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Eligibility:
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Full description
Background:
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 withdrawal of immunosuppressive drugs. If a remission does not occur after withdrawal of immunosuppression, patients are often treated with lymphocyte -DCI. Withdrawal of immunosuppression and DCI 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 withdrawal of immunosuppression followed by DCI, 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.
Primary Objective:
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.
Eligibility:
Patients with any CD19-expressing malignancy that is persistent or recurrent following successful engraftment after HLA-identical or >=9/10 matched sibling, 1-antigen mismatched sibling, or 9/10-matched unrelated donor (URD) alloHSCT and withdrawal of immunosuppression.
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 or chronic GVHD with no organ site with a score exceeding 1, except for the skin, for which a score of 1 or 2 will be allowable. The recipient must not have received systemic immunosuppressive drugs given for graft versus host disease for at least 28 days at the time of study enrollment. Patients must be on a dose of corticosteroids of an equivalent of 5 mg/day or less of prednisone. Corticosteroid creams, ointments, and eye drops are allowed.
Design:
The alloHSCT donor will undergo leukapheresis.
Patients will undergo apheresis to obtain peripheral blood mononuclear cells. These cells will be processed to produce anti-CD19 CAR stem memory T cells (anti-CD19 CAR Tscm). This process involves sorting the cells and then culturing the cells in vitro for 9 days. During the 9-day culture period, the cells will be transduced with gammaretroviruses encoding the FMC63-28Z.
CAR recipients will be monitored for development of acute treatment-related toxicities for at least 9 days after cell infusion as inpatients. Dose-limiting toxicities (DLTs) will include severe acute GVHD and Grade 4 toxicities not associated with GVHD.
A maximum of 126 evaluable 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 DCI.
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.
Enrollment
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Inclusion and exclusion criteria
Inclusion Criteria: Recipient
Recipients (patients with B-cell malignancy) must have received an HLA-identical or 9/10 matched sibling allogeneic hematopoietic stem cell transplant, a 1-antigen mismatched related transplant, or a greater than or equal to 9/10-matched unrelated donor (URD) alloHSCT for any CD19+ B-cell malignancy. Patients with any CD19+ B-cell malignancy that is persistent or relapsed after all of the following interventions are eligible:
Exception: Prior (DCI) DLI is not an eligibility requirement for patients with ALL, Burkitt lyphoma, ALL like high-grade lymphomas, or diffuse large B-cell lymphoma.
At least 28 days weeks must have elapsed since the latest trial of withdraw of immunosuppression or DLI until the patient can be deemed to have persistent disease.
CD19 expression must be detected on the majority of the malignant cells by immunohistochemistry or by flow cytometry in the Laboratory of Pathology, CCR, NCI, NIH. Definition of which cells are malignant must be determined for each patient by the Laboratory of Pathology using techniques to demonstrate monoclonality such as kappa/lambda restriction (other techniques can be used to determine monoclonality at the discretion of the Laboratory of Pathology). The choice of whether to use flow cytometry or immuohistochemistry will be determined by what is the most easily available tissue sample in each patient. Immunohistochemistry will be used for lymph node biopsies and bone marrow biopsies. Flow cytometry will be used for peripheral blood, fine needle aspirate, and bone marrow aspirate samples.
Patients must be 18-75 years of age.
Performance status: ECOG less than or equal to 2
Either no evidence of GVHD or minimal clinical evidence of acute GVHD and chronic GVHD while off of systemic immunosuppressive therapy for at least 28 days. Minimal clinical evidence of acute GVHD is defined as grade 0 to I acute GVHD. Minimal evidence of chronic GVHD is defined as chronic GVHD with no organ site with a score exceeding 1, except for the skin, for which a score of 1 or 2 will be allowable (as defined by the 2005 NIH consensus project) or no chronic GVHD. Subjects with disease that is controlled to stage I acute GVHD or chronic GVHD meeting the above criteria with local therapy only, e.g., topical cutaneous steroids, will be eligible for enrollment.
Ability to give informed consent.
Prior Therapy: Therapy with monoclonal antibodies and/or chemotherapy must be stopped at least 7 days prior to anti-CD19 CAR-transduced T cell infusion, and recovery of treatment-associated toxicity to less than or equal to grade 2 is required prior to infusion of cells. For patients that have received prior DLI, the last dose must be at least 28 days prior to anti-CD19 CAR-transduced T cell administration. Note that patients can be enrolled on this study at any time after or during therapy, but at least 14 days must elapse from the time of prior monoclonal antibody administration or chemotherapy until anti-CD19 CAR-transduced T cells are infused, and at least 28 days must elapse from the time of withdraw of immunosuppression, or DLI, or other immunomodulatory therapies such as lenalidomide until anti-CD19 CAR-transduced T cells are infused. Systemic immunosuppression given for graft versus host disease must be stopped at least 28 days prior to protocol entry. There is no time restriction in regard to prior intrathecal chemotherapy provided there is complete recovery from any acute toxic effects of such.
Recipients of unrelated donor transplants from a National Marrow Donor Program (NMDP) Center must sign a release of information form to authorize NMDP transfer of information to the NIH.
Previous allogeneic donor must be willing and available to donate again.
Patients of childbearing or child-fathering potential must be willing use an effective method of contraception while being treated on this study and for 4 months after the last cell infusion.
Normal left ventricular function as evaluated by echocardiograph within 4 weeks of anti- CD19-CAR-transduced T cell infusion
Inclusion Criteria: Donor
EXCLUSION CRITERIA:
Exclusion Criteria: Recipients
Exclusion Criteria: Donors
Primary purpose
Allocation
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85 participants in 3 patient groups
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Data sourced from clinicaltrials.gov
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