1472 A phase 1/2 study evaluating the safety and efficacy of autologous TAC T cells in subjects with claudin 18.2+ advanced solid tumors

<h3>Background</h3> 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. There are no approved therapeutic agents against CLDN18.2. The T cell antigen coupler (TAC) technology modifies T cells <i>ex vivo</i>, 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. <h3>Methods</h3> In this first-in-human study (NCT05862324), subjects will undergo leukapheresis and may receive bridging anticancer therapy during cell manufacturing. Prior to TAC01-CLDN18.2 infusion, subjects will undergo lymphodepletion chemotherapy. In Phase I, TAC01-CLDN18.2 will be 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 will be determined centrally using a validated clinical trial assay. Dose-limiting toxicities (DLTs) will be assessed 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 &lt;4 lines of prior therapy. <h3>Results</h3> The first two dose cohorts of Phase I have been completed, with no reported dose-limiting toxicities (DLT). All of the TAC-related adverse events were low-grade. No cytokine release syndrome was reported. One subject in cohort 2 experienced a grade 1 neurotoxicity, which resolved the same day without intervention. Six subjects reported a total of 6 serious adverse events, none related to TAC01-CLDN18.2. A 100% disease control rate was observed at first tumor assessment (Day 29) in the five eligible subjects for efficacy assessment. One subject in cohort 1 with heavily pre-treated PDAC (3 prior lines) with high CLDN18.2 expression has an ongoing, confirmed partial response. The subject received a second dose and is still on treatment (5 months). <h3>Conclusions</h3> Treatment with the lower doses of TAC01-CLDN18.2 is safe and shows promising clinical activity in a heavily pre-treated cancer population. Treatment of cohort 3 has begun. <h3>Ethics Approval</h3> This study was approved by MD Anderson’s Ethics Board; approval number 2023-0146. This study was approved by University of Cincinatti’s Ethics Board (Advarra); approval number Pro00071206. This study was approved by University of Southern California Health Sciences’ Ethics Board; approval number #HS-23-00306. This study was approved by CHUM’s Ethics Board; approval number 23.178. This study was approved by University of California San Diego Health’s Ethics Board (Advarra); approval number Pro00071206. This study was approved by Dana Farber Cancer Insitute’s Ethics Board; approval number 24-088. This study was approved by Memorial Sloan Kettering Cancer Center’s Ethics Board; approval number 24-136. This study was approved by University of Miami’s Ethics Board; approval number 20231138. All subjects gave informed consent before participating.