αPD1-MSLN-CAR T Cells for the Treatment of MSLN-positive Advanced Solid Tumors

Study Overview
=================
Brief Summary
-----------------
This is a single arm, open-label, dose escalation clinical study to evaluate the safety and tolerability of autologous mesothelin (MSLN)-targeted chimeric antigen receptor (MSLN-CAR) T cells secreting PD-1 nanobodies (αPD1-MSLN-CAR T cells) in patients with solid tumors.

Detailed Description
-----------------
This is a single arm, open-label, dose escalation clinical study to evaluate the safety and tolerability of autologous mesothelin (MSLN)-targeted chimeric antigen receptor (MSLN-CAR) T cells secreting PD-1 nanobodies (αPD1-MSLN-CAR T cells) in patients with solid tumors.The safety and efficacy of αPD1-MSLN-CAR T cells will be assessed in a standard 3+3 dose escalation approach. Four doses of CAR T cells will be evaluated in this study: 1×10^5 CAR+ T cells/kg, 3×10^5 CAR+ T cells/kg, 1×10^6 CAR+ T cells/kg, and 3×10^6 CAR+ T cells/kg.

Official Title
-----------------
An Exploratory Study of αPD1-MSLN-CAR T Cells Secreting PD-1 Nanobodies for the Treatment of MSLN-positive Advanced Solid Tumors

Conditions
-----------------
Solid Tumor

Intervention / Treatment
-----------------
* Biological: αPD1-MSLN-CAR T cells


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients must have a histological or cytological diagnosis of advanced solid tumors, such as ovarian cancer，Cholangiocarcinoma，colorectal cancer; -Patients must have failed established standard medical anti-cancer therapies； Greater than or equal to 18 years of age on day of signing informed consent； -Life expectancy >3 months； Eastern Cooperative Oncology Group (ECOG) performance status of 0 , 1 or 2; Subjects must meet blood coagulation parameters and have adequate venous peripheral access for apheresis. Patients must also have adequate mononuclear cells for CAR T cell manufacturing； Staining of MSLN must be greater than 10% of the cells in the tumor tissue and with apparent expression in the membrane. PD-L1 expression must be positive. Tissue obtained for the biopsy must be ≤1 year prior to enrollment for screening, not have been previously irradiated or exposed to chemotherapy. If unavailable, new tissue material from a recently obtained surgical or diagnostic biopsy is mandatory for this trial； Satisfactory organ and bone marrow function as defined by the following: Adequate bone marrow function in the opinion of the Investigator for lymphocyte-depleting chemotherapy: absolute neutrophil count must be greater than ≥ 1.5×109/L, lymphocyte count must be greater than ≥ 0.5×109/L, platelets must be greater than ≥ 90×109/L, hemoglobin must be greater than ≥ 90g/L without transfusion within 7 days or dependency on EPO; Total bilirubin must be less than or equal to two times (≤2.0x) the institutional normal upper limit; transaminases, serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST), must be less than or equal to 2.5 times (≤2.5x) the institutional normal upper limit (≤2.5x if there is hepatic metastasis); Creatinine must be less than or equal to one and one half times (≤ 1.5x) the institutional normal upper limit or eGFR ≥ 60ml/min/1.73m^2 [eGFR=186×（age）-0.203×SCr-1.154（mg/dl）,for female the eGFR shoud be timed by 0.742]; International normalized ratio (INR) or the PT is not greater than one and one half times (≤ 1.5) the upper limit of normal; Lung function: ≤ CTCAE grade 1 dyspnea and SaO2≥ 91%; Cardiac function: cardiac ejection fraction (LVEF) must be greater than fifty percent (≥50%) by echocardiogram or MUGA one month before enrollment. Subjects must have measureable disease as defined by RECIST 1.1 criteria; Subjects sufficiently understand the trial and willingly sign the informed consent; For concurrent medication: Systemic therapeutic corticosteroids must be stopped 72 hours before CAR-T infusion. However, patients using physiologic replacement doses of corticosteroids, or its equivalent, will be considered eligible; Immunosuppressive therapy must be stopped within four (4) weeks prior to enrollment; Male and Female subjects agree to use approved contraceptive methods (e.g. birth control pills, barrier device, intrauterine device, abstinence) during the study and for at least 12 months following the last dose of the study cell infusion and until no CAR-T cells can be detected after two consecutive PCR tests. Exclusion Criteria: Prior therapy with targeted therapy or cell therapy against MSLN； Prior therapy with any gene therapy (including CAR-T cell therapy) or any T cell therapy home and abroad； Active bacteria, viral or fungal infection, and not contained after anti-infective therapy (positive results in the blood ≤72 hours before infusion); Patient is positive for Syphilis, Human Immunodeficiency Virus (HIV) , active Hepatitis B (HBsAg reactive) or Hepatitis C (HCV RNA (qualitative) is detected); Patient has a medical condition such as autoimmune disease or organ transplantation that requires chronic systemic steroid therapy or requires any other form of immunosuppressive medication; History of severe cardiac or pulmonary disease, including hypertension that cannot be controlled by medication, and any of the conditions occurred within the past 6 months: congestive heart failure (New York Heart Association functional classification ≥3), cardiac angioplasty and stents, myocardial infarction, unstable angina, or other clinically significant heart disease； Detectable clinically relevant central nervous system (CNS) metastases and/or pathology such as epilepsy/seizure, brain Ischemia/ hemorrhage, dementia, cerebellar disease, or autoimmune disease affecting central nervous system； Patient has a history or current evidence of any condition such as neurotic, psychiatric, immune, metabolic and infectious disease, on any therapy, or laboratory abnormality that might confound the results of the study, interfere with the patient's participation for the full duration of the study, or is not in the best interest of the patient to participate, in the opinion of the treating Investigator； Patient has a known history of a hematologic malignancy, or of another malignant primary solid tumor concurrently, with the exception of : Patients with in situ cervical cancer or breast cancer with no evidence of disease for ≥ 3 years after curative treatments; Patients who underwent successful definitive resection of in situ cancer with no evidence of disease for ≥5 years; Has had chemotherapy, radioactive, small molecules, biological cancer therapy, immunotherapy or other investigational drugs within 4 weeks prior to the initiation of the study； Pregnant or breastfeeding women; Investigators think that patient has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the patient's participation for the full duration of the study and cooperation with the requirements of the trial, uncontrolled medical, psychological, familial, sociological, or geographical conditions, or is not in the best interest of the patient to participate

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CAR T cells therapy<br>The safety and efficacy of αPD1-MSLN-CAR T cells will be assessed in a standard 3+3 dose escalation approach. Four doses of CAR T cells will be evaluated in this study: 1×10^5 CAR+ T cells/kg, 3×10^5 CAR+ T cells/kg, 1×10^6 CAR+ T cells/kg, and 3×10^6 CAR+ T cells/kg. | Biological: αPD1-MSLN-CAR T cells<br>* The safety and efficacy of αPD1-MSLN-CAR T cells will be assessed in a standard 3+3 dose escalation approach. Four doses of CAR T cells will be evaluated in this study: 1×10^5 CAR+ T cells/kg, 3×10^5 CAR+ T cells/kg, 1×10^6 CAR+ T cells/kg, and 3×10^6 CAR+ T cells/kg.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose-limiting toxicity （DLT） | Safety | After 28 days of single infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose (MTD) | Tolerability | After 28 days of single infusion | 
| Objective response rate (ORR) | Clinical response will be assessed by RECIST 1.1 | Month 12 | 
| Progression-free survival (PFS) | PFS of patients receiving αPD1-MSLN-CAR T cells | Month 12 | 
| Overall survival (OS) | OS of patients receiving αPD1-MSLN-CAR T cells | Month 12 | 
| Peak Plasma Concentration (Cmax) | Pharmacokinetics (PK) | Month 12 | 
| Pharmacodynamics (PD) | PD of IL-2, IL-4, IL-6, IL-8, IL-10, IL-15, IFN-γ, TNF-α and MCP1 will be analysed after CAR T cell infusion | Day 28 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
CAR T cells ,Solid tumors