Background:~While great progress has been made in CAR T-cell therapy for the treatment of hematologic malignancies, its use in solid tumors is still at the exploratory stage.Transmembrane 4 L Six Family Member 1 (TM4SF1) protein mediates signal transduction events that play a role in the regulation of cell development, activation, growth and motility. It is a cell surface antigen and is highly expressed in different carcinomas.The investigators have developed novel TM4SF1-targeting CAR T-cells (CART-TM4SF1 cells) for the treatment of digestive system tumors.~These engineered T-cells can target and kill the TM4SF1-positive tumor cells in vitro or in mice. Both of the CAR molecules contain a safety switch based on epidermal growth factor receptor (EGFR) to ensure the safety.The investigators propose to investigate the feasibility, safety, and efficacy of CART-TM4SF1 cells for digestive system tumors in patients.~Objectives:~Primary objectives:~To determine the safety/tolerance dosages and adverse effects of CART-TM4SF1 cells cells in the treatment of TM4SF1-positive recurrent/refractory advanced tumors of digestive system.~To preliminarily evaluate the efficacy of CART-TM4SF1 cells in the treatment of TM4SF1-positive recurrent/refractory advanced tumors of digestive system.~Secondary objectives:~To determine the pharmacokinetic (PK)/pharmacodynamic (PD) characteristics of CART-TM4SF1 cells in humans.~To evaluate the overall survival (OS) and tumor regression after treatment.~To assess the life quality of patients~Study population:~The study population includes 12-24 patients with refractory/recurrent advanced digestive system tumors with positive expression of TM4SF1. The subjects will receive four incremental doses (3-6 subjects in each dose group), as well as safety and preliminary efficacy evaluation.~Design:~This is a single-center open-label clinical study.~Recruit patients with refractory/recurrent digestive system tumors, with written consent for this study. Perform biopsy to determine the expression of TM4SF1 of the tumor with immuno-histochemistry (IHC).~Collect peripheral blood mononuclear cell (PBMC) from the patients, isolate and activate the T cells and transfect them with TM4SF1 targeting CAR, expand the transfected T cells as needed, assess the quality and antitumor activity of the CAR-T products in vitro and then transfer them back the patients via systemic or local injections, and follow up closely to collect related results as needed.~Clinical and immunological responses will be evaluated closely in about 30 days and last up to 2 years after back-transfusion.
Transmembrane 4 L Six Family Member 1 (TM4SF1) is highly expressed in many tumors of digestive system .~The Chimeric Antigen Receptor T-cells (CAR-T) that target TM4SF1 has been generated in our good manufacturing practices (GMP) facility and the anti-tumor effects have been demonstrated in multiple in vitro and in vivo studies.~Clinical studies are proposed here to evaluate the anti-tumor activity of these cell therapy products for treatment of patients with TM4SF1 positive tumors of digestive system. In this study, the safety, tolerance, and preliminary efficacy of CART-TM4SF1 cells will be examined in patients with refractory/recurrent advanced pancreatic cancer, colorectal cancer, gastric cancer or liver cancer.~Clinical and immunological responses will be evaluated about 30 days and last up to 2 years after CAR-T cell infusion.