NCT05673434

A Clinical Study on the Safety and Efficacy of CAR-T Therapy for the TM4SF1-positive Tumors of Digestive System

• Status: Unknown
• Phase: N/A
• Study type: Interventional
• Enrollment: 24 (estimated)
• Sponsor: Changhai Hospital · Academic / Other
• Sex: All
• Age: 18 Years – 75 Years
• Healthy volunteers: Not accepted

Summary

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.

Detailed description

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: 1. 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. 2. To preliminarily evaluate the efficacy of CART-TM4SF1 cells in the treatment of TM4SF1-positive recurrent/refractory advanced tumors of digestive system. Secondary objectives: 1. To determine the pharmacokinetic (PK)/pharmacodynamic (PD) characteristics of CART-TM4SF1 cells in humans. 2. To evaluate the overall survival (OS) and tumor regression after treatment. 3. 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.

Conditions

• Digestive Tumor

Interventions

Type	Name	Description
BIOLOGICAL	TM4SF1-positive chimeric antigen receptor T-cell therapy	Specification: 50mL/bag. Storage: The prepared CAR T-cells are cryopreserved in a preserving medium . This product is manufactured under the current good manufacture practices (cGMP) conditions, with restrictions on chemical components, free from animal- or human-derived components and confirming to the United States Pharmacopeia (USP)\<71\> and \<85\> regulations. Preservation: The frozen CAR T-cells are preserved in the liquid nitrogen transfer tank. Usage: The frozen CAR T-cells are preserved at low temperature and transferred to the bedside. The cells are thawed by 36 degrees centigrade to 38 degrees centigrade. water bath. The frozen cells are gently massaged until complete thawing. Then they are transfused back to the patients intravenously. The transfusion will be finished within 10-20 min.

Timeline

• Start date: 2023-01-30
• Primary completion: 2024-07-30
• Completion: 2025-01-30
• First posted: 2023-01-06
• Last updated: 2023-01-06