Treatment of Chimeric Antigen Receptor Expressing Autologous T Cells as Immunotherapy for Patients with Liver Cancer

Status: administratively complete

This phase I trial studies the effects of immunotherapy IL-15 GPC3-CAR T cells (CATCH T cells), a specialized treatment made from T cells, a type of immune cell in your blood, can help treat those with liver cancer. Chemotherapy drugs such as cyclophosphamide and fludarabine work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. In the lab, several genes called a chimeric antigen receptor (CAR) are made, from an antibody called GC3 3. The antibody GC33 recognizes a protein called GPC3 which is found on the liver tumor. This CAR is called a GPC3-CAR. To make this CAR more effective, gene encoding a protein IL15 is also added. 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 IL15. This study will test T cells that have been made (called genetic engineering) with the IL15 GPC3-CAR (CATCH T cells) in patients with GPC3-positive liver cancer.

Inclusion Criteria

PROCUREMENT: Relapsed or refractory GPC3-positive hepatocellular carcinomas (as determined by immunohistochemistry with an extent score of >= grade 2 [>25% positive tumor cells] and an intensity score of >= 2 [scale 0-4]). * GPC3 expression will be evaluated by standard immunohistochemistry (IHC) at Texas Children’s Hospital/Baylor College of Medicine, Department of Pathology for all patients to meet procurement eligibility. All patients will send at least 5 unstained slides.
PROCUREMENT: Age >= 18 years.
PROCUREMENT: Lansky or Karnofsky score >= 60%.
PROCUREMENT: Life expectancy >= 16 weeks.
PROCUREMENT: Barcelona Clinic liver cancer stage A, B or C (for patients with hepatocellular carcinoma only.
PROCUREMENT: Child-pugh-turcotte score <7 (for patients with hepatocellular carcinoma only.
PROCUREMENT: Informed consent explained to, understood by and signed by patient/guardian. Patient/guardian given copy of informed consent.
TREATMENT: Age >= 18 years.
TREATMENT: Barcelona Clinic liver cancer stage A, B or C (for patients with hepatocellular carcinoma only.
TREATMENT: Life expectancy >= 12 weeks.
TREATMENT: Lansky or Karnofsky score >= 60%.
TREATMENT: Child-Pugh-Turcotte score < 7 (for patients with hepatocellular carcinoma only
TREATMENT: Creatinine clearance as estimated by Cockcroft Gault or Schwartz >= 60 ml/min.
TREATMENT: Serum aspartate aminotransferase (AST) < 5 times upper limit of normal (ULN).
TREATMENT: Total bilirubin < 3 times ULN for age.
TREATMENT: International normalized ratio (INR) =< 1.7 (for patients with hepatocellular carcinoma only).
TREATMENT: Absolute neutrophil count > 500/ul.
TREATMENT: Platelet count > 25,000/ul (can be transfused).
TREATMENT: Hemoglobin (Hgb) >= 7.0 g/dl (can be transfused).
TREATMENT: Pulse oximetry > 90% on room air.
TREATMENT: Refractory or relapsed disease after treatment with up-front therapy and at least one salvage treatment cycle.
TREATMENT: Recovered from acute toxic effects of all prior chemotherapy and investigational agents before entering this study.
TREATMENT: Sexually active patients must be willing to utilize one of the more effective birth control methods for 3 months after the T-cell infusion.
TREATMENT: Informed consent explained to, understood by and signed by patient/guardian. Patient/guardian given copy of informed consent.

Exclusion Criteria

PROCUREMENT: 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).
PROCUREMENT: History of organ transplantation
PROCUREMENT: Known HIV positivity
PROCUREMENT: Active bacterial, fungal or viral infection (except Hepatitis B or Hepatitis C virus infections)
TREATMENT: Pregnancy or lactation.
TREATMENT: Uncontrolled infection.
TREATMENT: 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).
TREATMENT: Known human immunodeficiency virus (HIV) positivity.
TREATMENT: Active bacterial, fungal or viral infection (except Hepatitis B or Hepatitis C virus infections).
TREATMENT: History of organ transplantation.
TREATMENT: 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.

PRIMARY OBJECTIVE:

I. To determine the safety of escalating doses of an intravenous injection of autologous anti-glypican-3 CAR-IL-15-iC9-expressing T-lymphocytes (15.GPC3-CAR T cells) in patients with GPC3-positive hepatocellular carcinomas after lymphodepleting chemotherapy.

SECONDARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD) of 15.GPC3-CAR T cells in treating patients with GPC3-positive hepatocellular carcinomas after lymphodepleting chemotherapy.

II. To assess the anti-tumor effect of infused 15.GPC3-CAR T cells in patients with GPC3-positive hepatocellular carcinomas.

EXPLORATORY OBJECTIVE:

I. To assess the in vivo persistence, phenotype and functional activity of infused 15.GPC3-CAR T cells in patients with GPC3-positive hepatocellular carcinomas.

OUTLINE: This is a phase II dose-escalation study of 15.GPC3-CAR T followed by a phase II study.

Patients receive cyclophosphamide intravenously (IV) over 1 hour and fludarabine IV over 30 minutes on days -4, -3, and -2. Patients receive 15.GPC3-CAR T IV between day 0 to 2. Patients also undergo contrast enhanced computer tomography (CT) or magnetic resonance imaging (MRI) before chemotherapy and 4 weeks after CAR T cell infusion.

After completion of study treatment, patients are followed up every 3 months for 1 year, every 6 months for 4 years and then every year for the next 10 years.

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Treatment of Chimeric Antigen Receptor Expressing Autologous T Cells as Immunotherapy for Patients with Liver Cancer

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