The UCLA/Caltech Program in Engineered Immunity is conducting a series of adoptive cell therapy clinical investigations using F5 MART T cell receptor (TCR) engineered T cells. T lymphocytes engineered to express this high affinity TCR are highly cytotoxic towards HLA A*0201/ MART-positive melanoma targets, release type I cytokines and are biologically very active when administered to patients. In a recently completed trial in which 109 F5 MART CTL were administered to 8 conditioned patients with metastatic melanoma, 6 showed evidence of dramatic tumor regression in measurable disease sites such as lung, liver, bone, lymph node and skin. All however, relapsed within three months. Our objective is to study the mechanism of sensitivity or resistance of early passage patient-derived melanoma cell lines from these patients, and from two successor trials, to F5 MART CTL-induced cytotoxicity. We hypothesize that epigenetically controlled deregulated activation of signaling pathways and an imbalance in the ratio of pro- and anti-apoptotic gene products favor an immune-resistant phenotype. Further, the acquired and/or inherent resistance can be reversed by chromatin remodeling molecules such as HDACi (SAHA). Successful execution of the proposed specific aims will identify epigenetically regulated signal transduction pathway(s) and apoptosis-associated gene products responsible for melanoma resistance to F5 MART CTL. This culminates in the utilization of small molecule inhibitors (sensitizing agents) that can specifically target the components of deregulated signaling pathways and by modulating the expression profile of apoptosis-related gene products favor a pro-apoptotic milieu, thus, conferring a sensitive phenotype.

Public Health Relevance

This grant will support the conduct of a comprehensive analysis of tumor cells derived from patients with metastatic skin cancer (melanoma) after receiving billions of their own white blood cells genetically engineered to recognize and kill their own melanoma cells. These scientific aims will help us better understand why some patients'melanoma cancer cells can be killed, and others not, and to potentially identify improvements to make this kind of cancer treatment more effective.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21CA149938-02
Application #
8337740
Study Section
Special Emphasis Panel (ZRG1-OTC-W (02))
Program Officer
Thurin, Magdalena
Project Start
2011-09-23
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2014-08-31
Support Year
2
Fiscal Year
2012
Total Cost
$296,171
Indirect Cost
$103,852
Name
University of California Los Angeles
Department
Surgery
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095