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

Inclusion Criteria:

1. Aged≥18 years old and ≤75 years old when signing the informed consent; regardless of gender;
2. Body weight\>40kg;
3. Pathologically confirmed as pancreatic cancer, colorectal cancer, gastric cancer or lung cancer;
4. Recurrent/refractory solid tumors unresponsive to the current standard treatment;
5. At least one measurable lesion according to the RECIST 1.1 criteria, that is, the long diameter of the non-lymph-node lesion≥10 mm, or the short diameter of the lymph node lesion ≥15 mm on CT or MRI cross-sectional imaging; the longest axis of the measurable lesion≥10 mm on CT scan (slice thickness≤5 mm in CT scan);
6. Acceptable hemopoietic ability: absolute neutrophil count (ANC) \>1.5×10\^9/L, platelet count \>1.0×10\^11/L, hemoglobin (HGB) \>90g/L (no blood transfusion within two weeks), absolute lymphocyte count (ALC )\>500×10\^9/L;
7. Acceptable liver and kidney functions: aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 ULN in subjects without liver metastases and ≤3.5 upper limit of normal (ULN) in those with liver metastases; bilirubin≤1.5 ULN (excluding hyperbilirubinemia or non-liver-derived hyperbilirubinemia); creatinine ≤1.5 ULN and creatinine clearance rate≥40 mL/min;
8. prothrombin time (PT)/international normalized ratio (INR) \<1.5 ULN and partial thromboplastin time (PTT)/activated partial thromboplastin time (APTT) \<1.5 ULN;
9. Positive for TM4SF1 or EpCAM expression (expression≥25%), with three classifications; (1) Recurrent or existing lesions at the primary site with tumor tissue samples collected within 1 year, which are positive for TM4SF1 or EpCAM by immunohistochemistry; (2) New metastatic lesions at the non-primary sites, which are positive for TM4SF1 or EpCAM by immunohistochemistry; (3) Remaining tumor lesions at the primary site with tumor tissue samples collected more than 1 year ago, and the lesions are positive for TM4SF1 or EpCAM by immunohistochemistry based on re-biopsy.
10. Women of child-bearing age (15-49 years old) must be negative for pregnancy test at 7 days before initiation of the treatment.
11. Eastern Cooperative Oncology Group (ECOG) scores≤2.
12. Expected survival no less than 12 weeks.

Exclusion Criteria:

1. History of any radiotherapy and chemotherapy within 4 weeks before a single blood collection;
2. History of any anti-programmed cell death protein 1 (PD1) and anti-Programmed cell death 1 ligand 1 (PD-L1) treatments within 12 weeks before a single blood collection;
3. History of organ transplantation;
4. Pregnancy or lactation;
5. Uncontrolled infectious diseases, such as baseline hepatitis B virus (HBV) DNA≥2000 IU/ml, positive for anti-human immunodeficiency virus （HIV） antibody and hepatitis C virus (HCV)-RNA;
6. Other active infection with clinical significance;
7. History of other active malignancies in the past 5 years, excluding basal or squamous skin carcinoma, superficial bladder cancer, and breast cancer in situ which have completely healed and require no follow-up treatment;
8. Serious autoimmune diseases or immunodeficiency disease, including those with confirmed severe autoimmune diseases and requiring long-term use (over 2 months) of systemic immunosuppressants (steroids) or having immune-mediated symptomatic diseases, such as ulcerative colitis, Crohn's disease, rheumatoid arthritis, systemic lupus erythematosus (SLE) and autoimmune vasculitis (eg., Wegener's granulomatosis);
9. Allergic diathesis and allergic to immunotherapy or relevant drugs;
10. Organ failure; Heart: Grade III and IV ; or with hypertension uncontrolled by the standard treatment, history of myocarditis or myocardial infarction within 1 year; Liver: Class C according to the Child-Turcottei-Pugh System (CTP); Kidneys: Kidney failure and uremic syndrome; Lungs: Serious symptoms of respiratory failure; Brain: Disturbance of consciousness;
11. Active bleeding, and thrombotic diseases requiring treatment;
12. Uncontrollable pleural and peritoneal effusion requiring clinical treatment or intervention;
13. T-cell cancers, such as T-cell lymphoma;
14. Current on systemic steroid or steroid inhalers;
15. Any mental diseases, including dementia and changes in mental status that may influence the understanding about the informed consent and questionnaire;
16. Participating in other clinical trials in the past 30 days;
17. Judged as serious uncontrollable diseases by the researchers, or other conditions that may interfere with the treatment and therefore being ineligible.