Phase I Study of GPC3 Targeted CAR-T Cell Therapy in Advanced GPC3 Expressing Hepatocellular Carcinoma (HCC)
Background: A new cancer treatment takes a person s own T cells, modifies them in a laboratory so they can better fight cancer cells, and then gives them back to the person. Researchers want to see if this treatment can help people with a certain type of liver cancer.
Objective: To see if a personalized immune treatment, anti-GPC3 CAR-T cells, is safe.
Eligibility: Adults aged 18 years and older who have Glypican-3 (GPC3) positive HCC, a type of liver cancer.
Design: Participants will be screened with the following: Blood and urine tests Medical history Physical exam Heart function tests Review of their symptoms and their ability to perform their normal activities Tumor biopsy Imaging scan of the chest, abdomen, and pelvis Participants will have leukapheresis. They may have an IV (intravenous catheter, a small tube put into an arm vein) inserted into each arm or get a central line. Blood will be removed. A machine will separate the white blood cells from their blood. The rest of their blood will be returned to them. Participants will be admitted to the hospital for about 2 weeks. They will get the chemotherapy drugs fludarabine and cyclophosphamide by IV for 3 days. Then they will receive the modified white blood cells by IV. Participants will have frequent blood draws. They will give blood and tumor samples for research. Participants will have follow-up visits for the next 15 years. Then they will be contacted by email or phone for the rest of their life. If their disease does not get worse after 5 years, they will continue to be invited to do imaging studies every 6 months.
⁃ Histopathological confirmation of HCC by the NCI Laboratory of Pathology
⁃ Participants must:
‣ have progressed on the prior first line of standard therapy
∙ OR
• -been intolerant of the standard of care chemotherapy for HCC.
⁃ Participants must have at least 1 focus of disease that is amenable to mandatory tumor biopsy prior to study treatment initiation to determine tumor GPC3 expression and be willing to undergo this. Ideally, the biopsied lesion should not be one of the target measurable lesions, although this can be up to the discretion of the investigators.
⁃ Tumor must have GPC3 positivity of \>= 25% by immunohistochemistry on freshly collected biopsy
⁃ Participants must have at least 1 measurable lesion by RECIST version 1.1
⁃ Participants must have a disease that is not amenable to potentially curative resection, ablation, or transplantation.
⁃ Age \>= 18 years.
⁃ Performance status (ECOG) 0-1
⁃ Participants must have adequate organ and marrow function as defined below:
∙ ANC: \>= 1,000/mcL
∙ Platelets: \>= 75,000/mcL
∙ Hemoglobin: \>= 8 g/dL
∙ total bilirubin: If cirrhosis present: Part of Child Pugh requirement
∙ If no cirrhosis: bilirubin should be \<= 1.5 x ULN
∙ ALT or AST: \<= 5 x ULN.
∙ Creatinine: \< 1.5x institution upper limit of normal
∙ OR
∙ Measured or calculated creatinine clearance (CrCl): \>= 50 mL/min/1.73 m\^2 for participant with creatinine levels
∙ (eGFR may also be used in place of CrCl) (A): \>= 1.5 X institutional ULN
∙ ALT (SGPT)=alanine aminotransferase (serum glutamic pyruvic transaminase);
∙ AST (SGOT)=aspartate aminotransferase (serum glutamic oxaloacetic transaminase); GFR=glomerular filtration rate; ULN=upper limit of normal.
∙ (A)Creatinine clearance (CrCl) or eGFR should be calculated per institutional standard.
⁃ Normal cardiac ejection fraction (\>= 50% by echocardiogram) and no evidence of hemodynamically significant pericardial effusion as determined by an echocardiogram within 4 weeks before treatment initiation.
⁃ Room air oxygen saturation of 92% or greater.
⁃ Treatment-related toxicities must be resolved to \<= grade 1.
⁃ For participants with brain metastases: Participants with \<=3 (three or fewer) brain metastases that have been treated with surgery or stereotactic radiosurgery or other form of treatment are eligible. Lesions that have been treated with stereotactic radiosurgery must be clinically stable for one month before protocol treatment.
⁃ The study drugs are harmful to developing human fetus. For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) at the study entry, for the duration of study therapy, and up to 180 days after the last dose of the study drug(s). Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.
⁃ HBV infected participants must be on antivirals and have HBV DNA \< 100IU/mL. HCV infected participants can be enrolled with close HCV RNA level monitoring.
⁃ Participants must be able to understand and be willing to sign a written informed consent.
⁃ For participants that do not have a legally authorized representative in place, one must be identified before study treatment starts