A Phase I Trial of Autologous T-Lymphocytes Genetically Targeted to the B-Cell Specific Antigen CD19 in Pediatric and Young Adult Patients with Relapsed B-Cell Acute Lymphoblastic LeukemiaPrincipal Investigator: Lewis B. Silverman, MD
Relapsed/refractory B-cell acute lymphoblastic leukemia and CAR T-cellsThe prognosis for pediatric and young adult patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL) is dismal and novel treatment options are urgently needed. We are pleased to provide information about a new trial opening at the Dana-Farber/Boston Children’s Cancer and Blood Disorders Center. It is a phase 1 clinical trial, led by Memorial Sloan Kettering Cancer Center in New York, NY, testing Chimeric Antigen Receptor (CAR) T-cells, a targeted therapy utilizing tumor-specific T-cells.
CAR T-cell therapy is a promising option for patients with leukemia for several reasons:
Patients with recurrent leukemia in their bone marrow may have defective T-cells that are less able to kill leukemia cells. By genetically modifying T-cells so that they target the B-cell-specific antigen CD 19 (which is almost always expressed by B-ALL cells), they may be able to better recognize and kill leukemia cells. The concept is to utilize genetic engineering to “re-direct” T-cells to this antigen and also provide additional genetic information to the cell that allows it to better respond to the tumor itself. The genetic engineering is accomplished using a DNA shuttle (or vehicle) to insert new DNA information into the T-cells in ahighly specialized laboratory (called a GMP laboratory).
The genetically engineered T-cells express the CAR specific for CD19 that helps them recognize and destroy the B-ALL leukemia cells.
About the trialThis is a phase I trial being carried out in only two centers for pediatric and young adult patients with relapsed/refractory CD19+ B-ALL. The purpose of this study is to test the safety of giving genetically modified T-cells made from autologous (the patient’s own) blood. These T-cells are collected from the patient’s blood via apheresis, modified by gene transfer in the laboratory, and then re-infused into the patient.
The ability of tumor-specific T-cells to eradicate tumors is most clearly illustrated in patients with relapsed chronic myelogenous leukemia (CML) after allogeneic bone marrow transplantation. In this setting, the adoptive transfer of donor T-cells alone is often sufficient to induce a second remission. However, using T-cells from another person (allogeneic donors) can lead to other complications, such as graft versus host disease (GVHD). Generating tumor-directed CAR T-cells from the patient’s own blood(autologous T-cells) avoids the problem of GVHD that can occur when using cells from allogeneic donors, and may enhance the efficacy of the infused T-cells. Other studies have demonstrated the safety and efficacy of genetically-modified autologous CD19-specific T-cells in patients with ALL, chronic lymphocytic leukemia, and non-Hodgkin lymphoma.
The goal of this trial is to extend this novel and promising immunotherapy to pediatric and young adult patients with relapsed/refractory CD19+ B-ALL for whom no current curative or life extending therapy currently exists.
EligibilityPatients with very high-risk newly diagnosed B-ALL or with relapsed B-ALL can enroll for leukocyte collection as a first step in generating tumor-specific T-cells. Patients who meet these eligibility criteria will undergo leukapheresis or collection of peripheral blood mononuclear cells (PBMC) from whole blood after signing informed consent. PBMC collection may occur at the time of diagnosis or relapse, or after the initiation of therapy, depending upon the patient’s disease status and number of circulating peripheral blood lymphocytes. A special catheter may need to be inserted to allow for leukapheresis, depending on the patients' age and size.
Treatment planT-cell infusion will be offered only to patients who have relapsed/refractory disease that has not responded to standard therapies. Patients who meet criteria for T-cell infusion will sign a separate informed consent document. Following recovery from chemotherapy and once the required number of genetically-modified T-cells are generated from collected PBMCs, the patient will be admitted to the Stem Cell Transplant Unit at Dana-Farber/Boston Children’s to receive conditioning chemotherapy (typically cyclophosphamide). Two days following completion of this chemotherapy, patients will receive two daily infusions of the CAR T-cells.
Patients will remain in the hospital to be closely monitored for adverse events, including cytokine release syndrome, a self-limited condition which may occur in the first few days after infusion and lead to fever, hypotension, and respirator distress. Neurologic complications have also been observed in the first few days after CAR T-cell infusion. Once patients have stabilized after the infusion, they will be followed closely as outpatients at the Jimmy Fund Clinic at Dana-Farber/Boston Children’s.
For more information about the trial or to refer a patient, contact:Colleen Dansereau, RNGene Therapy Program ManagerPhone: 617-919-7008Email: email@example.com
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