Anti-MUC1 CAR T Cells and PD-1 Knockout Engineered T Cells for NSCLC

Study Overview
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Brief Summary
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The study is to assess the safety and efficacy of the anti-MUC1 CAR T cells and /or PD-1 knockout engineered T cells for patients with advanced non-small cell lung cancer.

Detailed Description
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This is a combined phase 1 and 2 clinical study. The study is to assess the safety and efficacy of the anti-MUC1 CAR T cells and /or PD-1 knockout engineered T cells for patients with advanced non-small cell lung cancer. The treatment outcomes will be compared.

Official Title
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A Clinical Study of Anti-MUC1 CAR T Cells and PD-1 Knockout Engineered T Cells for Patients With Advanced Non-small Cell Lung Cancer

Conditions
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Lung Neoplasm Malignant, Non-small Cell Lung Cancer

Intervention / Treatment
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* Biological: CAR-T Cells
* Combination Product: CAR-T combining PD-1 Knockout
* Biological: PD-1 knockout
* Drug: PD-1 mAb
* Other: Sham control


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: MUC1 is expressed in malignancy tissues by immuno-histochemical (IHC). Eastern cooperative oncology group (ECOG) performance status of 0-1 or karnofsky performance status (KPS) score is higher than 60. Patients have a life expectancy > 12 weeks. Adequate venous access for apheresis or venous sampling, and no other contraindications for leukapheresis. Negative pregnancy test for females of child-bearing potentials. Adequate bone marrow, liver and renal function as assessed by the following laboratory requirements: White blood cell count (WBC) ≥ 2500c/ml, Platelets ≥ 50×10^9/L, Hb ≥ 9.0g/dL, lymphocyte (LY) ≥ 0.7×10^9/L, LY% ≥ 15%, Alb ≥ 2.8g/dL, serum lipase and amylase < 1.5×upper limit of normal, serum creatinine ≤ 2.5mg/dL, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 5×upper limit of normal, serum total bilirubin ≤ 2.0mg/dL. These tests must be conducted within 7 days prior to registration. Signed informed consent form. Exclusion Criteria: Number of T cells is less than 10% or the amplification of the T cells via artificial antigen presenting cell (aAPC) stimulation is less than 5 times. Patients with symptomatic central nervous system (CNS) involvement. Pregnant or nursing women. Known HIV infection. Serious illness or medical condition which would not permit the patient to be managed according to the protocol, including active uncontrolled infection, major cardiovascular, coagulation disorders, respiratory or immune system, myocardial infarction, cardiac arrhythmias, obstructive/restrictive pulmonary disease, or psychiatric or emotional disorders. History of severe immediate hypersensitivity to any of the agents including cyclophosphamide, fludarabine, or aldesleukin. Concurrent use of systemic steroids. Recent or current use of inhaled steroids is not exclusionary. Previously treatment with any gene therapy products. The existence of unstable or active ulcers or gastrointestinal bleeding. Patients with portal vein vascular invasion or extrahepatic, are excluded from this study. Patients with a history of organ transplantation or are waiting for organ transplantation.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CAR-T<br>Anti-MUC1 CAR-T cells will be prepared ex vivo and infused back to the patients. | Biological: CAR-T Cells<br>* Using the T cells from the patients to produce anti-MUC1 CAR-T Cells and then the cells will be infused back to the patients.<br>|
| Experimental: CAR-T combining PD-1 knockout<br>Anti-MUC1 CAR-T cells and PD-1 knockout Engineered T cells will be prepared ex vivo and infused back to the patients. | Biological: CAR-T Cells<br>* Using the T cells from the patients to produce anti-MUC1 CAR-T Cells and then the cells will be infused back to the patients.<br>Combination Product: CAR-T combining PD-1 Knockout<br>* Using the T cells from the patients to prepare anti-MUC1 CAR-T Cells and PD-1 knockout T cells, then the cells will be infused back to the patients<br>Biological: PD-1 knockout<br>* Using the T cells from the patients to prepare PD-1 knockout T cells, then the cells will be infused back to the patients<br>|
| Experimental: PD-1 knockout<br>PD-1 knockout Engineered T cells will be prepared ex vivo and infused back to the patients. | Biological: PD-1 knockout<br>* Using the T cells from the patients to prepare PD-1 knockout T cells, then the cells will be infused back to the patients<br>|
| Active Comparator: PD-1 mAb<br>Patients will be treated with a FDA approved monoclonal antibody for an identical course of treatment. This group will serve as PD-1 antibody treated group. | Drug: PD-1 mAb<br>* Patients will be treated with an identical course with a FDA approved monoclonal antibody against PD-1<br>* Other names: Keytruda;|
| Placebo Comparator: Sham Control<br>Patient's T cells will be separate without genetic or engineered modification ex vivo and infused back to the patients. | Other: Sham control<br>* Patient's T cell will treated ex vivo with modification and then infused back in a similar time course.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with adverse events and dose limiting toxicities as assessed by CTCAE v4.0 | Safety and tolerability of dose of CART-cells and PD-1 Knockout T cells will be assessed using CTCAE v4.0. | approximately 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response Rate | Will be assessed according to the revised RECIST guideline v1.1 | 6 months | 
| Overall Survival - OS | Measure the time from enrollment to death | Up to 24 months | 
| Progression free survival - PFS | Time from enrollment to date of first documented progression or date of death. | Up to 12 months | 
| Median CAR-T cell persistence | Will be measured by quantitative RT-PCR | 4 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CAR-T cell therapy, MUC+, PD-1 Knockout, Non-small cell lung cancer