Clinical Study of Redirected Autologous T Cells With a Chimeric Antigen Receptor in Patients With Malignant Tumors

Exclusion Criteria

• •4. Disease progression after most recent systemic therapy (chemotherapy, MoAb, etc.).
• •D. Mantle Cell Lymphoma
• •1. At least 2 prior chemotherapy regimens (not including single agent monoclonal antibody (Rituxan) therapy);
• •2. Disease progression after most recent systemic therapy (chemotherapy, MoAb, etc.)；
• •3. Relapsed after prior autologous SCT.
• •E. B-Cell Prolymphocytic Leukemia (PLL)
• •F. CD19-positive Diffuse Large B Cell Lymphoma
• •1. At least 2 prior chemotherapy regimens (not including single agent monoclonal antibody (Rituxan) therapy;
• •2. Stage III-IV disease.
• •3. Less than 6 months between last chemotherapy and disease progression (most recent progression free interval \< 6 months);
• •4. Disease progression after most recent therapy (chemotherapy, MoAb, etc.).
• •4. Expected survival \> 12 weeks.
• •5. At least one measurable lesion (≥ 10 mm) for patients with lymphoma.
• •6. ECOG scores 0-1, or KPS scores \> 70.
• •7. Adequate venous access for apheresis or venous sampling, and no other contraindications for leukapheresis.
• •8. WBC ≥ 2.5×10\^9/L; PLT ≥ 60×10\^9/L (for patients with lymphoma); Hb ≥ 9.0 g/dL; LY ≥ 0.47×10\^9/L; LY% ≥ 15%.
• •9. Serum Alb ≥ 30 g/L.
• •10. Serum creatinine ≤ 1.5 ULN.
• •11. ALT ≤ 2.5 ULN; AST ≤ 2.5 ULN.
• •12. Serum total bilirubin ≤ 1.5 ULN. The above lab results should not include those obtained from continuous supportive treatment that is ongoing.
• •II. Myeloma
• •1. Patients aged between 18 \~ 75 with relapsed or refractory multiple myeloma.
• •2. Bone marrow sample is confirmed as BCMA-positive by flow cytometry or pathological examination.
• •3. Patients with relapsed or refractory malignancies who meet the following descriptions:
• •1. Curative efficacy is little or disease progressed after 2 courses of standard treatment regimen;
• •2. Disease relapsed after chemotherapy or HSCT. Curative efficacy is little or disease progressed after 2 courses of original treatment regimen;
• •3. More than 30 days between last treatment and disease progression;
• •4. There is no indication for HSCT at present;
• •5. Disease progression is defined as per "Chinese Guidelines for Diagnosis and Treatment of Multiple Myeloma (Version 2015)". One or more of the following conditions should be met:
• •i. Serum M-protein increases ≥ 25% (absolute increase should be ≥ 5 g/L). If serum M protein is ≥ 50 g/L at baseline, increase of serum M protein can be ≥ 10 g/L; ii. Urine M-protein increases ≥ 25% (absolute increase should be ≥ 200 mg/24 h); iii. If the serum and urine M-protein are not detectable, a ≥ 25% increase in the difference between involved and uninvolved FLC levels is required (absolute increase should be ≥ 100 mg/L); iv. Bone marrow plasma cell percentage increases ≥ 25% (absolute increase should be ≥ 10%); v. Size of existing bone lesions or soft tissue plasmacytomas increased by ≥ 25%, or development of new lytic bone lesions or oft tissue plasmacytomas; vi. Development of hypercalcemia that can be attributed to plasma cell proliferative disorder (corrected calcium is \> 2.8 mmol/L or 11.5 mg/dL).
• •4. Expected survival \> 12 weeks.
• •5. Disease is measurable, and at least one of the following conditions should be satisfied:
• •1. Serum M-protein is ≥ 10 g/L;
• •2. 24-hour urine M-protein is ≥ 200 mg;
• •3. Serum FLC is ≥ 5 mg/dL;
• •4. Plasmacytomas that can be measured or evaluated by imaging;
• •5. Bone marrow plasma cell percentage is ≥ 20%.
• •6. ECOG scores 0 - 1 or CCI scores ≤ 2.
• •7. Adequate venous access for apheresis and venous blood sampling, and no other contraindications for leukapheresis.
• •8. WBC ≥ 1.5×10\^9/L; PLT ≥ 45×10\^9/L; Hb ≥ 9.0 g/dL.
• •9. Serum creatinine ≤ 1.5 ULN.
• •10. ALT ≤ 2.5 ULN; AST ≤ 2.5 ULN. The above lab results should not include those obtained from continuous supportive treatment that is ongoing.
• •III. Hepatocellular Carcinoma (HCC)
• •1. Patients aged 18 \~ 70 with refractory hepatocellular carcinoma.
• •2. Patients with HCC that cannot be eradicated by resection who have received ablation or resection in the last 4 to 12 weeks.
• •3. IHC testing confirmed as GPC3-positive HCC.
• •4. Expected survival \> 12 weeks.
• •5. At least one measurable lesion (≥ 10 mm).
• •6. Cirrhosis of the liver: Child-Pugh Class A, or Child-Pugh Class B scored at 7.
• •7. ECOG scores 0 - 1 or KPS scores \> 70.
• •8. Adequate venous access for apheresis and venous blood sampling, and no other contraindications for leukapheresis.
• •9. Hematology:
• •WBC ≥ 2.5×10\^9/L; PLT ≥ 60×10\^9/L; Hb ≥ 9.0 g/dL; MID ≥ 1.0×10\^9/L; LY ≥ 0.4×10\^9/L.
• •10. Blood Chemistry:
• •Serum Alb ≥ 30 g/L; Serum lipase and serum amylase \< 1.5 ULN; Serum creatinine ≤ 1.5 ULN; ALT ≤ 5 ULN; AST ≤ 5 ULN; Serum total bilirubin ≤ 2.5 ULN.
• •11. Coagulation Test:
• •Prothrombin time is at most 4 seconds longer than normal value.
• •12. Able to understand and sign the informed consent. All test results should be within their normal ranges, and patients are not receiving continuous supportive treatment.
• •IV. Pancreatic Carcinoma and Adenocarcinoma of Esophagogastric Junction
• •1. Patients aged 18 \~ 70 with pathologically confirmed advanced pancreatic carcinoma and adenocarcinoma of esophagogastric junction.
• •2. IHC testing confirmed as Claudin18.2 positive.
• •3. Patients with advanced pancreatic carcinoma and adenocarcinoma of esophagogastric junction that cannot be eradicated by resection.
• •4. Expected survival after first dose of study drug \> 12 weeks.
• •5. At least one measurable lesion (≥ 10 mm) available for imaging assessment.
• •6. ECOG scores 0 - 1.
• •7. Adequate venous access for apheresis and venous blood sampling, and no other contraindications for leukapheresis.
• •8. WBC ≥ 2.5×10\^9/L; PLT ≥ 100×10\^9/L; Hb ≥ 9.0 g/dL; MID ≥ 1.5×10\^9/L; LY ≥ 0.47×10\^9/L; LY% ≥ 15%.
• •9. Serum Alb ≥ 30 g/L.
• •10. Serum lipase and serum amylase \< 1.5 ULN.
• •11. Serum creatinine ≤ 1.5 ULN.
• •12. ALT ≤ 2.5 ULN; AST ≤ 2.5 ULN; If osseous metastasis or liver metastasis is developed and alkaline phosphatase is \> 2.5 ULN, than ALT and AST should be \< 1.5 ULN.
• •13. Serum total bilirubin ≤ 1.5 ULN.
• •14. PT: INR \< 1.7; PT \< (ULN + 4) s All test results should be within their normal ranges, and patients are not receiving continuous supportive treatment.
• •1. Transduction of target lymphocytes \< 10%, expansion in response to αCD3/CD28 costimulation \< 5-fold.
• •2. Pregnant or lactating women.
• •3. HIV positive, or HCV positive
• •4. Uncontrolled active infection, including active tuberculosis and HBV DNA copies ≥ 1×10\^3 copies/mL.
• •5. Concurrent use of systemic steroids. Recent or current use of inhaled steroids is not exclusionary.
• •6. Allergic to immunotherapies and related drugs.
• •7. Patients with heart disease for which treatment is needed or with poorly controlled hypertension.
• •8. Hyponatremia: serum sodium level \< 125 mmol/L.
• •9. Baseline serum potassium \< 3.5 mmol/L (taking potassium supplements before participating in the study to raise potassium level is acceptable).
• •10. Previous treatment with chemoradiotherapy, immunotherapy and tumor-targeting drug conducted 2 weeks prior to participation in this study or blood collection.
• •11. Patients have undertaken immunosuppressor for graft-versus-host disease (GVHD) within 4 weeks before participation in this study or blood collection, or the patient is diagnosed with acute or chronic GVHD.
• •12. Other severe disease that may restrain patients from participating in this study (e.g. diabetes, severe cardiac dysfunction, myocardial infarction or unstable arrhythmias or unstable angina in recent 6 months, gastric ulcer, active autoimmune disease, etc.).