PD-1 Knockout Engineered T Cells for Metastatic Non-small Cell Lung Cancer

Study Overview
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Brief Summary
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This study will evaluate the safety of PD-1 knockout engineered T cells in treating metastatic non-small cell lung cancer. Blood samples will also be collected for research purposes.

Detailed Description
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This is a dose-escalation study of ex-vivo knocked-out, expanded, and selected PD-1 knockout-T cells from autologous origin. Patients are assigned to 1 of 3 treatment groups to determine the maximal tolerant dose. After the lower number of cycles are considered tolerant, an arm of the next higher number of cycles will be open to next patients. Biomarkers and immunological markers are collected and analyzed as well.

Official Title
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A Phase I Clinical Trial of PD-1 Knockout Engineered T Cells Treating Patients With Advanced Non-small Cell Lung Cancer

Conditions
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Metastatic Non-small Cell Lung Cancer

Intervention / Treatment
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* Drug: Cyclophosphamide
* Other: PD-1 Knockout T Cells


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Pathologically verified stage IV non-small cell lung cancer with measurable lesions (On CT: longest diameter of tumoral lesion >=10 mm, shorted diameter of lymph node >=15 mm; measurable lesions should not have been irradiated) Progressed after all standard treatment Performance score: 0-1 Expected life span: >= 6 months Toxicities from prior treatment has resolved. Washout period is 4 weeks for chemotherapy, and 2 weeks for targeted therapy Major organs function normally Women at pregnant ages should be under contraception Willing and able to provide informed consent Exclusion Criteria: Pathology is mixed type Emergent treatment of tumor emergency is needed Poor vasculature Coagulopathy, or ongoing thrombolytics and/or anticoagulation Blood-borne infectious disease, e.g. hepatitis B History of mandatory custody because of psychosis or other psychological disease inappropriate for treatment deemed by treating physician With other immune diseases, or chronic use of immunosuppressants or steroids Compliance cannot be expected Other conditions requiring exclusion deemed by physician

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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A - Two cycles<br>Peripheral blood lymphocytes will be collected and Programmed cell death protein 1(PDCD1) gene will be knocked out by CRISPR Cas9 in the laboratory (PD-1 Knockout T cells). The lymphocytes will be selected and expanded ex vivo and infused back into patients. Cyclophosphamide at 20mg/kg single dose will be administered 3 days i.v. before cell infusion. A total of 1 x 10^7/kg PD-1 Knockout T cells will be infused in one cycle. Each cycle is divided into three administrations, with 20% infused in the first administration, 30% in the second, and the remaining 50% in the third. Patients will receive a total of two cycles of treatment. | Drug: Cyclophosphamide<br>* To deplete Tregs before collecting peripheral blood<br>* Other names: Cytoxan;Other: PD-1 Knockout T Cells<br>* Autologous lymphocytes are collected and PDCD1 gene is knocked out in the laboratory. Cells are selected and expanded ex vivo. Cells are infused back to the patients for treatment<br>|
| Experimental: B- Two cycles<br>Peripheral blood lymphocytes will be collected and Programmed cell death protein 1(PDCD1) gene will be knocked out by CRISPR Cas9 in the laboratory (PD-1 Knockout T cells). The lymphocytes will be selected and expanded ex vivo and infused back into patients. Cyclophosphamide at 20mg/kg single dose will be administered 3 days i.v. before cell infusion. A total of 2 x 10^7/kg PD-1 Knockout T cells will be infused in one cycle. Each cycle is divided into three administrations, with 20% infused in the first administration, 30% in the second, and the remaining 50% in the third. Patients will receive a total of two cycles of treatment. | Drug: Cyclophosphamide<br>* To deplete Tregs before collecting peripheral blood<br>* Other names: Cytoxan;Other: PD-1 Knockout T Cells<br>* Autologous lymphocytes are collected and PDCD1 gene is knocked out in the laboratory. Cells are selected and expanded ex vivo. Cells are infused back to the patients for treatment<br>|
| Experimental: C- Two cycles<br>Peripheral blood lymphocytes will be collected and Programmed cell death protein 1(PDCD1) gene will be knocked out by CRISPR Cas9 in the laboratory (PD-1 Knockout T cells). The lymphocytes will be selected and expanded ex vivo and infused back into patients. Cyclophosphamide at 20mg/kg single dose will be administered 3 days i.v. before cell infusion. A total of 4 x 10^7/kg PD-1 Knockout T cells will be infused in one cycle. Each cycle is divided into three administrations, with 20% infused in the first administration, 30% in the second, and the remaining 50% in the third. Patients will receive a total of two cycles of treatment. | Drug: Cyclophosphamide<br>* To deplete Tregs before collecting peripheral blood<br>* Other names: Cytoxan;Other: PD-1 Knockout T Cells<br>* Autologous lymphocytes are collected and PDCD1 gene is knocked out in the laboratory. Cells are selected and expanded ex vivo. Cells are infused back to the patients for treatment<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/or Dose Limiting Toxicities as a Measure of Safety and Tolerability of Dose of PD-1 Knockout T Cells Using Common Terminology Criteria for Adverse Events (CTCAE v4.0) in Patients |  | Dose Escalation - Approximately 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients With Overall Response | Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. | 3 months | 
| Number of Patients With Disease Control at 8 Weeks | Response will be evaluated according to RECIST v1.1 for target lesions at Week 8：Complete Response (CR), Disappearance of all extranodal target lesions; Partial Response (PR) ≥ 30% decrease in the sum of diameters of target lesions; Stable Disease (SD) Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD; Disease control = CR +PR+SD | 8 weeks | 
| Progression Free Survival (PFS) | Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions | The time from the date of first edited T cell infusion to the date of disease progression or death due to any reason. | 
| Overall Survival (OS) | OS is defined as the time interval from date of first edited T cell infusion to the date of death due to any reason | The duration from date of first edited T cell infusion to the date of death due to any reason | 
| Number of Participants With Genes Mutations in Peripheral Blood Circulating Tumor DNA (ctDNA) | Driver genes mutaion stauts of Participants in ctDNA from peripheral blood were assessed by next generation sequencing (NGS), to explore the positive rate of sepicif driver genes (e.g. EGFR, ALK, ROS1, etc.) and the relationship between gene mutation status and clinical response | Baseline | 
| Interleukin-6 Change in the Peripheral Blood. | Peripheral Interleukin-6 level at different timepoint (Baseline, 1 month and 3 month) was measured using rate nephelometry | Baseline, 1 month and 3 month | 
| Interleukin-10 Change in the Peripheral Blood. | Peripheral Interleukin-10 level at different timepoint (Baseline, 1 month and 3 month) was measured using chemiluminescence. | Baseline, 1 month and 3 month | 
| Tumor Necrosis Factor-a Change in the Peripheral Blood. | Peripheral Tumor Necrosis Factor-a level at different timepoint (Baseline, 1 month and 3 month) was measured using chemiluminescence. | Baseline, 1 month and 3 month | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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lung cancer, immune checkpoint, PD-1, CRISPR, autologous cell infusion