An Open Label, Randomized Controlled Clinical Study on the Safety and Efficacy of Virus Activated Killer Immune Cells (VAK) in the Treatment of Malignant Pleural and Peritoneal Effusion
试验速览
- 阶段
- 早期 1 期
- 状态
- 招募中
- 发起方
- 入组人数
- 90
- 试验地点
- 1
- 主要终点
- Incidence of AEs and SAEs
研究概览
简要总结
Theory of VAK：
- Immune cells (T cells for example) of cancer subjects may be domesticated by the tumor microenvironment, and have low efficacy to kill cancer cells. They could be restimulated by virus antigen, and play a powerful tumor killing role while intrapleural to subjects.
- Releasing of tumor-associated antigen could induce specific anti-tumor immune response.
Preparation of VAK：
- Separate the immune cells and tumor cells from Malignant Pleural and Peritoneal Effusion.
- Incubate the immune cells with inactivated viruses and tumor cells.
- Wash to remove impurities.
- Intrapleural the immune cells to patients
详细描述
There are a large number of immune cells in immune tolerance state in the tumor microenvironment. The theoretical basis of this clinical study is to use ultraviolet inactivated oncolytic herpes simplex virus type 2 (UV-oHSV2) to activate PBMC or immune cells in immune tolerance state in malignant pleural and peritoneal fluid in vitro, and to transfusion the activated immune cells back to the patient's peripheral blood or pleural and peritoneal fluid to kill tumor cells in malignant pleural and peritoneal fluid to further control the volume of malignant pleural and peritoneal fluid.
Our study indicated that UV-oHSV2 potently activated human peripheral blood mononuclear cells leading to increased antitumor activity in vitro and in vivo. We also found that UV-oHSV2 could induce NK cells (isolated from healthy donors' PBMC or patient pleural effusion) proliferation, secretion of IFN-γ. We further found that UV-oHSV2 could enhance NK cells (isolated from healthy PBMC or patient pleural effusion) antitumor ability in vitro and in vivo.
Based on the above research, we carried out an open, single center, prospective clinical trial to evaluate the safety and effectiveness of VAK cells in the treatment of malignant pleural and peritoneal effusions.
The detailed protocol as follow:
Isolation of lymphocytes from the patient's pleural effusions or ascites:
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Willing to sign informed consent;
- •Pathological confirmed advanced malignant tumor with malignant pleural or peritoneal effusion;
- •Vital signs stable, Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2;
- •Age ≥ 18 years old, gender unlimited;
- •Expected survival period more than 3 months;
- •Subjects agree to take effective contraceptive measures at the time of enrollment and within 4 months after enrollment. The pregnancy test of female patients must be negative;
- •Sufficient bone marrow, liver and kidney functions. Laboratory tests within 7 days before the first drug use meet the following requirements:
- •Coagulation function: APTT ≤ 1.5 × ULN, while INR or PT ≤ 1.5 × ULN (not receiving anticoagulant therapy); ② Blood routine examination: Hgb ≥ 80g / L, WBC > 3 × 10^9/L、NEU≥1.0 × 10^9/L、PLT≥80 × 10^9/L;
- •Liver function: total bilirubin ≤ 1.5 times the upper limit of normal value (ULN); AST and alt ≤ 2.5 times ULN (if abnormal liver function is mainly caused by tumor infiltration, it can be ≤ 5 times ULN; alkaline phosphatase ≤ 2.5 times ULN; ④ Renal function: bun and Cr ≤ 1.5 times ULN, creatinine clearance ≥ 40ml / min (calculated by Cockcroft Gault formula).
排除标准
- •Subjects requiring emergency treatment due to intestinal obstruction or vascular compression;
- •Subjects with active hemolytic anemia;
- •Subjects with active central nervous system metastases were excluded, except those with brain metastases or asymptomatic cancer cells found in cerebrospinal fluid;
- •Pregnant or lactating female;
- •Systemic active infection, serious coagulation disorder or serious heart, respiratory and immune system diseases;
- •Congenital or acquired immune function defects (such as HIV infection), hepatitis B infection (HBV-DNA ≥ 10 ^ 4 / ml), hepatitis C infection (HCV antibody and HCV RNA positive);
- •Subjects who had serious infection within 4 weeks before the first medication were excluded, including but not limited to infectious complications, bacteremia and severe pneumonia requiring hospitalization;
- •Subjects with active autoimmune diseases or a history of autoimmune diseases that may recur, but the following are not excluded:
- •Type 1 diabetes
- •Hypothyroidism (if controlled by hormone replacement therapy only)
- •Controlled celiac disease ④ Skin diseases without systemic treatment (such as vitiligo, psoriasis, alopecia) ⑤ Any other disease that does not recur without external triggers.
- •Those who had severe hypersensitivity to the drugs used in this protocol in the past;
- •Subjects who are ready for or have previously received tissue / organ transplantation;
- •Subjects with large pericardial effusion were excluded;
- •Exclude those who have suffered from other malignant tumors within 2 years, except for cervical carcinoma in situ, low-risk gastrointestinal stromal tumor, skin basal cell carcinoma, skin squamous cell carcinoma, thyroid papillary carcinoma and breast ductal carcinoma in situ that have been effectively removed;
- •Exclude subjects who have been vaccinated or will be vaccinated with live vaccine within 4 weeks before the first administration;
- •Other circumstances that the investigator considers inappropriate for clinical trials.
研究组 & 干预措施
Virus Activated Killer immune Cells（VAK）
The VAK should be given once a week, three times a circle. The VAK could given 1 or 2 circle for each subject. The dosage of Pleural Effusion（more than 10^5/kg cells in 30-50mL solvent） differs from Peritoneal Effusion（more than 10^4/kg cells in 30-50mL solvent）
干预措施: Virus Activated Killer immune Cells (Drug)
saline
50ml of saline was injected once a week,three times a circle.The saline could given 1 or 2 circle for each subject.
干预措施: Saline (Drug)
结局指标
主要结局
Incidence of AEs and SAEs
时间窗: 28 days after the last treatment.
Incidence of adverse events (AEs) and serious adverse events (SAEs) graded according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v5.0.
次要结局
- Overall Survival(up to 2 year.)
- ORR of Malignant Pleural and Peritoneal Effusion by WHO 1997(28 days after the last treatment.)
- Progression Free Survival(up to 1 year.)
研究者
Sheng Hu
chief physician
Hubei Cancer Hospital