CAR T and PD-1 Knockout Engineered T Cells for Esophageal Cancer

Study Overview
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Brief Summary
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The study is to assess the safety and efficacy of the immunotherapies using anti-MUC1 CAR T cells and /or PD-1 knockout engineered T cells in the treatment of patients with advanced esophageal cancer.

Detailed Description
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This is a combined phase 1 and 2 clinical study. The aim of the study is to assess the safety and efficacy of the immunotherapies using anti- MUC1 CAR T cells alone, anti- MUC1 CAR T combining PD-1 knockout engineered T cells, and PD-1 knockout engineered T cell only in the treatment of patients with advanced esophageal cancer. The treatment outcomes from each group will be compared.

Official Title
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Combination Therapy of Anti-MUC1 CAR T Cells and PD-1 Knockout Engineered T Cells for Advanced Esophageal Cancer

Conditions
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Advanced Esophageal Cancer

Intervention / Treatment
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* Biological: Anti-MUC1 CAR-T cells
* Biological: PD-1 knockout Engineered T cells
* Combination Product: CAR-T combined with PD-1 Knockout T cells


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Confirmed diagnosis of advanced esophageal cancer (phase IIIb-IV) according to NCCN clinical practice guidelines in Oncology:Esophageal and Esophagogastric Junction Cancers (2018.V1). MUC1 is highly 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, HBV and HCV 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: 80 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: Treatment with Anti-MUC1 CAR-T cells<br>Anti-MUC1 CAR-T cells will be prepared ex vivo using the T cells from the patients and infused back to the patients. | Biological: Anti-MUC1 CAR-T cells<br>* Using the T cells from the patients' blood to produce anti-MUC1 CAR-T Cells and then the cells will be infused back to the patients.<br>|
| Experimental: Combination Therapy: CAR-T combining PD-1 knockout T Cells<br>Anti-MUC1 CAR-T cells and PD-1 knockout Engineered T cells will be prepared ex vivo using the T cells from the patients and infused back to the patients. | Combination Product: CAR-T combined with PD-1 Knockout T cells<br>* Using the T cells from the blood of 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>|
| Experimental: Treatment with PD-1 knockout Engineered T cells<br>PD-1 knockout Engineered T cells will be prepared ex vivo using the T cells from the patients and infused back to the patients. | Biological: PD-1 knockout Engineered T cells<br>* Using the T cells from the blood of the patients to prepare PD-1 knockout T cells, then the cells will be infused back to the patients.<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 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response Rate | Will be assessed according to the revised RECIST guideline v1.1 | 12 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 | 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Esophageal cancer, Neoplasms, Esophageal, Cancer of Esophagus, Solid tumor