Administration of Anti-CD19-chimeric-antigen-receptor-transduced T Cells From the Original Transplant Donor to Patients With Recurrent or Persistent B-cell Malignancies After Allogeneic Stem Cell Transplantation
- Allogeneic hematopoietic stem cell transplantation (alloHSCT) is a procedure that transplants bone marrow cells (stem cells) from a matching donor into a recipient in order to allow the donor stem cells to produce cells that will attack the recipient's cancer cells. AlloHSCT is performed when chemotherapy, immunotherapy, or radiation therapy do not adequately control cancer growth. However, cancers that are not controlled by alloHSCT frequently become resistant to other standard treatment options.
- The outcomes of alloHSCT might be improved if certain kinds of white blood cells (T cells) could be manipulated so that they generate a more potent effect against the cancer cells. This effect can be augmented by genetically engineering donor T cells to specifically recognize cancerous cells in order to attack them. For this purpose, researchers are studying a specific kind of genetically engineered T cell known as the anti-CD19-CAR-transduced T cell. More research is needed to determine if this T cell will be an effective treatment for certain kinds of B cell cancer (such as non-Hodgkin's lymphoma and chronic lymphocytic leukemia) that has not been controlled with alloHSCT.
- To assess the safety and effectiveness of administering allogeneic anti-CD19-CAR-transduced T cells to patients with B-cell cancer that has not responded to alloHSCT.
- Individuals between 18 and 75 years of age who have received allogeneic hematopoietic stem cell transplantation for a B cell cancer, but whose cancer has either not responded to or recurred after the transplant.
- Recipients must have the same stem cell donor from their previous procedure.
- Before the start of the study, all participants will be screened with a medical history and blood tests. Recipients will have tumor imaging scans, additional blood tests, and other tests as directed by the study doctors.
- Donor participants will undergo apheresis to provide white blood cells for researchers to use in the treatment.
- Recipients will have dose escalation to determine the most effective yet safe dose of anti-CD19 T cells. There will be four dose levels of anti-CD19 T cells. The first patients enrolled will have the smallest dose, and the dose will be increased when a level has been determined to be safe. To reduce the risk of side effects, participants who received a stem cell transplant from an unrelated donor will receive a lower dose of anti-CD19 T cells than those who received a transplant from a related donor.
- Recipients will be hospitalized for 3 days after receiving the cell infusion, and will need to come to clinic for follow-up visits 1, 2, 3, 4, 8, and 12 weeks after the infusion.
- Additional scans and frequent blood tests will be required for the first 3 months after the infusion, followed by less frequent visits over time.
- Recipients will be followed for a maximum of 15 years after receiving the infusion.
|Study Design:||Allocation: Non-Randomized
Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Administration of Anti-CD19-Chimeric-Antigen-Receptor-Transduced T-cells From the Original Transplant Donor to Patients With Recurrent or Persistent B-Cell Malignancies After Allogeneic Stem Cell Transplantation|
- To assess the safety of administering allogeneic anti-CD19-CAR-transduced T cells to patients with B-cell malignancies that are persistent or relapsed after alloHSCT. The allo anti-CD19-CAR transduced T cells will be derived from the original d...
- To determine if administering anti -CD19-CAR transduced T cells can cause regression of B-cell malignancies that are relapsed or persistent after alloHSCT. To measure persistence of anti-CD19-CAR transduced T cells in the blood of patients.
|Study Start Date:||February 2010|
|Estimated Study Completion Date:||October 2014|
|Estimated Primary Completion Date:||October 2014 (Final data collection date for primary outcome measure)|
Genetic: Anti-CD19-CAR-transduced T cells
Many patients with advanced B-cell malignancies that cannot be cured by chemotherapy and monoclonal antibodies have prolonged relapse-free survival after allogeneic hematopoietic stem cell transplantation (alloHSCT); however, a substantial fraction of patients with B-cell malignancies relapse following alloHSCT.
The first therapeutic maneuver attempted when patients without graft-versus-host disease (GVHD) relapse after alloHSCT is usually withdraw of immunosuppressive drugs. If a remission does not occur after withdraw of immunosuppression, patients are often treated with donor lymphocyte infusions (DLI). Withdraw of immunosuppression and DLI can lead to complete remissions in patients with B-cell malignancies that relapse after alloHSCT. Unfortunately, a substantial fraction of patients do not enter a complete remission after withdraw of immunosuppression followed by DLI, and these therapies are often complicated by GVHD.
The outcomes of alloHSCT might be improved if T cells could be manipulated so that they generate a more potent graft-versus-malignancy (GVM) effect than unmanipulated T cells.
We hypothesize that the GVM effect against B-cell malignancies can be augmented by genetically engineering donor T cells to express receptors that specifically recognize antigens expressed by malignant B cells.
Chimeric antigen receptors (CARs) consist of an antigen recognition moiety combined with T-cell signaling domains. CARs are capable of activating T cells in an antigen-specific manner.
Expression of the CD19 antigen is limited to B cells and perhaps follicular dendritic cells. Most malignant B cells express CD19.
We have constructed a retroviral vector encoding an anti-CD19 CAR. Large numbers of T cells that have been transduced with this retroviral vector can be generated in vitro for clinical adoptive T cell therapy. These anti-CD19-CAR-transduced T cells specifically recognize a variety of CD19+ target cells and kill primary chronic lymphocytic leukemia (CLL) cells in vitro.
Anti-CD19-CAR-expressing T cells have not been previously used to treat patients after alloHSCT.
To assess the safety of administering allogeneic anti-CD19-CAR-transduced T cells to patients with B-cell malignancies that are persistent or relapsed after alloHSCT. The allogeneic anti-CD19-CAR-transduced T cells will be derived from the original allogeneic transplant donor.
To determine if administering anti-CD19-CAR-transduced T cells can cause regression of B-cell malignancies that are relapsed or persistent after alloHSCT.
To measure persistence of adoptively-transferred anti-CD19-CAR-transduced T cells in the blood of patients.
To assess the impact of a pentostatin plus cyclophosphamide conditioning regimen plus allogeneic anti-CD19 CAR T cells in patients who have residual malignancy after receiving allogeneic anti-CD19 CAR T cells alone.
Patients with any CD19-expressing malignancy that is persistent or recurrent following successful T-cell engraftment after HLA-identical sibling, 1-antigen mismatched related, or greater than or equal to 7/8-matched unrelated donor (URD) alloHSCT and sequential treatment with withdraw of immunosuppression and DLI. Patients with acute lymphoblastic leukemia will also be eligible after alloHSCT and withdraw of immunosuppression whether or not they have received a DLI.
The same donor that provided cells for the alloHSCT must be willing and able to undergo leukapheresis so that cells can be obtained to prepare the anti-CD19-CAR-transduced T cells.
The recipient must have at most grade I acute GVHD (see Appendix 1) or at most mild global score chronic GVHD (see Appendix 9). The recipient must not have received systemic immunosuppressive drugs for at least 28 days at the time of study enrollment.
The alloHSCT donor will undergo leukapheresis.
Peripheral blood mononuclear cells (PBMC) from the alloHSCT donor will be cultured with the anti-CD3 monoclonal antibody OKT3 and interleukin-2 (aldesleukin). The cells will then be transduced with replication-incompetent gammaretroviruses encoding an anti-CD19 CAR. The transduced T cells will proliferate in vitro for 15 to 20 days. The transduced T cells are referred to as anti-CD19-CAR-transduced T cells.
Separate dose-escalations will be performed for recipients of related (HLA-identical and 1-antigen mismatched) transplants and URD transplants. For each dose-escalation, at least 3 patients will be studied until a maximum tolerated dose (MTD) is determined or the highest dose level studied is found to be safe.
After MTDs are determined for recipients of related transplants and for recipients of URD transplants, subsequent patients enrolled on this protocol will be treated with the MTD of cells for their transplant type.
Recipients will be monitored for development of acute treatment-related toxicities for at least 10 days after cell infusion as inpatients. Dose-limiting toxicities (DLTs) will include severe acute GVHD and 4 toxicities not associated with GVHD.
A maximum of 36 patients (donors plus recipients) will be treated.
Assessment of safety is a primary objective of this clinical trial. Safety will be defined as a lack of severe acute post-infusional toxicities and an incidence of GVHD that is not higher than historical rates of GVHD occurring after standard DLI.
Anti-CD19-CAR-transduced T-cell persistence in the peripheral blood will be measured at multiple time points from 1 week to 1 year after anti-CD19-CAR-transduced T cell infusion by flow cytometry.
To assess for an anti-malignancy effect of the infused cells, patients will be staged using standard staging systems.
For patients who have residual malignancy after their original anti-CD19 CAR infusion, additional treatments with pentostatin and cyclophosphamide followed by anti-CD19 CAR T cells or anti-CDCAR T cells alone are potentially possible.
|Contact: James N Kochenderfer, M.D.||(301) email@example.com|
|United States, Maryland|
|National Institutes of Health Clinical Center, 9000 Rockville Pike||Recruiting|
|Bethesda, Maryland, United States, 20892|
|Contact: For more information at the NIH Clinical Center contact National Cancer Institute Referral Office (888) NCI-1937|
|Principal Investigator:||James N Kochenderfer, M.D.||National Cancer Institute (NCI)|