The studies address the problem of relapse of B-lineage acute lymphoblastic leukemia (B-ALL) after umbilical cord blood transplant (UCBT). We hypothesize that the incidence of relapse following allogeneic UCBT can be reduced by targeting post-transplant minimal residual disease (MRD) with adoptively transferred donor-derived leukemia-specific T-cells. As a strategy to reproducibly generate effector cells for adoptive therapy after UCBT, we have designed a new chimeric antigen receptor (CAR), designated CD19RCD28, which re-directs the antigen specificity of T cells to the B-cell lineage-restricted cell-surface molecule CD19. Genetically-modified CD19-CAR* cytotoxic T lymphocytes (CTL's) are activated through chimeric CD28 and CD3, and lyse B-cell malignant target cells in a CAR-regulated manner. T-cell isolation, genetic modification, and expansion Standard Operating Procedures at MDACC will manufacture clinical cell doses in accordance with quality control/assurance standards mandated by the FDA. The studies proposed in Specific Aim #1 will evaluate the feasibility and safety of adoptive therapy using three escalating doses (108/m2-1010/m2) of donor-derived CD19RCD28+HyTK+ CTL-clones versus oligoclonal/polyclonal T-cell lines, after reduced intensity allogeneic UCBT for high-risk CD19* B-ALL. We hypothesize that the lymphodepleting preparative regimen will promote homeostatic proliferation of transferred T-cells, as well as, limit anti-transgene rejection responses. The correlative studies in Specific Aim #2 focus on delineating the magnitude and duration of persistence of transferred clones versus lines at the three prescribed T-cell dose levels using vector-specific Q-PCR and TCR spectratyping analyses on serially acquired PBMC specimens. We will also evaluate the utility of administering recombinant human IL-2 for enhancing the expansion of transferred T-cells in vivo. The correlative studies proposed in Specific Aim 3 will evaluate the bone marrow and lymph node trafficking of transferred clones versus lines, and, the functional status of transferred T-cells in these anatomic sites of B-ALL MRD. In aggregate, the results of the studies proposed will facilitate the evolution of targeting post-UCBT MRD with CD19-specific T-cells for enhanced disease-free survival of patients with B-lineage ALL, and substantiate the rationale to expand this approach to a broader array of CD19+ malignancies treated by HCT.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA124782-05
Application #
8081715
Study Section
Clinical Oncology Study Section (CONC)
Program Officer
Merritt, William D
Project Start
2007-08-20
Project End
2013-05-31
Budget Start
2011-07-01
Budget End
2013-05-31
Support Year
5
Fiscal Year
2011
Total Cost
$283,822
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Pediatrics
Type
Other Domestic Higher Education
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
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