Currently, there are no effective treatments for disease recurrence following allogeneic hematopoietic stem- cell transplant (HSCT). T-cell therapy can target malignancies using mechanisms independent of chemo- radiotherapy, with non-overlapping and generally mild toxicities. Thus, we are investigating adoptive immunotherapy as a strategy to augment the graft-versus-tumor (GVT) effect after allogeneic HSCT. However, this approach has been limited by problems delineating immunogenic epitopes for a large number of HLA alleles, T-cell tolerance to leukemia-associated antigens, and the difficulty of manufacturing patient- specific T cells in a timely manner. As an alternative strategy, we propose to use T cells genetically modified to express a chimeric antigen receptor (CAR) specific a desired tumor antigen independent of MHC. To target B-cell malignancies, we have designed a CAR which re-directs the antigen-specificity of T cells to the B cell lineage-restricted cell-surface molecule CD19. CD19 is expressed on the majority of B-lineage leukemia or lymphoma cells, but is absent on hematopoietic stem cells and non-hematopoietic cells. Genetically modified CD19-specific T cells are activated via chimeric CD3-^ upon CAR binding CD19, resulting in antigen-dependent cytokine production, killing and proliferation. These preclinical data were used to open a Phase I clinical trial (BB-IND 11411) infusing autologous CD19-specific T cells (expressing the first-generation CAR) in patients with relapsed follicular lymphoma. In this grant, we propose a new clinical trial to infuse pre-prepared CD19-specific T cells derived from umbilical cord blood (UCB) in patients with relapsed B-lineage leukemia/lymphoma after allogeneic HSCT. Significantly, this trial will be (i) the """"""""first-in- human"""""""" infusion of CD19-specific T cells after allogeneic HSCT, (ii) the first to infuse T cells expressing a second-generation CAR capable of providing a fully-competent T-cell activation signal (through chimeric CD3-?; and CD28), and (iii) the first to image distribution of genetically modified T cells and their activation status in vivo by positron emission tomography (PET), an example of radio-gene-therapy. We hypothesize that the a priori generation of banks of a homogenous population of UCB-derived HLA-unmatched CD19- specific T-cell clones will permit infusion of T cells in a safe and timely manner in a patient population with little chance of survival. T-cell isolation, genetic modification, and expansion will follow Standard Operating Procedures at MDACC, and T-cell doses will be manufactured in our Good Manufacturing Process (GMP) facility in accordance with quality control/assurance standards mandated by the FDA for a master cell bank. Lav language: T cells will be developed which can destroy B-lineage disease. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21CA116127-02
Application #
7455223
Study Section
Special Emphasis Panel (ZCA1-SRRB-K (J1))
Program Officer
Muszynski, Karen
Project Start
2007-06-25
Project End
2010-05-31
Budget Start
2008-06-01
Budget End
2010-05-31
Support Year
2
Fiscal Year
2008
Total Cost
$168,750
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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Krishnamurthy, Janani; Rabinovich, Brian A; Mi, Tiejuan et al. (2015) Genetic Engineering of T Cells to Target HERV-K, an Ancient Retrovirus on Melanoma. Clin Cancer Res 21:3241-51
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Maiti, Sourindra N; Huls, Helen; Singh, Harjeet et al. (2013) Sleeping beauty system to redirect T-cell specificity for human applications. J Immunother 36:112-23
Deniger, Drew C; Switzer, Kirsten; Mi, Tiejuan et al. (2013) Bispecific T-cells expressing polyclonal repertoire of endogenous ?? T-cell receptors and introduced CD19-specific chimeric antigen receptor. Mol Ther 21:638-47
Zhang, Minying; Maiti, Sourindra; Bernatchez, Chantale et al. (2012) A new approach to simultaneously quantify both TCR ?- and ?-chain diversity after adoptive immunotherapy. Clin Cancer Res 18:4733-42

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