The genetic modification of T lymphocytes is the basis for novel approaches to study and establish tumor? immunity. The genetic transfer of antigen receptors is indeed a powerful approach to rapidly generate tumorspecific? T lymphocytes. However, while necessary, tumor antigen recognition is not sufficient to permit tumor? eradication. To achieve this goal, primed CTLs must expand to sufficient numbers, migrate to tumor sites,? mature into effector cells and carry out their cytolytic function unimpeded. The genetic strategies we are? pursuing aim to increase recognition of tumor antigens, enhance anti-tumor functions and sustain T cell? function in cancer patients. Most important for our understanding of human tumor immunology and? therapeutic goals, gene addition and knockdown strategies can be applied to human T lymphocytes, on? which we focus in this project.
The specific aims are based on our published and preliminary data.
Aim 1 : To? investigate the biological properties and therapeutic potential of tumor specific CD8+ T cells co-stimulated by? CD28 and 4-1BB. We hypothesize that concerted CD28 and 4-1BB signals sustain CD8+ T cell proliferation? and survival, and may thus augment the therapeutic potency of genetically targeted T lymphocytes.
Aim 2 :? To investigate the effect of ex vivo IL-15 on the proliferation, survival, differentiation and therapeutic potential? of adoptively transferred human primary T lymphocytes.
This aim builds on our recent finding that IL-15? enhances the therapeutic potential of cultured 19z1-transduced PBLs upon adoptive transfer to tumorbearing? mice. We hypothesize that IL15 increases therapeutic efficacy through several mechanisms, most? importantly T cell survival.
Aim 3 : To establish an efficient protocol for T'cell transduction and expansion in a? closed system and perform a phase I clinical trial to assess the safety, persistence and therapeutic activity of? autologous 19-28z-transduced T lymphocytes in patients with relapsed, chemo-refractory chronic? lymphocytic leukemia. We hypothesize that patient T cells expressing a CD28/ -like chimeric antigen? receptor will induce durable remissions, more so in cyclophosphamide-treated recipients. Our investigation? critically depends on the Gene Transfer and Somatic Cell Engineering Core, to genetically modify patient T? cells, the Imaging Core, to study T cell migration and persistence in vivo, and the Administrative Core, for? biostatistics and data management.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA059350-15
Application #
7655361
Study Section
Subcommittee G - Education (NCI)
Project Start
Project End
Budget Start
2008-05-01
Budget End
2009-04-30
Support Year
15
Fiscal Year
2008
Total Cost
$357,733
Indirect Cost
Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065
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Smith, Eric L; Staehr, Mette; Masakayan, Reed et al. (2018) Development and Evaluation of an Optimal Human Single-Chain Variable Fragment-Derived BCMA-Targeted CAR T Cell Vector. Mol Ther 26:1447-1456
Budhu, Sadna; Schaer, David A; Li, Yongbiao et al. (2017) Blockade of surface-bound TGF-? on regulatory T cells abrogates suppression of effector T cell function in the tumor microenvironment. Sci Signal 10:
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Sadelain, Michel; Rivière, Isabelle; Riddell, Stanley (2017) Therapeutic T cell engineering. Nature 545:423-431
Yeku, Oladapo O; Brentjens, Renier J (2016) Armored CAR T-cells: utilizing cytokines and pro-inflammatory ligands to enhance CAR T-cell anti-tumour efficacy. Biochem Soc Trans 44:412-8
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Boice, Michael; Salloum, Darin; Mourcin, Frederic et al. (2016) Loss of the HVEM Tumor Suppressor in Lymphoma and Restoration by Modified CAR-T Cells. Cell 167:405-418.e13

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