CELL INTELLIGENCE · 肿瘤细胞治疗研究

Procurement Eligibility

Inclusion Criteria:

* Relapsed or refractory 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 ≥18 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 ≥ 18 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/μl
  * platelet count \> 25,000/μl (can be transfused)
  * Hgb ≥ 7.0 g/dl (can be transfused)
  * Pulse oximetry \>90% on room air
* Refractory or relapsed disease after treatment with up- front therapy and at least one salvage treatment cycle
* 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 (≥ 0.5 mg prednisone equivalent/kg/day, dose adjustment or discontinuation of medication must occur at least 24hrs 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)

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 dose-limiting toxicity is any Grade 3 or Grade 4 nonhematologic toxicity that fails to return to Grade 2 within 72 hours; Grade 2 to 4 allergic reaction to CAR T cell infusion; Grade 4 hematologic toxicity that persists for 28 days or greater; Grade 3 and 4 expected reactions due to CRS and neurotoxicity are 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 7 days. Grade 4 CRS and neurologic toxicities will be reported to the FDA in an expedited fashion. · 4 weeks
次要终点：Percent of Patients with best response as either complete response or partial response；Median T cell persistence

• CATCH T cells · EXPERIMENTAL · GPC3-CAR and the IL15 (CATCH 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 CATCH 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 we can put a new gene (a tiny part of what makes-up DNA and carriesa person's traits) into T cells that will make them recognize cancer cells and kill them . In the lab, we made several genes called a chimeric antigen receptor (CAR), from an antibody called GC33. The antibody GC33 recognizes a protein called GPC3 that is found on the hepatocellular carcinoma the patient has. The specific CAR we are making is called GPC3-CAR. To make this CAR more effective, we also added a gene encoding protein called IL15. This protein 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 IL 15. This study will test T cells that we have made with CATCH T cells in patients with GPC3-positive solid tumors such as the ones participating in this study. 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 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 (CATCH T cells) in patients with GPC3-positive solid tumors. The CATCH 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 CATCH 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 CATCH T cells will help people with GPC3-positive solid tumors.