CLDN18.2. A 67% disease control rate was observed at first tumor assessment (Day 29). Two subjects with high CLDN18.2 expression had partial responses. One of them was enrolled in cohort 1 with heavily pre-treated PDAC (3 prior lines) and has an ongoing, confirmed partial response. This subject received a second dose and is still on treatment (10 months). Conclusions: Treatment with TAC01-CLDN18.2 is safe and shows promising clinical activity in a heavily pre-treated cancer population. Treatment of cohort 3 is ongoing. Clinical trial information: NCT05862324 .