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.
Patients with advanced colorectal cancer confirmed by histology or cytology, who were not eligible to standard treatment at this stage.
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.
Nitrosourea or mitomycin C within 6 weeks before surgery;
Oral fluorouracils and small molecule targeted drugs for 1 week before surgery.
Received other unmarketed investigational drug or treatment within 4 weeks before sampling;
Had undergone major organ surgery (excluding needle biopsy) within 4 weeks before sampling or had significant lesions Trauma, or the need for elective surgery during the trial;
Single group
transfusion of 5×10^8 PD-1 knockout TILs per kg body weight
Biological/VaccineObtaining 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.
transfusion of 1×10^9 PD-1 edited TILs per kg body weight
Biological/VaccineObtaining 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.
transfusion of 2×10^9 PD-1 edited TILs per kg body weight
Biological/VaccineObtaining 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.
transfusion of maximum dose without side effects among group A, B and C
Biological/VaccineObtaining 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.
Tolerance as the highest dose without side effects
Without the following side effects from each drug: 1. Cyclophosphamide: suppression of bone marrow, nausea, mucositis, rash, hemorrhagic cystitis, myocardial injury, alopecia, infertility, nausea and vomiting, syndrome of abnormal secretion of antidiuretic hormone (SIADH). 2. Fludarabine: myelosuppression, fever, chills, nausea and vomiting, malaism, fatigue, anorexia, weakness, neurotoxicity and interstitial pneumonia. 3. General antibiotics: anaphylaxis, renal insufficiency, nausea, vomiting, liver damage, myelosuppression, photosensitivity. 4. High-dose IL-2: High-dose IL-2 has a variety of side effects. Since the most common side effects are due to the adjuvant drugs used in the treatment, the main interventions we will take to reduce the occurrence of serious side effects include: timely monitoring of patients after drug administration and cell infusion, providing adequate clinical support measures and complete first aid protocols, and adjusting according to patients' response.
Safety as severe treatment related complications
The rates of complications occurred, including : 1. Cyclophosphamide: suppression of bone marrow, nausea, mucositis, rash, hemorrhagic cystitis, myocardial injury, alopecia, infertility, nausea and vomiting, syndrome of abnormal SIADH. 2. Fludarabine: myelosuppression, fever, chills, nausea and vomiting, malaism, fatigue, anorexia, weakness, neurotoxicity and interstitial pneumonia. 3. General antibiotics: anaphylaxis, renal insufficiency, nausea, vomiting, liver damage, myelosuppression, photosensitivity. 4. High-dose IL-2: High-dose IL-2 has a variety of side effects. Since the most common side effects are due to the adjuvant drugs used in the treatment, the main interventions we will take to reduce the occurrence of serious side effects include: timely monitoring of patients after drug administration and cell infusion, providing adequate clinical support measures and complete first aid protocols, and adjusting in real time according to patients' response.
Objective response rate
Overall survival
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