Glypican 3-specific Chimeric Antigen Receptor Expressed in Autologous T Cells as Immunotherapy for Patients With Pediatric Solid Tumors
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 入组人数
- 10
- 试验地点
- 1
- 主要终点
- Number of Patients with Dose Limiting Toxicity
研究概览
简要总结
This study enrolls patients who have GPC3-positive solid tumors currently. Patients may be considered if the cancer has come back, has not gone away after standard treatment or the patient cannot receive standard treatment. This research study uses special immune system cells called GAP T cells, a new experimental treatment.
The body has different ways of fighting infection and disease. No single way seems perfect for fighting cancers. This research study combines two different ways of fighting cancer: antibodies and T cells. Antibodies are types of proteins that protect the body from infectious diseases and possibly cancer. T cells, also called T lymphocytes, are special infection-fighting blood cells that can kill other cells, including cells infected with viruses and tumor cells. Both antibodies and T cells have been used to treat patients with cancers. They have shown promise, but have not been strong enough to cure most patients.
Investigators have found from previous research that they can put a new gene into T cells that will make them recognize cancer cells and kill them. In preclinical studies, the investigators made several genes called a chimeric antigen receptor (CAR), from an antibody called GC33 that recognizes glypican-3, a proteoglycan found on solid tumors including pediatric liver cancers (GPC3-CAR). This study will test T cells genetically engineered with a GPC3-CAR (GAP T cells) in patients with GPC3-positive solid tumors (currently only enrolling liver tumors).
The GAP T cells are an investigational product not approved by the Food and Drug Administration.
The purpose of this study is to find the biggest dose of GAP T cells that is safe, to see how long they last in the body, to learn what the side effects are and to see if the GAP T cells will help people with GPC3-positive solid tumors. This study enrolls patients who have GPC3-positive solid tumors (currently only enrolling liver tumors).
详细描述
Approximately 18-30 subjects will participate in the treatment part of this study.
Maximum of 180 mL of blood (not exceeding 3ml/kg/day) is collected from patients to grow the T cells and a retrovirus (a special virus that can insert the GPC3 CAR gene into the T cells) is used to genetically engineer them. After the CAR gene was put into the T cells, the investigators make sure that they are able to kill GPC3 positive solid tumor cells in the laboratory.
LYMPHODEPLETION CHEMOTHERAPY:
Several studies suggest that the infused T cells need room to be able to proliferate and accomplish their functions and that this may not happen if there are too many other T cells in circulation. Because of that, participants will receive treatment with cyclophosphamide (Cytoxan) and fludarabine for 3 days before receiving the T-cell infusion. These drugs will decrease the numbers of the participants' own T cells before the investigators infuse the GAP T CELLS.
WHAT THE INFUSION WILL BE LIKE:
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
- 1 Year 至 21 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Relapsed or refractory GPC3-positive* solid tumors (currently only enrolling liver tumors)
- •Age ≥ 1 year and ≤ 21 years
- •Lansky or Karnofsky score ≥60%
- •Life expectancy ≥16 weeks
- •Child-Pugh-Turcotte score <7 (for patients with hepatocellular carcinoma only)
- •Informed consent explained to, understood by and signed by patient/guardian. Patient/guardian given copy of informed consent
排除标准
- •History of hypersensitivity reactions to murine protein-containing products OR presence of human anti-mouse antibody (HAMA) prior to enrollment (only patients who have received prior therapy with murine antibodies)
- •History of organ transplantation
- •Known HIV positivity
- •Active bacterial, fungal or viral infection (except Hepatitis B or Hepatitis C virus infections)
- •Severe previous toxicity from cyclophosphamide or fludarabine
- •Treatment Eligibility
- •Inclusion Criteria:
- •Age ≥ 1 year and ≤ 21 years
- •Barcelona Clinic Liver Cancer Stage A, B or C (for patients with hepatocellular carcinoma only)
- •Life expectancy of ≥ 12 weeks
- •Lansky or Karnofsky score ≥ 60%
- •Child-Pugh-Turcotte score < 7 (for patients with hepatocellular carcinoma only)
- •Adequate organ function:
- •Creatinine clearance as estimated by Cockcroft Gault or Schwartz ≥ 60 ml/min
- •serum AST< 5 times ULN
- •total bilirubin < 3 times ULN for age
- •INR ≤1.7 (for patients with hepatocellular carcinoma only)
- •absolute neutrophil count > 500/microliter
- •platelet count > 25,000/microliter (can be transfused)
- •Hgb ≥7.0 g/dl (can be transfused)
- •pulse oximetry >90% on room air
- •Recovered from acute toxic effects of all prior chemotherapy and investigational agents before entering this study
- •Sexually active patients must be willing to utilize one of the more effective birth control methods for 3 months after the T-cell infusion.
- •Informed consent explained to, understood by and signed by patient/guardian. Patient/guardian given copy of informed consent
- •Exclusion Criteria
- •Pregnancy or lactation
- •Uncontrolled infection
- •Systemic steroid treatment (greater than or equal to 0.5 mg prednisone equivalent/kg/day, dose adjustment or discontinuation of medication must occur at least 24 hours prior to CAR T cell infusion)
- •Known HIV positivity
- •Active bacterial, fungal or viral infection (except Hepatitis B or Hepatitis C virus infections)
- •History of organ transplantation
- •History of hypersensitivity reactions to murine protein-containing products OR presence of human anti-mouse antibody (HAMA) prior to enrollment (only patients who have received prior therapy with murine antibodies)
- •Severe previous toxicity from cyclophosphamide or fludarabine
- •GPC3 expression will be evaluated by standard immunohistochemistry (IHC). A tumor is considered GPC3 positive, when the staining is Grade 2 (>25% positive tumor cells) or above with an intensity score of 2 or above on a scale of 0 to 4.
研究组 & 干预措施
GAP T cells + Fludarabine and Cytoxan
GPC3-Car (GAP T cells) along with lymphodepleting chemotherapy (Cytoxan and Fludarabine) will be administered to patients with GPC3-positive solid tumors.
干预措施: GAP T cells (Genetic)
GAP T cells + Fludarabine and Cytoxan
GPC3-Car (GAP T cells) along with lymphodepleting chemotherapy (Cytoxan and Fludarabine) will be administered to patients with GPC3-positive solid tumors.
干预措施: Cytoxan (Drug)
GAP T cells + Fludarabine and Cytoxan
GPC3-Car (GAP T cells) along with lymphodepleting chemotherapy (Cytoxan and Fludarabine) will be administered to patients with GPC3-positive solid tumors.
干预措施: Fludara (Drug)
结局指标
主要结局
Number of Patients with Dose Limiting Toxicity
时间窗: 6 weeks
A dose limiting toxicity is defined as any toxicity that is considered to be primarily related to the GPC3-CAR T cells. Specifically those which are Grade 5; non-hematologic Grade 3-4 not returning to Grade 2 within 72 hours; Grade 2-4 allergic reaction; Hematologic Grade 4 that fails to return to Grade 2 or baseline (whichever is more severe) within 14 days; all grade 4 CRS and neurologic toxicities and grade 3 CRS and neurologic toxicities that fail to return to Grade 1 within 7 days.
次要结局
- Percent of Patients with best response as either complete remission or partial remission(6 weeks)
- Median T cell persistence(15 years)
研究者
David Steffin, MD
Assistant Professor
Baylor College of Medicine