TCR-T Cell Therapy on Advanced Solid Tumors

Brief summary public domain (ClinicalTrials.gov)

The primary aim of this study is to evaluate the efficacy of KRAS mutant antigen specific TCR-T cells in the treatment of patients with advanced solid tumors. The secondary aim is to evaluate the pharmacokinetic/pharmacodynamic characteristics of TCR-T cell therapy in patients with advanced solid tumors and the survival of TCR-T cells. The investigators will evaluate the changes of tumor microenvironment after treatment of advanced solid tumors with KRAS mutant antigen specific TCR-T cells; Evaluating the correlation between cytokines and the occurrence of CRS and neurotoxicity

Detailed description public domain (ClinicalTrials.gov)

1.This study is a prospective and single arm clinical study. In this trial, 18 patients with advanced solid tumors with KRAS G12V or G12D mutations and matching HLA-A subtypes are recruited for autologous Tumor-T Cell Receptor (TCR) -Mediated T Cells therapy(TCR-T) therapy.Within 3 - 5 days after pretreatment, subjects will receive a single TCR-T infusion with an infusion dose of about 1 × 10⁹～1 × 10¹⁰. Once every 12 hours within 24 hours after TCR-T cell infusion, recombinant human interleukin-2 will be injected intravenously for 5 days . After 3 months of treatment, the patient's condition was evaluated. If the subject did not occur tumor progression and did not occur adverse events (AEs) of level 3 or higher, a second TCR-T cell reinfusion can be performed based on researcher's judgment (informed consent form needs to be signed again). The study will evaluate the safety of TCR-T treatment by observing adverse events after cell therapy; evaluate the effectiveness of TCR-T compared to the results or historical data of the subject's own previous standard treatment regimen;and collect blood before and after cell infusion, measure the number and activity of TCR-T cells, and evaluate the pharmacokinetic (PK) characteristics of TCR-T.

Intervention public domain (ClinicalTrials.gov)

Biological: TCR-T therapy. 1.Preprocessing strategy： 1. Cyclophosphamide: 300-450mg/m², dissolved in 100ml 0.9% sodium chloride saline, intravenous drip for 60minutes, and 0.4g Mesna injected at 0hour, 4hours and 8 hours after cyclophosphamide,4days and 5 days before TCR-T cell infusion. 2. Fludarabine: 30mg/m² , dissolved in 100ml 0.9% sodium chloride saline, intravenous drip for 30minutes before 3 to 5days before TCR-T cell infusion. 2.Within 3-5 days after pretreatment, subjects will receive a single TCR-T reinfusion with an infusion dose of about 1 × 10⁹～1 × 10¹⁰. 3.Once every 12 hours within 24 hours after TCR-T cell infusion, recombinant human interleukin-2 (injection unit: 500000 units /m², once every 12 hours, subcutaneous injection) will be injected intravenously for 5 days (10 times in total). 4.After 3 months of treatment, If the subject did not occur tumor progression and did not occur adverse events (AEs) of level 3 or higher, a second TCR-T cell reinfusion can be performed.

Arm public domain (ClinicalTrials.gov)

TCR-T treatment group (experimental): Within 3-5 days after pretreatment, subjects will receive a single TCR-T infusion with an infusion dose of about 1 × 10⁹～1 × 10¹⁰.Once every 12 hours within 24 hours after TCR-T cell infusion, recombinant human interleukin-2 will be injected intravenously for 5 days. After 3 months of treatment, the patient's condition was evaluated. If the subject did not occur tumor progression and did not occur adverse events (AEs) of level 3 or higher, a second TCR-T cell reinfusion can be performed .

Primary outcome public domain (ClinicalTrials.gov)

objective response rate（ORR）. The objective response rate is calculated based on the patient population with measurable lesions at baseline, with efficacy determined by comparing tumor burden before and after treatment. According to RECIST 1.1 criteria，Complete Response (CR): Disappearance of all target lesions with no new lesions. Partial Response (PR): ≥30% reduction in the sum of diameters of target lesions. Progressive Disease (PD): ≥20% increase in the sum of diameters of target lesions or appearance of new lesions. Stable Disease (SD): Changes not meeting any of the above thresholds. Time frame: At 12months after the TCR-T cell infusion.

Secondary outcome public domain (ClinicalTrials.gov)

Peak plasma concentration (Cmax). Time frame: 1、3、7、14、28days and 2months、3 months、6 months、9 months、12months after the TCR-T cell infusion.

Secondary outcome public domain (ClinicalTrials.gov)

Area under the plasma concentration versus time curve (AUC). Time frame: 1、3、7、14、28days and 2months、3 months、6 months、9 months、12months after the TCR-T cell infusion.

Secondary outcome public domain (ClinicalTrials.gov)

Peak time (Tmax). Time frame: 1、3、7、14、28days and 2months、3 months、6 months、9 months、12months after the TCR-T cell infusion.

Secondary outcome public domain (ClinicalTrials.gov)

Cell number of TCR-T cells in peripheral blood. Time frame: 1、3、7、14、28days and 2months、3 months、6 months、9 months、12months after the TCR-T cell infusion.

Secondary outcome public domain (ClinicalTrials.gov)

Peak value of cytokines. Time frame: 1、3、7、14、28days and 2months、3 months、6 months、9 months、12months after the TCR-T cell infusion.

Secondary outcome public domain (ClinicalTrials.gov)

Adverse events. Time frame: 12months after TCR-T infusion.

Eligibility public domain (ClinicalTrials.gov)

Inclusion Criteria： 1. Age greater than 18 years old； 2. Subjects with advanced solid tumors confirmed by histology/cytology who have failed standard treatment, are intolerant to standard treatment, or for whom no standard treatment exists. . Non-small cell lung cancer: Recurrent/metastatic non-small cell lung cancer previously treated with platinum-based chemotherapy and/or immunotherapy and/or anti-angiogenic therapy; ii. Pancreatic cancer: Recurrent/metastatic pancreatic cancer that has failed at least one prior systemic therapy; iii. Colorectal cancer: Recurrent/metastatic colorectal cancer that has failed at least two prior systemic therapies (including oxaliplatin, irinotecan, fluoropyrimidine-based agents, anti-angiogenic drugs, etc.); iiii. Other tumors: Other advanced solid tumors that have failed standard treatment, are intolerant to standard treatment, or for which no standard treatment exists; 3. Previous tissue pathology or peripheral blood testing confirmed the presence of KRAS G12V or G12D mutations with matching HLA subtypes； 4. Expected survival duration of more than 3 months； 5. Eastern Cooperative Oncology Group( ECOG )score ≤2； 6. All participants voluntarily participate in this study and sign an informed consent. And the subjects have good compliance and can cooperate with investigators follow-up study. 7. Patients at least have had at least one measurable lesion as defined by RECIST v1.1 criteria； 8. Female participants can not be pregnant or lactating and their serum or urine human chorionic gonadotropin tests must be negative within 72 hours prior to study enrollment；All subjects must be using a medically accepted means of contraception ( (e.g., oral contraceptives, intrauterine device) during the course of this study and for at least 3 months after completion of study therapy. 9. Organ function and bone marrow reserve are in good condition, and the following requirements must be met: 1)Absolute neutrophil count≥1.5×10⁹/L, Absolute lymphocyte count ≥0.5×10⁹/L；2)Platelet count≥50×10⁹/L；3)Hemoglobin≥90g/L；4)Bilirubin \< 1.5 times upper limit of normal（Bile duct obstruction due to tumor compression were excluded)；5)Serum creatinine ≤ 1.5 times the upper limit of normal range or creatinine clearance ≥ 60 mL/min.6)Serum alanine aminotransferase or aspartate aminotransferase is \< 2.5 times the upper limit of the normal value (ULN) (if patients with liver metastasis, ≤5 times the ULN).7)Coagulation function normalised：INR≤1.5，PTT\<1.2 …

Enrollment public domain (ClinicalTrials.gov)

Enrollment: 1 participants (actual).

Why stopped public domain (ClinicalTrials.gov)

In light of the impending acquisition of the project partner, Shanghai Bintie Biotechnology Co., Ltd., the company has resolved to close all IT centers and discontinue the clinical research project.