Interleukin-15 Armored Glypican 3-specific Chimeric Antigen Receptor Expressed in Autologous T Cells for Solid Tumors

Interleukin-15 Armored Glypican 3-specific Chimeric Antigen Receptor Expressed in Autologous T Cells for Solid Tumors

Interleukin-15 Armored Glypican-3-specific Chimeric Antigen Receptor Expressing Autologous T Cells as Immunotherapy for Patients With SOLID TUMORS (CATCH)

Center for Cell and Gene Therapy, Baylor College of Medicine, The Methodist Hospital Research Institute

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.

Approximately 118-27 subjects will participate in the treatment part of this study. Maximum of 180 mL of blood (approximately 12 tablespoons) is collected from patients to grow the T cells and a retrovirus (a special virus that can insert the GPC3 CAR gene into the T cells) is used to genetically engineer them. After the CAR gene was put into the T cells, the investigators make sure that they are able to kill GPC3 positive solid tumor cells in the laboratory. LYMPHODEPLETION CHEMOTHERAPY: Several studies suggest that the infused T cells need room to be able to increase in numbers/multiply and accomplish their functions and that this may not happen if there are too many other T cells in circulation . Because of that, participants will receive treatment with lymphodepletion chemotherapy. This chemotherapy means the participant will receive both cyclophosphamide (Cytoxan) and fludarabine. Participants will receive these drugs for 3 days before receiving the T-cell infusion. These drugs will decrease the numbers of the participants own T cells before the investigators infuse the CATCH T cells. WHAT THE INFUSION WILL BE LIKE: After making these cells, they will be frozen. If the patient agrees to participate in this study, at the time the patient is scheduled to be treated, the cells will be thawed and injected into the patient over 5 to 10 minutes. The participant will receive the CATCH T CELLS 48 to 72 hours after completing the chemotherapy. This is a dose escalation study, which means that the investigators do not know the highest dose of CATCH T cells that is safe. To find out, the investigators will give the cells to at least 3 participants at one dose level. If that is safe, the investigators will raise the dose given to the next group of participants. The dose each patient gets depends on how many participants get the agent before that patient and how they react. The investigator will tell each patient this information. Treatment eligibility are characteristics that must be met such as current health status and other items that ensure patients who could be made worse by participating in the study are not exposed to that risk. The eligibility also ensures researchers achieve accurate results. This will help the participant think about possible harms and benefits. Since the treatment is experimental, what is likely to happen at any dose is not known. All of the treatments will be given by the Center for Cell and Gene Therapy at Texas Children's Hospital. Medical tests before treatment: Physical exam and History Blood tests to measure blood cells, kidney and liver function. Pregnancy test (if the participant is a female who can get pregnant) If the participant is infected with the hepatitis B virus (HBV) the investigators will do a test to measure the levels of the virus Measurements of the patient's tumor by scans (either CT or MRI). Side effects are rare and include risk of developing an unrelated cancer due to radiation exposure from the machine, but this is unlikely. Medical tests during and after treatment: Physical exams and History Blood tests to measure blood cells, kidney and liver function If the patient is infected with the hepatitis B virus (HBV) we will repeat the test and monitor the levels of the virus Measurements of the patient's tumor by scans (same scans used before treatment) (4 - 6 weeks after the infusion) and AFP (if applicable at 1, 2, and 4 weeks after the infusion). Tumor biopsy of an accessible tumor between 2-4 weeks after the infusion and as clinically indicated thereafter. For additional clinically indicated tumor biopsies we will ask for a portion of the sample for research. We will not obtain biopsies if the patient's tumors are not accessible. FOLLOW-UP STUDIES The investigators will follow the participant during and after the injections. To learn more about the way the T cells are working in the participant's body, up to 60 mL (up to 5 tablespoons, no more than 3ml/kg/day) of blood will be taken from the participant before the chemotherapy, before the T-cell infusion, 1 to 4 hours after the infusion, 3 to 4 days after the infusion (this time point is optional ) at 1 week, 2 weeks, 4 weeks and 8 weeks after the injection, every 3 months for 1 year, every 6 months for 4 years and then every year for the next 10 years. Total participation time for this study will be 15 years. During the time points listed above, if the T cells are found in the participant's blood at a certain amount an extra half of a tablespoon of blood may need to be collected for additional testing. The investigators will use this blood to look for the frequency and activity of the cells that the investigators have given; that is, to learn more about the way the T cells are working and how long they last in the body. The investigators will also use this blood to see if there are any long-term side effects of putting the new gene (chimeric antigen receptor, CAR) into the cells. In addition to the blood draws, because the participants have received cells that have had a new gene put in them, the participants will need to have long term follow up for 15 years so the investigators can see if there are any long-term side effects of the gene transfer. Once a year, the participants will be asked to have their blood drawn and answer questions about their general health and medical condition. The investigators may ask the participants to report any recent hospitalizations, new medications, or the development of conditions or illness that were not present when the participants enrolled in the study and may request that physical exams and/or laboratory tests be performed if necessary. When tumor biopsy is performed for clinical reasons the investigators will request permission to obtain excess sample to learn more about the effects of the treatment on the participant's disease. In the event of death, the investigators will request permission to perform an autopsy to learn more about the effects of the treatment on the participant's disease and if there were any side effects from the cells with the new gene. In addition, the investigators would like to ask for participant permission to use tumor biopsy for research purposes only. Associated risk with the biopsy will be discussed with each participant in detail in a procedure specific consent form. The investigators will test the sample to see if the GAP T cells can be found in the tumor and what effect they had on the tumor cells. If participants develop a second abnormal cancer growth, significant blood or nervous system disorder during the trial, a biopsy sample of the tissue will be tested.

Liver Cell Carcinoma, Solid Tumor, Wilms Tumor, Malignant Rhabdoid Tumor, Yolk Sac Tumor, Rhabdomyosarcoma, Liposarcoma, Embryonal Sarcoma of the Liver

GPC3-CAR and the IL15 (CATCH T cells) will be administered to patients with GPC3-positive solid tumors.

Four different dosing schedules will be evaluated. Three to six patients will be evaluated on each dosing schedule. The following dose levels will be evaluated: DL1: 3x10^7/m2 DL2: 1x10^8/m2 DL3: 3x10^8/m2 DL4: 1x10^9/m2 The doses are calculated according to the actual number of GPC3-CAR transduced T cells.

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.

Response rates will be estimated as the percent of patients whose best response is either complete response or partial response (see Section 7.6) by combining the data from lesions recorded via imaging or by AFP for each patient pre- and post-infusion. To compare with historical data, a 95% confidence interval will be calculated for the response rate.

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)