CELL INTELLIGENCE · 肿瘤细胞治疗研究

Procurement Inclusion Criteria:

* Diagnosis of GPC3-positive recurrent glioblastoma with previous resection planned for repeat resection.
* Age ≥18 years
* Karnofsky score ≥60%
* Informed consent explained to, understood by and signed by patient/guardian. Patient/guardian given copy of informed consent
* GPC3 expression (as determined by immunohistochemistry) with an extent score of ≥ Grade 2 (\>25% positive tumor cells) and an intensity score of ≥ 2 (scale 0-4).

Procurement 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).
* Exhibits other risk factors of which administration of investigational agent is deemed not in the patient's best interest, in the opinion of the investigator

Treatment Inclusion Criteria:

* Age ≥ 18 years
* Diagnosis of recurrent glioblastoma with previous resection
* Karnofsky score ≥ 60%-
* Stable neurologic exam for 7 days prior to enrollment
* Stable or decreasing dose of steroids over past 7 days prior to surgery and administration of therapy (max allowable dose is 0.1mg/kg dexamethasone or equivalent per day)
* 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
* absolute neutrophil count \> 500/μl
* platelet count \> 100,000/μl (can be transfused but must be achieved prior to enrollment)
* 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.

Treatment Exclusion Criteria:

* Pregnancy or lactation
* Uncontrolled infection
* Known HIV positivity
* Active bacterial, fungal or viral infection
* 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 15.GPC3-CAR T cells. Specifically those which are Grade 5; hematologic dose-limiting toxicity is any Grade 4 non-hematologic toxicity that fails to return to Grade 2 within 72 hours; Grade 4 allergic reaction to CAR T cell administration; Grade 4 \\reactions due to CRS and neurotoxicity are rarely seen with the use of CAR-based immunotherapy. Grade 3 cytokine release syndrome (CRS) infusion reactions and neurologic toxicity will only be reported to the FDA if they fail to return to Grade 1 within 72 hours. Grade 4 CRS and neurologic toxicities will be reported to the FDA in an expedited fashion. · 4 weeks
次要终点：Response Rate；Maximum Tolerated Dose (MTD)

• 15.GPC3-CAR T cells · EXPERIMENTAL · GPC3-CAR and IL15 will be administered to patients with GPC3-positive glioblastoma.

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 participants with cancers. They have shown promise, but have not been strong enough to cure most participants. The study team has found from previous research that we can put a new gene (a tiny part of what makes-up DNA and carries the participants traits) into T cells that will make them recognize cancer cells and kill them. In the lab, the study team has made several genes called a chimeric antigen receptor (CAR), from an antibody called GC33. The antibody GC33 recognizes a protein found on the participants brain tumor. This CAR is called GPC3-CAR. To make this CAR more effective, the study has also added a gene that includes IL15. IL15 is a 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 killed tumor cells better in the laboratory when compared with CAR T cells that did not have IL15. This study will test T cells with the IL15 GPC3-CAR (GO-CART T cells) in participants with GPC3-positive brain tumors. T cells made to carry a gene called iCasp9 can be killed when they encounter a specific drug called AP1903. The study team will insert the iCasp9 and IL15 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 study team 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 (GO-CART T cells) in participants with GPC3-positive brain tumors. The GO-CART T cells are an investigational product not approved by the Food and Drug Administration.