The long-term goal of Project 1 (C. Rooney and L. Wang) is to improve the expansion and persistence of adoptively transferred tumor-specific T cells using two novel approaches. (1) Incorporation of a third- generation chimeric antigen receptor (CAR) for GD2 containing intracellular signaling domains for CD28 and OX40 is hypothesized to enhance and sustain T- cell responses intratumorally, while providing resistance to inhibitory ligands elaborated within the tumor microenvironment. (ii) An extratumoral proliferative boost should be attained by engrafting the GD2.CAR onto T cells specific for the varicella-zoster virus (VZV), for which there exists a potent live-attenuated booster vaccine that increases the in vivo proliferation of VZV-specific T cells via their TCRs. These broad concepts will be explored in a clinical trial of GD2.CAR-engrafted VZV-specific T cells for the treatment of patients with advanced GD2-positive sarcomas ( A i m s 1 and 2). Because this will be a """"""""first-in-man"""""""" study, the transduced T cells will also incorporate an inducible safety switch based on dimerization of the caspase-9 molecule, which was validated in a recent clinical trial against graft-vs.-host disease. Unfortunately, the youngest pediatric sarcoma patients will be VZV-negative, making it difficult to generate VZV-specific autologous T cells and to justify vaccination of these seronegative patients with a live-attenuated virus. Hence, Aim 3 will evaluate in a preclinical model a cellular vaccine against GD2 that should provide extratumoral stimulation via the CAR. This effort will rely on the JF neuroblastoma (NB) cell line, which has been extensively tested as a cellular vaccine for NB. GD2 is strongly expressed by JF cells and can be presented to GD2,CAR-positive T cells both directly by the JFNB cells and indirectly by local antigen- presenting cells. Genetic modification of JFNB cells to express cytokines, such as ILI 5 and GM-CSF, that enhance T-cell proliferation and recruit and activate dendritic cells should promote extratumoral proliferation of the CAR-positive T cells in ananalogous way to stimulation of the native T cell receptor by VZV. In part therefore our project uses concepts developed in Project 3 and provides potential ways of increasing the safety and efficacy of projects 2 and 3 (the iC9 safety gene) and Project 4 (the DNR for TGFbeta).

Public Health Relevance

Progress in the development of T-cell therapy for advanced sarcomas and other high-risk solid tumors has been slowed by the weak expression or absence of targetable tumor antigens and poor performance of infused T cells . Project 1 seeks to address this problem by combining improved antigen receptor capabilities with a novel vaccination strategy to ensure adequate T-cell stimulation, both within and outside the tumor site.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
2P01CA094237-11
Application #
8435584
Study Section
Special Emphasis Panel (ZCA1-RPRB-B (O1))
Project Start
2001-12-01
Project End
2018-01-31
Budget Start
2013-02-05
Budget End
2014-01-31
Support Year
11
Fiscal Year
2013
Total Cost
$291,271
Indirect Cost
$104,861
Name
Baylor College of Medicine
Department
Type
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
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Gomes-Silva, Diogo; Mukherjee, Malini; Srinivasan, Madhuwanti et al. (2017) Tonic 4-1BB Costimulation in Chimeric Antigen Receptors Impedes T Cell Survival and Is Vector-Dependent. Cell Rep 21:17-26
Szoor, Arpad; Vaidya, Abishek; Velasquez, Mireya Paulina et al. (2017) T Cell-Activating Mesenchymal Stem Cells as a Biotherapeutic for HCC. Mol Ther Oncolytics 6:69-79
Yagyu, Shigeki; Hoyos, Valentina; Del Bufalo, Francesca et al. (2016) Multiple mechanisms determine the sensitivity of human-induced pluripotent stem cells to the inducible caspase-9 safety switch. Mol Ther Methods Clin Dev 3:16003

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