CELL INTELLIGENCE · 肿瘤细胞治疗研究

Procurement Eligibility

Inclusion Criteria:

* Diagnosis of GPC3-positive\* solid tumors (as determined by immunohistochemistry with an extent score of \>=Grade 2 \[\>25% positive tumor cells\] and an intensity score of \>= 2 \[scale 0-4\]).
* Age ≥1 year and ≤ 21 years
* Lansky or Karnofsky score ≥60%
* Life expectancy ≥16 weeks
* Barcelona Clinic Liver Cancer Stage A, B or C (for patients with hepatocellular carcinoma only)
* 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

Exclusion Criteria:

* 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)

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)
* 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
* Total bilirubin \< 3 times ULN for age
* INR ≤1.7 (for patients with hepatocellular carcinoma only)
* Absolute neutrophil count \> 750/µl
* Platelet count \> 75,000/µl (Needs to be confirmed prior to treatment whether with or without transfusion)
* Hgb ≥ 8.0 g/dl (Needs to be confirmed prior to treatment whether with or without transfusion)
* Pulse oximetry ≥ 92% on room air
* Incurable disease after treatment with up- front therapy (Patients who have relapsed disease despite a standard of care salvage therapy)
* Wash out period, such that patient has recovered from acute toxic effects of all prior chemotherapy and investigational agents before entering this study, and returned to their clinical baseline, as determined by history and physical exam.
* Sexually active patients must be willing to utilize one of the more effective birth control methods for 6 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 \[except Hepatitis B (HBV patients with active disease who meet the criteria for anti-HBV therapy should be on a suppressive antiviral therapy prior to initiation of cancer therapy) or Hepatitis C virus infections (should have completed curative antiviral treatment with HCV viral load below the limit of quantification\]
* Congestive heart failure (as defined by New York Heart Association Functional Classification III or IV), unstable angina, serious uncontrolled cardiac arrhythmia, a myocardial infarction within 6 months prior to study entry or a history of myocarditis
* Active autoimmune or inflammatory disorder
* Live vaccines within 30 days prior to enrollment
* 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)

主要终点：Number of Patients with Dose Limiting Toxicity · 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 7 days 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. · 4 weeks
次要终点：Percent of Patients with best response as either complete remission or partial remission；Median T cell persistence；Manufacturing feasibility of 21.15.GBBz T cells

• CARE T cells · EXPERIMENTAL · GPC3-CAR and the IL15 plus IL21 (CARE T cells) will be administered to patients with GPC3-positive solid tumors.

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 CARE 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 (a tiny part of what makes-up DNA and carries a person's traits) into T cells that will make them recognize cancer cells and kill them. In the lab, investigators made several genes called a chimeric antigen receptor (CAR), from an antibody called GPC3. The antibody GPC3 recognizes a protein found solid tumors including pediatric liver cancers. This CAR is called GPC3-CAR. To make this CAR more effective, investigators also added two genes that includes IL15 and IL21, which are protein that helps CAR T cells grow better and stay in the blood longer so that they may kill tumors better. The mixture of GPC3-CAR and IL15 plus IL21 killed tumor cells better in the laboratory when compared with CAR T cells that did not have IL15 plus IL21 .This study will test T cells that investigators made (called genetic engineering) with GPC3-CAR and the IL15 plus IL21 (CARE T cells) in patients with GPC3-positive solid tumors. T cells made to carry a gene called iCasp9 can be killed when they encounter a specific drug called AP1903. The investigators will insert the iCasp9 and IL15 plus IL21 together into the T cells using a virus that has been made for this study. The drug (AP1903) is an experimental drug that has been tested in humans with no bad side-effects. The investigators will use this drug to kill the T cells if necessary due to side effects. This study will test T cells genetically engineered with a GPC3-CAR and IL15 plus IL21 (CARE T cells) in patients with GPC3-positive solid tumors. The CARE 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 CARE 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 CARE T cells will help people with GPC3-positive solid tumors.