Single Center Single Arm Clinical Prospective Study of Neoantigen Reactive T Cells (NRTs) Combined With Programmed Cell Death-1（PD-1） Inhibitor in the Treatment of Chinese Patients With Advanced Refractory Solid Tumors
试验速览
- 阶段
- 1 期
- 发起方
- 入组人数
- 40
- 试验地点
- 1
- 主要终点
- Number of participants with Adverse Events
研究概览
简要总结
The purpose of this study is to see the safety and efficient of neoantigen reactive T cells (NRTs) combined with programmed cell death-1(PD-1) inhibitor（SHR-1210）in the treatment of Chinese patients with advanced refractory solid tumors.
详细描述
The tumor-specific "none-self" immunogenic neoantigens encoded by either viral genes or somatic mutation genes, possess the potential to induce specific anti-cancer immunity, including cellular and humoral immune responses. Today, numerous clinical trials demonstrate that although these "none-self" antigens initiate the antigen-specific immunoglobulin G antibodies and cluster of differentiation 4（CD4）+/cluster of differentiation 8（CD8）+T-cells response, not all of them show a clinical benefit in the response rate, progression-free survival or overall survival.Immune tolerance induced by PD-1 or programmed cell death-ligand1（ PD-L1）maybe play a vital role for these negative outcomes.Personalized cell therapy plus checkpoint inhibitors maybe own a breakthrough in the treatment of those malignant diseases without standard options.Our center has successfully established a new method for preparing personalized neoantigen reactive T cells(NRTS) for adoptive cell therapy(ACT). Today, we will carry out a single center single arm clinical prospective study of NRTs combined with PD-1 inhibitor(SHR-1210) for the treatment of Chinese patients with advanced refractory solid tumors. Participants are assigned to receive 4 circles of cell therapy,and prior to each cycle's immunocytes treatment,preconditional chemotherapy and SHR-1210 will be carried out, and IL-2 continuous intravenous infusion（CIV） will also be given for 5 consecutive days after each time's cell infusion. The safety and clinical response rate（RR） are evaluated. Biomarkers and immunological markers are also monitored.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Adult patients aged 18 to 75 years old
- •Histologic or cytologic confirmation of advanced refractory solid tumors with no available curative treatment options
- •At least one measurable disease: diameter ≥20mm or spiral computed tomography(CT)≥10mm; and can providing with tumor specimen (for testing the expression of PD -L1 and the infiltrating lymphocytes)
- •Must be human leukocyte antigen (HLA)-A2/A24/A11 positive
- •Eastern Cooperative Oncology Group(ECOG)<0-2 and expected survival time 3 months or more
- •At least one new antigen can induce T cell secrete interferon - gamma (IFN - gamma) twice as normal controls during the new antigens screening
- •Without anticancer treatment more than one month
- •Hematology Index including: Neutrophile granulocyte greater than 1.5×10^9/L; Hemoglobin greater than 10g/dL; Platelet greater than 100×10^9/L
- •Biochemical index including: Serum bilirubin not greater than 1.5x upper limit of reference range (ULN); glutamic-pyruvic transaminase（ALT） or glutamic-oxalacetic transaminase（AST） not greater than 2.5x ULN; Creatinine clearance no less than 60ml/min
- •Peripheral venous channel open and no contraindications to separating lymphocytes
- •Negative pregnancy test for women of childbearing potential, and patients must be willing to practice birth control during the regimen
- •Provision of informed consent
- •Be able to follow the research program and follow up process
排除标准
- •Those who now are undergoing other antitumor drug therapy (including chemotherapy, systemic steroids therapy, surgery, target therapy or immune therapy);
- •Prior treatment with PD-1 monoclonal antibody(mAb） or PD-L1 mAb;
- •Prior malignancy active within the previous 5 years except for locally curable cancers that have been apparently cured, such as basal cell skin cancer or carcinoma in situ of the cervix;
- •History with pulmonary tuberculosis, and positive tests for Acquired Immune Deficiency Syndrome(HIV),hepatitis C virus(HCV),hepatitis B virus(HBV);
- •Patients with any active autoimmune disease or a documented history of autoimmune disease, or history of syndrome that required systemic steroids or immunosuppressive medications, such as hypophysitis, pneumonia, colitis, hepatitis, nephritis, hyperthyroidism or hypothyroidism; Severe, uncontrolled medical condition that would affect patients' compliance or obscure the interpretation of toxicity determination or adverse events, including active severe infection, uncontrolled diabetes, angiocardiopathy (heart failure > class II New York Heart Association(NYHA), heart block >II grade, myocardial infarction, unstable arrhythmia or unstable angina within past 6 months, cerebral infarction within past 3 months) or pulmonary disease ( interstitial pneumonia, obstructive pulmonary disease or symptomatic bronchospasm).
- •Evidence with central nervous system(CNS) disease
- •Pregnant or nursing
- •Psychiatric medicines abuse without withdrawal, or history of psychiatric illness.
- •Hypersensitivity to investigational drugs or its components.
研究组 & 干预措施
Neoantigen Reactive T Cells + SHR-1210
Peripheral blood lymphocytes will be collected and neoantigen reactive T cells(NRTs) will be generated in the laboratory;Both Fludarabine 30mg/m2/D and Cyclophosphamide 300mg/m2/D will be i.v. for 3 days before cell infusion; NRTs 0.5~1 x 10^10, will be i.v.Q3 weeks for total 4 doses;programmed cell death-1（PD1） inhibitor SHR-1210,200mg,will be i.v. Q3 weeks for total 4 doses,2 day2 prior to each NRTs infusion;Interleukin-2 (IL-2) will be continuous intravenous infused since the first day of the cell infusion for 5 consecutive days, 4000,000 international unit per day.All Patients will receive a total of 4 cycles of treatment.
干预措施: Neoantigen Reactive T Cells(NRTs) (Biological)
Neoantigen Reactive T Cells + SHR-1210
Peripheral blood lymphocytes will be collected and neoantigen reactive T cells(NRTs) will be generated in the laboratory;Both Fludarabine 30mg/m2/D and Cyclophosphamide 300mg/m2/D will be i.v. for 3 days before cell infusion; NRTs 0.5~1 x 10^10, will be i.v.Q3 weeks for total 4 doses;programmed cell death-1（PD1） inhibitor SHR-1210,200mg,will be i.v. Q3 weeks for total 4 doses,2 day2 prior to each NRTs infusion;Interleukin-2 (IL-2) will be continuous intravenous infused since the first day of the cell infusion for 5 consecutive days, 4000,000 international unit per day.All Patients will receive a total of 4 cycles of treatment.
干预措施: SHR-1210 (Biological)
Neoantigen Reactive T Cells + SHR-1210
Peripheral blood lymphocytes will be collected and neoantigen reactive T cells(NRTs) will be generated in the laboratory;Both Fludarabine 30mg/m2/D and Cyclophosphamide 300mg/m2/D will be i.v. for 3 days before cell infusion; NRTs 0.5~1 x 10^10, will be i.v.Q3 weeks for total 4 doses;programmed cell death-1（PD1） inhibitor SHR-1210,200mg,will be i.v. Q3 weeks for total 4 doses,2 day2 prior to each NRTs infusion;Interleukin-2 (IL-2) will be continuous intravenous infused since the first day of the cell infusion for 5 consecutive days, 4000,000 international unit per day.All Patients will receive a total of 4 cycles of treatment.
干预措施: Fludarabine (Drug)
Neoantigen Reactive T Cells + SHR-1210
Peripheral blood lymphocytes will be collected and neoantigen reactive T cells(NRTs) will be generated in the laboratory;Both Fludarabine 30mg/m2/D and Cyclophosphamide 300mg/m2/D will be i.v. for 3 days before cell infusion; NRTs 0.5~1 x 10^10, will be i.v.Q3 weeks for total 4 doses;programmed cell death-1（PD1） inhibitor SHR-1210,200mg,will be i.v. Q3 weeks for total 4 doses,2 day2 prior to each NRTs infusion;Interleukin-2 (IL-2) will be continuous intravenous infused since the first day of the cell infusion for 5 consecutive days, 4000,000 international unit per day.All Patients will receive a total of 4 cycles of treatment.
干预措施: Cyclophosphamide (Drug)
Neoantigen Reactive T Cells + SHR-1210
Peripheral blood lymphocytes will be collected and neoantigen reactive T cells(NRTs) will be generated in the laboratory;Both Fludarabine 30mg/m2/D and Cyclophosphamide 300mg/m2/D will be i.v. for 3 days before cell infusion; NRTs 0.5~1 x 10^10, will be i.v.Q3 weeks for total 4 doses;programmed cell death-1（PD1） inhibitor SHR-1210,200mg,will be i.v. Q3 weeks for total 4 doses,2 day2 prior to each NRTs infusion;Interleukin-2 (IL-2) will be continuous intravenous infused since the first day of the cell infusion for 5 consecutive days, 4000,000 international unit per day.All Patients will receive a total of 4 cycles of treatment.
干预措施: Interleukin-2 (Biological)
结局指标
主要结局
Number of participants with Adverse Events
时间窗: up to 6 months
using Common Terminology Criteria for Adverse Events (CTCAE v4.0) in patients
次要结局
- Response Rate(At 3, 6 and 12 months)
- Progression free survival (PFS)(At 6,9 and 12 months)
研究者
Zhengyun Zou
Chief physician
The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School