NCT07035002

Study on the Safety and Tolerability of PD-1 Knockout Tumor-infiltrating T Cells (TILs) in the Treatment of Advanced Colorectal Cancer

• Status: Recruiting
• Phase: Phase 1
• Study type: Interventional
• Enrollment: 29 (estimated)
• Sponsor: Ruijin Hospital · Academic / Other
• Sex: All
• Age: 18 Years – 70 Years
• Healthy volunteers: Not accepted

Summary

TIL from tumor tissue of advanced colorectal cancer patients were cultured, modified and expanded in vitro, and then transfused back to the patients after quality control. The safety and efficacy of the treatment were investigated. The fundamental cause of oncogenesis lies in the accumulation of gene mutations. A large number of gene mutations in tumor cells lead to changes in the encoded amino acid sequence, resulting in the production of tumor-specific proteins. Human T cells recognize tumor-specific peptides (tumor neoantigens) that are presented on the MHC molecules on the surface of tumor cells, leading to T cell enrichment within the tumor. However, due to the immunosuppressive effect of tumors through various ways, the enriched T cells in tumors cannot effectively kill tumor cells. One of the most common examples is that tumors up-regulate the expression of immune checkpoint protein PD-L1, which binds to PD-1 on the surface of T cells and inhibits T cell function. Therefore, in this study, we will obtain tumor tissue via surgery resection or biopsy, and then isolate TIL cells in the tumor under GMP conditions, and further use gene editing technology to knockout PD-1, the obtained gene-edited T cells will have the characteristics of specific recognition of tumor cells, but not sensitive to the immunosuppressive function of tumor cells, so as to achieve the therapeutic effect on tumor patients.

Detailed description

Study name: Study on the safety and tolerability of PD-1 gene knockout tumor-infiltrating T cells (TIL) in the treatment of advanced colorectal cancer. About the study: TIL from tumor tissue of advanced colorectal cancer patients were cultured, modified and expanded in vitro, and then transfused back to the patients after quality control. The safety and efficacy of the treatment were investigated. The fundamental cause of oncogenesis lies in the accumulation of gene mutations. A large number of gene mutations in tumor cells lead to changes in the encoded amino acid sequence, resulting in the production of tumor-specific proteins. Human T cells recognize tumor-specific peptides (tumor neoantigens) that are presented on the MHC molecules on the surface of tumor cells, leading to T cell enrichment within the tumor. However, due to the immunosuppressive effect of tumors through various ways, the enriched T cells in tumors cannot effectively kill tumor cells. One of the most common examples is that tumors up-regulate the expression of immune checkpoint protein PD-L1, which binds to PD-1 on the surface of T cells and inhibits T cell function. Therefore, in this study, we will obtain tumor tissue via surgery resection or biopsy, and then isolate TIL cells in the tumor under GMP conditions, and further use gene editing technology to knockout PD-1, the obtained gene-edited T cells will have the characteristics of specific recognition of tumor cells, but not sensitive to the immunosuppressive function of tumor cells, so as to achieve the therapeutic effect on tumor patients. Objectives of the study: Primary objective: To evaluate the safety and tolerability of PD-1 knockout TILs transfer treatment. Secondary objectives: Objective response rate (ORR) and overall survival (OS) of PD-1 knockout TILs transfer treatment. Subjects: The subjects were patients with advanced colorectal cancer confirmed by histology or cytology, who were not eligible to standard treatment at this stage. There were no restrictions on sex and region of origin, and patients volunteered to receive surgery or biopsy to obtain tumor tissue for TILs preparation. Aged ≥18 and ≤70 years old. At least one tumor lesion that could be evaluated according to RECIST, version 1.1. ECOG score was 0 or 1. Adequate bone marrow and organ function. A total of 20 patients were enrolled. The expected survival time of the enrolled patients was no less than 6 months. Research setting/location: Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine Study intervention: TILs were isolated from tumor tissue and infused back into patients after PD-1 knockout and expanded culturing. The patients were treated with cyclophosphamide and fludarabine before TILs transfusion. The evaluation of efficacy included: the concentration of cytokines in blood, the number and duration of TILs in blood, adverse complications, evaluations of tumor size based on RESIST v1.1(by B-ultrasound, CT or MRI), tumor biomarkers, tumor related ctDNA. Study Duration: The overall study duration was 24 months, including the time from the recruitment of the first patient to the completion of the data analysis of the last patient. Duration of subject participation: Each enrolled patient was followed up for 12 months after completion of the TILs transfusion.

Conditions

• Colorectal Cancer (CRC)
• Tumor Infiltrating Lymphocytes
• PD-1

Interventions

Type	Name	Description
BIOLOGICAL	transfusion of 5×10^8 PD-1 knockout TILs per kg body weight	Obtaining individual tumor tissue via surgery resection or biopsy, and then isolating TILs in the tumor under GMP conditions, and further using gene editing technology to knockout PD-1 to finally obtain gene-edited TILs-T cells, and transfusing them back to the patient.
BIOLOGICAL	transfusion of 1×10^9 PD-1 edited TILs per kg body weight	Obtaining individual tumor tissue via surgery resection or biopsy, and then isolating TILs in the tumor under GMP conditions, and further using gene editing technology to knockout PD-1 to finally obtain gene-edited TILs-T cells, and transfusing them back to the patient.
BIOLOGICAL	transfusion of 2×10^9 PD-1 edited TILs per kg body weight	Obtaining individual tumor tissue via surgery resection or biopsy, and then isolating TILs in the tumor under GMP conditions, and further using gene editing technology to knockout PD-1 to finally obtain gene-edited TILs-T cells, and transfusing them back to the patient.
BIOLOGICAL	transfusion of maximum dose without side effects among group A, B and C	Obtaining individual tumor tissue via surgery resection or biopsy, and then isolating TILs in the tumor under GMP conditions, and further using gene editing technology to knockout PD-1 to finally obtain gene-edited TILs-T cells, and transfusing them back to the patient.

Timeline

• Start date: 2024-12-31
• Primary completion: 2025-12-01
• Completion: 2026-12-01
• First posted: 2025-06-24
• Last updated: 2025-06-24

Locations

1 site across 1 country: China