ET 140202 -T Cell Combined With TAE or Sorafenib in the Treatment of Liver Cancer

The molecular target for ET140202-T cells is HLA-A02 complexed with a HLA-A02-restricted peptide of alpha fetoprotein (AFP), which is expressed on 60-80 percent of hepatocellular carcinoma (HCC). This clinical study evaluates the safety and pharmacokinetics of ET140202-T cells with TAE or Sorafenib in patients with HCC who have no available curative therapeutic options and a poor overall prognosis.

• Sorafenib combined with ET140202-T cell (Combination product): 1. Sorafenib starting dose of 400mg b.i.d. a.c. 2. Autologous T cells transduced with lentivirus encoding an anti-AFP (ET140202) expression construct by intravenous (IV) infusion
• TAE combined with ET140202-T cell (Combination product): 1. Transarterial embolization(TAE) treatment 2. Autologous T cells transduced with lentivirus encoding an anti-AFP (ET140202) expression construct -intravenous (i.v.)
• ET140202-T cell (Biological): Autologous T cells transduced with lentivirus encoding an anti-AFP (ET140202) - expression construct -intravenous (i.v.)

Primary outcomes

• Frequency of ARTEMIS T cell treatment-related adverse events [28 days up to 2 years]: Include but not limited to: Fever, chills, nausea, vomiting, jaundice and other gastrointestinal symptoms; Fatigue, hypotension, respiratory distress; Tumor lysis syndrome; Cytokine release syndrome; Neutropenia, thrombocytopenia; Liver and kidney dysfunction. Assessed at all visits.

Secondary outcomes

• Rate of disease response by RECIST in the liver [2 years]: Response rates will be estimated as the percent of patients with objective response (OR)，which was defined as any of complete remission (CR), partial response (PR) at 2 years.
• Rate of disease response by RECIST at non-liver sites [2 years]: Response rates will be estimated as the percent of patients with objective response (OR), complete remission (CR), partial response (PR), stable disease (SD), no response (NR), overall survival (OS).
• Progression free survival (PFS) [at 4 months, 1 year, 2 years]: Progression free survival (PFS) at 4 months, 1 year and 2 years
• Median Survival（MS） [at 4 months, 1 year, 2 years]: Median Survival（MS）at 4 months, 1 year and 2 years
• Overall survival（OS） [at 2 years]: overall survival（OS）at 2 years
• AFP serum levels [2 years]: Percent change compared to the baseline
• Number of ET140202-T cells in peripheral blood [2 years]: Number of ET140202-T cells in peripheral blood will be presented as Time to peak, Time to baseline level
• Alpha-fetoprotein (AFP) expression in tumors [4-8 weeks]: Percent of AFP-positive cells in randomly selected fields in tumor biopsies.
• IL-6 serum levels [4-8 weeks]: Amount change compared to the baseline
• IL-2 serum levels [4-8 weeks]: Amount change compared to the baseline
• IL-10 serum levels [4-8 weeks]: Amount change compared to the baseline
• TNF-α serum levels [4-8 weeks]: Amount change compared to the baseline
• IFN-γ serum levels [4-8 weeks]: Amount change compared to the baseline

Sex: All, ages: 18 Years to 75 Years

Inclusion Criteria:

* AFP-expressing HCC and serum AFP >10 x ULN
* Abandon or failure in first or second line treatment
* Molecular HLA class I typing confirms participant carries at least one HLA-A02 allele
* Child-Pugh score of A or B, ECOG 0-2, Life expectancy > 6 months
* Measurable disease as defined by: at least 1 liver lesion that can be accurately and serially measured.
* Negative serum pregnancy test for women with childbearing potential
* Adequate organ function as defined below:

  1. A pretreatment measured creatinine clearance (absolute value) of ≥50 ml/minute.
  2. Patients must have a serum direct bilirubin ≤3 x ULN, ALT and AST ≤5 x ULN.
  3. Ejection Fraction measured by echocardiogram or MUGA >50% (evaluation done within 6 weeks of screening does not need to be repeated)
  4. DLCO or FEV1 >45% predicted
  5. Absolute neutrophil count (ANC) ≥ 1500/mm3 (10\^9/L), Platelet count ≥ 50,000/mm3 (10\^9/L)
  6. INR ≤1.5 x ULN
  7. Informed Consent/Assent: All subjects must have the ability to understand and the willingness to sign a written informed consent.

Exclusion Criteria:

* Patients with decompensated cirrhosis: Child-Pugh Score C
* Patients with tumor infiltration in the portal vein, hepatic veins or inferior vena cava that completely blocks circulation in liver.
* Patients with an organ transplantation history
* Patients with dependence on corticosteroids
* Patients with active autoimmune diseases requiring systemic immunosuppressive therapy
* Patients who are currently receiving or received within past 30 days anti-cancer therapy, local treatments for liver tumors (radiotherapy, embolism, ablation) or liver surgery
* Patients currently receiving other investigational treatments (biotherapy, chemotherapy, or radiotherapy)
* Participants with other active malignancies (except non-melanoma skin cancer and cervical cancer) within two years. Patients with a history of successfully-treated tumors with no sign of recurrence in the last two years may be enrolled.
* Patients with other uncontrolled diseases, such as active infections Acute or chronic active hepatitis B or hepatitis C.
* Women who are pregnant or breast-feed
* HIV-infection

• Xue Hui, PHD, Study chair, First Affiliated Hospital of Xian Jiaotong University