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
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
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
Anti-CD19-CAR-expressing T cells have not been previously used to treat patients after
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
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
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.
- INCLUSION CRITERIA:
Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
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...
James N Kochenderfer, M.D.
National Cancer Institute (NCI)
United States: Federal Government
|National Institutes of Health Clinical Center, 9000 Rockville Pike||Bethesda, Maryland 20892|