A Pilot Study of NK Cell Combined With PD-1 Antibody as Second Line Therapy for Advanced Driver Mutation Negative Non-small Cell Lung Cancer

Study Overview
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Brief Summary
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PD-1 antibody has been approved as second line therapy for driven mutation negative non-small cell lung cancer, but overall response rate is only between 15-20%. Basic study found NK cell can enhance anti-tumor ability of PD-L1 antibody. This study evaluates the efficacy and safety of NK cell combined with PD-1 antibody for advanced driven mutation negative non-small cell lung cancer (NSCLC) as second-line therapy.

Detailed Description
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The incidence of non-small cell lung cancer is high, and most patients are in advanced stage at the time of diagnosis, and the overall prognosis is poor. Currently, patients with advanced non-small cell lung cancer are treated individually according to the molecular and histological features of the tumor. For patients with negative driver mutation in EGFR, ALK, ROS1, BRAF and other driving genes, platinum-based dual chemotherapy combined with PD-1/PD-L1 monoclonal antibody is recommended for first-line treatment. In patients who have not used PD-1/PD-L1 antibody in first-line therapy, the second-line treatment regimen is the first choice for the recommended single-agent PD1/PD-L1 antibody. However, the current efficacy of PD-1/PD-L1 antibody for second-line treatment of advanced non-small cell lung cancer is limited, only between 15-20%. NK cells secrete IFN to promote the expression of PD-L1 in tumor cells and enhance the role of PD-1 inhibitors. At the same time, PD-1 antibodies can bind to NK cell surface PD-1, prevent NK cell depletion, and enhance NK cell anti-tumor. Therefore, the application of NK cells combined with PD-1 antibody in the treatment of patients with advanced non-small cell lung cancer may achieve better results.

Official Title
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A Pilot Study of NK Cell Combined With PD-1 Antibody as Second Line Therapy for Advanced Driver Mutation Negative Non-small Cell Lung Cancer

Conditions
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Non-small Cell Lung Cancer

Intervention / Treatment
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* Combination Product: NK cell and PD-1 antibody


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: (1) Age ≥ 18 years old. (2) Locally advanced (IIIB/IIIC phase) or metastatic NSCLC (squamous or non-squamous) confirmed by histological examination. (3) Disease progression occurred after platinum-based chemotherapy in the previous line, and measurable lesions existed according to RECIST v1.1. (4) Patients must be able to provide fresh or archived tumor tissue and pathology reports. Non-squamous NSCLC must be able to provide a report that is confirmed to be wild-type EGFR by tissue-based assays. (5) ECOG PS ≤ 1. (6) The vital organs are fully functional, and the following results are obtained for each laboratory indicator (accepting the results of the examinations made within ≤ 28 days before randomization): Cardiac ultrasound indicates a cardiac ejection fraction ≥ 50%; blood oxygen saturation ≥ 90%; Absolute neutral cell count (ANC) ≥ 1.5 x 109/L, platelet count ≥ 100 x 109/L, hemoglobin ≥ 90g/dL; Creatinine (Cr) ≤ 2.5 times normal range; Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 times normal range, total bilirubin (TBIL) ≤ 1.5 times normal range. (7) No contraindications for apheresis and cell separation. (8) Male or female with fertility needs to agree to take effective contraceptive measures during the study period and at least 120 days after the end of medication. (9) A written informed consent can be provided and the research requirements are understood and followed. Exclusion Criteria: (1) Previously received immunological checkpoint inhibitors targeting PD-1, PD-L1 or CTLA-4 and other immunotherapies (including but not limited to interferon or IL-2, chimeric antigen receptor T Cells, vaccines, etc.). (2) NSCLC with EGFR gene mutation or ALK gene translocation. (3) The toxicity caused by previous anticancer treatment has not recovered to baseline level or returned to stability (except for hair loss, rash, pigmentation or specific laboratory abnormalities). (4) A history of severe allergic reactions to other monoclonal antibodies. (5) History of interstitial pneumonia, non-infectious pneumonia or uncontrolled systemic diseases, including diabetes, hypertension, and pulmonary fibrosis. (6) Clinically severe pericardial effusion. (7) Pleural effusion or ascites that is clinically uncontrolled and requires thoracentesis or abdominal puncture drainage within 2 weeks prior to randomization. (8) Active pia mater disease or unstable brain metastasis. (9) Major surgery, open biopsy or severe traumatic injury was performed ≤ 28 days prior to randomization, or major surgical procedures were expected during the study. (10) Other malignant tumors other than NSCLC (except for surgically resected non-melanoma skin cancer, fully treated cervical carcinoma in situ, cured local prostate cancer, fully treated low-grade bladder cancer, Curatively treated breast ductal carcinoma in situ, or a malignant tumor diagnosed 2 years ago, but there is currently no evidence of disease in the absence of treatment ≤ 2 years prior to randomization). (11) Severe chronic or active infections requiring systemic antibacterial, antifungal or antiviral treatment, including HIV, HBV, HCV infection. (12) Active autoimmune disease or a history of autoimmune disease but may recur. (13) Subjects who require systemic treatment with corticosteroids or other immunosuppressive agents within 14 days prior to randomization. (14) Those who have undergone organ transplantation or hematopoietic stem cell transplantation. (15) Any live vaccine against infectious diseases (eg, influenza, chickenpox, etc.) was used within 28 days prior to randomization. (16) Meet any of the following cardiovascular disease criteria: Evidence of acute or positive myocardial ischemia There are currently symptomatic pulmonary embolisms Acute myocardial infarction occurred within ≤6 months before randomization. Has reached the New York Heart Association grading standard (see Appendix 5) 3 or 4 before randomization ≤ 6 months Grade of heart failure. A ≥2 grade ventricular arrhythmia occurred within ≤6 months before randomization. A cerebrovascular accident (CVA) or transient ischemic attack (TIA) occurred within ≤6 months before randomization. (17) Pregnant and lactating women. (18) If the patient is unable to follow the study procedures, limitations, and requirements, the investigator believes that the patient is not allowed to participate in the study.

Ages Eligible for Study
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Minimum Age: 18 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: NK cell combined with PD-L1 antibody<br>Autologous peripheral blood mononuclear cells (PBMCs) are collected by apheresis on D0, then induced into NK cells and infused into the patients 14 days later (D14) as the initial transfusion. There are 3 consecutive transfusion days (D14-D16), total NK cells infused at least 3×10^9 . 200mg PD-L1 antibody(Sintilimab Injection) will be given on D14, 1 hour after NK cells infusion. NK cells and PD-L1 antibody will be infused every 21 days until disease progression or unacceptable adverse events. | Combination Product: NK cell and PD-1 antibody<br>* Each patient enrolled the study will received both NK cell and PD-1 antibody.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival(PFS) | From the random date until the date when the objective disease progression (evaluated by the investigator according to RECIST 1.1) or for any reason (whichever occurs first) is confirmed, based on the ITT set. | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate(ORR) | The proportion of patients with CR or PR (evaluated by the investigator according to RECIST 1.1), based on the ITT set. | 12 months | 
| Overall Survival(OS) | The time from the random date to the date of death for any reason, based on the ITT population. | 12 months | 
| Duration of Response(DoR) | The time from the first confirmed objective remission to recurrence (evaluated by the investigator according to RECIST 1.1) or for any reason, whichever occurs first. | 12 months |