Overview
Patients eligible for this study have a type of blood cancer Acute Myeloid Leukemia (AML) which has come back or has not gone away after treatment.
The body has different ways of fighting disease and infection, and this research study combines two different ways of fighting cancer with antibodies and T cells with the hope that they will work together. T cells (also called T lymphocytes) are special infection-fighting blood cells that can kill other cells including tumor cells. Antibodies are types of proteins that protect the body from bacterial and other infectious diseases. 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 when used alone.
T lymphocytes can kill tumor cells but there normally are not enough of them to kill all the tumor cells. Some researchers have taken T cells from a person's blood, grown more of them in the laboratory and then given them back to the person. The antibody used in this study targets CLL-1. This antibody sticks to AML cells because of a substance (protein) on the outside of these cells called CLL-1. For this study, the antibody to CLL-1 has been changed so that instead of floating free in the blood, it is now joined to the T cells. When T-cells contain an antibody that is joined to them, they are called chimeric antigen receptor T-cells or CAR-T cells.
In the laboratory, the investigators have also found that T cells work better if proteins that stimulate T cells are also added, such as one called CD28. Adding the CD28 makes the cells grow better and last longer in the body, thus giving the cells a better chance of killing the leukemia or lymphoma cells. In this study we are going to attach the CLL-1 chimeric receptor that has CD28 added to it to the patient's T cells. We will then test how long the cells last.
These CLL-1 chimeric antigen receptor T cells with CD28 are investigational products not approved by the Food and Drug Administration.
Description
To make the CLL1-CD28 chimeric antigen receptor T cells, the investigators will collect the patient's blood and stimulate them with growth factors to make the cells grow. To get the CLL-1 antibody and CD28 to attach to the surface of the T cell, we put the antibody gene into the T cell. This is done using a virus called a retrovirus that has been made for this study and will carry the antibody gene into the T cell. This virus also helps investigators find the T cells in the patient's blood after they are injected. Because the patient will have received cells with a new gene in them the patient will be followed for a total of 15 years to see if there are any long term side effects of gene transfer.
When the patient enrolls on this study, the patient will be assigned a dose of CLL-1 chimeric antigen receptor- T cells. Several studies suggest that the T cells that we give to the patient need room to be able to grow and work well and that this may not happen if there are too many other T cells already in circulation the patient's body. Because of that, the patient will receive two chemotherapy medications before receiving the CLL-1 chimeric antigen receptor- T cells.
One medication is called cyclophosphamide and the other fludarabine. The patient will receive 3 daily doses of each drug, ending at least one day before receiving the chimeric antigen receptor- T cells. These drugs will lower the numbers of the patient's T cells before we give them the CLL-1 chimeric antigen receptor T cells and will also help lower the number of other cells that may block the chimeric antigen receptor- T cells from working well. Although we do not expect any effect on the patient's cancer with the doses that will be received, these drugs are part of many treatment plans that are used to treat leukemia.
Patients will be given an injection of cells into the vein through an IV at the assigned dose. The injection will take from 1 to 10 minutes. Before patients receive the injection, they may be given a dose of Benadryl and Tylenol. The treatment will be given by the Center for Cell and Gene Therapy at Texas Children's Hospital or Houston Methodist Hospital.
Investigators will monitor patients in the clinic after the injection for up to 3 hours, and they will have to remain locally for at least 3 weeks after the infusion. If patients have any side effects, they may have to be admitted to the hospital for evaluation and management. If after a 4 week evaluation period following the infusion, the patient has achieved a complete response, his/her cancer doctors may decide if you should go on to have a bone marrow transplant, at which time the patient will be removed from the treatment portion of the study.
BEFORE BEING TREATED, PATIENTS WILL RECEIVE A SERIES OF STANDARD MEDICAL TESTS:
- Physical exam and History
- Blood tests to measure blood cells, kidney and liver function
- Pregnancy test for female patients who are of child bearing potential -Measurements of your tumor by bone marrow studies
PATIENTS WILL RECEIVE STANDARD MEDICAL TESTS DURING TREATMENT AND AFTER:
- Physical exams and History
- Blood tests to measure blood cells, kidney and liver function
- Measurements of your tumor by bone marrow studies 4-6 weeks after the infusion and then per standard of care.
To learn more about the way the CLL-1 chimeric receptor-T cells are working and how long they last in the body, extra blood will be drawn. The total amount on any day is about 10 teaspoons (50 mL) or no more than 3 mL per 2.2 pounds body weight in children. This amount is considered safe but may be lowered if you are anemic. This blood may be taken from a central line if you have one. Blood will be taken before the chemotherapy drugs, several hours after the T cell infusion, at 1 week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, and 8 weeks after the infusion, at 3 months, 6 months, 9 months, at 1 year, every 6 months for 4 years, then yearly for a total of 15 years.
If patients have a bone marrow exam while they are on this study, we may ask to have a piece of bone marrow to look for CLL-1 chimeric receptor- T cells.
If a patient decides to withdraw at any time during the study, both samples and data collected during his/her participation will be kept.
Eligibility
PROCUREMENT
Inclusion Criteria:
- Diagnosis of Acute Myeloid Leukemia (AML) AND suitable for consideration of allogeneic Hematopoietic Stem Cell Transplant with confirmation of an identified eligible donor by a FACT accredited transplant center and with confirmation that the center plans to proceed with transplant if CLL-1.CAR treatment induces response they consider adequate to proceed to allogeneic HSCT
- CLL-1 positive tumor with at least 30% CLL-1 blasts by flow cytometry or immunohistochemistry (tissue) assessed by a CLIA certified Flow Cytometry/Pathology laboratory
- Age <75 years NOTE: The first three (3) patients treated on the study should be adults (18 yrs of age).
- Hgb 7.0 g/dL(can be transfused)
- Life expectancy greater than 12 wks
- If apheresis required to collect blood
- PT and APTT <1.5x ULN
- Serum Creatinine < 1.5 x ULN
- AST < 1.5 x ULN
- Informed consent
Exclusion Criteria:
- Active infection requiring antibiotics.
- Active infection with HIV or HTLV
- Clinically significant fungal infection requiring ongoing antifungal therapy without improvement, viral infection or uncontrolled viral reactivation of EBV, CMV, Adv, BK-virus, or HHV-6.
- Active second cancer (except non-melanoma skin cancer or in situ breast cancer or cervix cancer)or other cancer treated 2 years prior to enrollment
- Ongoing treatment with immune suppression for prophylaxis or treatment of GVHD including high dose steroids (eg prednisone > 0.5mg/kg)
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TREATMENT
Inclusion Criteria:
- Diagnosis of Acute Myeloid Leukemia (AML) AND suitable for consideration of allogeneic Hematopoietic Stem Cell Transplant with confirmation of an identified eligible donor by a FACT accredited transplant center and with confirmation that the center plans to proceed with transplant if CLL-1.CAR treatment induces a response they consider adequate to proceed to allogeneic HSCT
- CLL-1 positive tumor with at least 30% CLL-1 blasts by flow cytometry or immunohistochemistry (tissue) assessed by a CLIA certified Flow Cytometry/Pathology laboratory
- Age <75 yearsNOTE: The first three (3) patients treated on the study should be adults (18 yrs of age).
- AST less than 5 times the upper limit of normal
- Bilirubin less than 3 times the upper limit of normal
- Estimated GFR > 60ml/min
- Pulse oximetry of > 90% on room air
- Karnofsky/Lansky > 60
- Recovered from acute toxic effects of prior chemo at least one week before study entry
- Available autologous transduced activated peripheral blood T-cell product with 20% expression of CLL-1.CAR.28z by flow cytometry
- Life expectancy > 12 weeks
- Sexually active patients must be willing to utilize one of the more effective birth control methods during the study and for 6 months after the study is concluded. The male partner should use a condom
- Informed consent explained to, understood by, and signed by patient/guardian. Patient/guardian given copy of informed consent.
Exclusion Criteria:
- Currently receiving any investigational agents or having received any tumor vaccines within the previous 6 weeks.
- History of hypersensitivity reactions to murine protein-containing products.
- Pregnant or lactating.
- Active infection with HIV or HTLV.
- Clinically significant fungal infection requiring ongoing antifungal therapy without improvement, viral infection or uncontrolled viral reactivation of EBV, CMV, Adv, BK-virus, or HHV-6.
- Cardiac criteria: Prolonged QTc with maximum interval as defined by age with ; Atrial fibrillation/flutter; Myocardial infarction within the last 12 months; Cardiac echocardiography with LVSF<30% or LVEF<50%; Cardiac dysfunction NYHA III or IV; Cardiac echocardiography with clinically significant pericardial effusion.
- CNS abnormalities: Presence of CNS disease defined as detectable cerebrospinal blast cells in a sample of CSF with 5 WBCs per mm3 or chloroma on imaging, History or presence of an underlying CNS disorder such as a seizure disorder requiring current use of antiepileptic medications, cerebrovascular ischemia/hemorrhage, dementia, cerebellar disease, or any autoimmune disease with CNS involvement.
- Use of Serotherapy with Campath or Anti-Thymocyte Globulin (ATG) within the last 28 days
- Use of Donor Lymphocyte Infusion (DLI) or other cellular therapy product within 30 days
- Acute GVHD Grade 2 or extensive chronic GVHD
- Currently receiving > 0.5 mg/kg of Prednisone equivalent