CAR T Cell Receptor Immunotherapy for Patients With B-cell Lymphoma
The NCI Surgery Branch has developed an experimental therapy for treating patients with B cell lymphomas or leukemias that involves taking white blood cells from the patient, growing them in the laboratory in large numbers, genetically modifying these specific cells with a type of virus (retrovirus) to attack only the tumor cells, and then providing the cells back to the patient. This type of therapy is called gene transfer. In this protocol, we are modifying the patient s white blood cells with a retrovirus that has the gene for anti-CD19 incorporated in the retrovirus.
The purpose of this investigate is to determine a safe number of these cells to infuse and to see if these particular tumor-fighting cells (anti-CD19 cells) cause tumors to shrink.
– Adults age 18-68 with B cell lymphomas or leukemias voicing the CD19 molecule.
Work up stage: Patients will be seen as an outpatient at the NIH clinical Center and go through a history and physical examination, scans, x-rays, lab tests, and other tests as needed
Leukapheresis: If the patients meet all of the requirements for the explore they will go through leukapheresis to obtain white blood cells to make the anti-CD19 cells.
Treatment: Once their cells have grown, the patients will be admitted to the hospital for the conditioning chemotherapy and the anti-CD19 cells. They will stay in the hospital for about
Four weeks for the treatment.
Go after up: Patients will come back to the clinic for a physical exam, review of side effects, lab tests, and scans about every 1-3 months for the very first year, and then every six months to one year as long as their tumors are shrinking. Go after up visits will take up to two days.
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
- We have constructed a retroviral vector that encodes an anti-CD19 chimeric antigen receptor (CAR) that recognizes the CD19 antigen. This chimeric receptor also contains the signaling domains of CD28 and CD3-zeta. The retroviral vector can be used to mediate genetic transfer of this CAR to T cells with high efficiency (> 50%) without the need to perform any selection.
- In co-cultures with CD19-expressing target cells, anti-CD19-CAR-transduced T cells secreted significant amounts of IFN-y and IL-2.
- We have developed a process for cryopreserving the cell product which may lead to the capability for this product to be manufactured at a central location and shipped to other institutions for treatment of a broader patient population
- Primary objectives
- With the approval of amendment S, determine the safety and feasibility of the administration of cryopreserved anti-CD19-CAR engineered peripheral blood lymphocytes with a nonmyeloablative conditioning regimen in patients with Bcell lymphomas.
Patients of eighteen years of age or older must:
- have a CD19-expressing B-cell malignancy of any type
- be a non-responder to, or recurred after one or more standard chemotherapy-containing regimens for their malignancy
- presently require treatment due to progressive malignancy
- deemed to be incurable by standard therapy
Patients may not have:
- a history of allogeneic stem cell transplantation
- CNS disease
- PBMC obtained by leukapheresis (approximately five X one hundred nine cells) will be cultured in the presence of anti-CD3 (OKT3) and aldesleukin in order to stimulate T-cell proliferation.
- Transduction is initiated by exposure of approximately one hundred eight to five X one hundred eight cells to retroviral vector supernatant containing the anti-CD19 CAR.
- With the approval of amendment S, patients will receive fludarabine and cyclophosphamide chemotherapy (NMA) for lymphocyte-depletion, followed by cryopreserved anti-CD19-CAR-transduced T cells.
- Patients will be followed until disease progression
- Patients who have responded to treatment and then progress may receive one retreatment
- Patient must have a CD19-expressing B cell malignancy. Patients with Diffuse large B-cell lymphoma, Primary Mediastinal B-cell lymphoma, and Diffuse large B-cell lymphoma transformed from follicular lymphoma must have measurable disease after at least two prior chemotherapy regimens one of which must have contained doxorubicin and rituximab.
- Confirmation of diagnosis of B cell malignancy and positivity for CD19 confirmed by the Laboratory of Pathology of the NCI. The choice of whether to use flow Cytometry or immunohistochemistry will be determined by what is the most lightly available tissue sample in each patient. Immunohistochemistry will be used for lymph knot biopsies, flow Cytometry will be used for peripheral blood, fine needle aspirates and bone marrow samples.
- Patients must have indications for treatment for their B cell malignancy at the time of enrollment on this trial.
- Greater than or equal to eighteen years of age and less than or equal to age 70.
- Willing to sign a durable power of attorney.
- Able to understand and sign the Informed Consent Document.
- Clinical spectacle status of ECOG zero or 1.
- Life expectancy of greater than three months.
- Patients of both genders must be willing to practice birth control from the time of enrollment on this investigate and for four months after treatment.
- Women of child bearing potential must have a negative pregnancy test because of the potentially dangerous effects of the treatment on the fetus.
- 1. Seronegative for HIV antibody. (The experimental treatment being evaluated in this protocol depends on an intact immune system. Patients who are HIV seropositive can have decreased immune -competence and thus be less responsive to the experimental treatment and more susceptible to its toxicities.).
- Two. Seronegative for hepatitis B antigen and hepatitis C antibody unless antigen negative. If hepatitis C antibody test is positive, then patients must be tested for the presence of antigen by RT-PCR and be HCV RNA negative.
- 1. Absolute neutrophil count greater than or equal to 1000/mm(Three) without the support of filgrastim.
- Two. Platelet count greater than or equal to 50,000/mm(Trio).
- Three. Hemoglobin greater than 8.0 g/dl.
- Four. Lymphocyte count less than or equal to Four,000/ mm(Three)
- 1. Serum ALT/AST less or equal to five times the upper limit of normal.
- Two. Serum creatinine less than or equal to 1.6 mg/dl
- Trio. Total bilirubin less than or equal to 1.Five mg/dl, except in patients with Gilbert’s Syndrome who must have a total bilirubin less than Trio.0 mg/dl
- Patients that require urgent therapy due to tumor mass effects such as bowel obstruction or blood vessel compression.
- Patients that have active hemolytic anemia.
Patients with active brain metastases, or with a history of any CNS metastases or cerebrospinal fluid malignant cells.
Note: patients who are asymptomatic but are found to have malignant cells in the CSF on lumbar puncture prior to treatment will be considered eligible.
Concurrent opportunistic infections (The experimental treatment being evaluated in this protocol depends on an intact immune system. Patients who have decreased immune competence may be less responsive to the experimental treatment and more
susceptible to its toxicities).
Within four weeks prior to embarking the chemotherapy regimen:
- Finish history and physical examination, including, weight and vital signs, noting in detail the exact size and location of any lesions that exist. (Note: patient history may be obtained within eight weeks.)
- Chest x-ray
- EKG
- Baseline CT of the chest, abdomen and pelvis, PET scan, and brain MRI to evaluate the status of disease. Extra scans and x-rays may be performed if clinically indicated based on patients signs and symptoms.
- HIV antibody titer and HbsAG determination, and anti HCV, (Note: may be performed within three months of the chemotherapy embark date).
- Anti CMV antibody titer, HSV serology, and EBV panel (Note: patients who are known to be positive for any of the above do not need to be retested; may be performed within three months of chemotherapy commence date)
Patients with a LVEF of less than or equal to 55% will not proceed to treatment,
(Note: may be performed within eight weeks of treatment).
Patients may go through lumbar puncture (LP) for flow cytometry of the CSF in order to assess the presence of CD19 positive lymphocytes for potential correlation with neurologic toxicity. Patients who have no neurologic symptoms at the time of LP
will be eligible for enrollment regardless of the results of the flow cytometry.
Within fourteen days prior to beginning the chemotherapy regimen:
Urinalysis and culture, if indicated
Within seven days prior to kicking off the chemotherapy regimen: