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.
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.
|Jazirehi, Ali R; Kurdistani, Siavash K; Economou, James S (2014) Histone deacetylase inhibitor sensitizes apoptosis-resistant melanomas to cytotoxic human T lymphocytes through regulation of TRAIL/DR5 pathway. J Immunol 192:3981-9|
|Jazirehi, Ali R; Torres-Collado, Antoni X (2013) Epigenetic fine-tuning of NF-?B-Sox9 circuitry in cancer stem cells. Epigenomics 5:363-64|
|Bonavida, Benjamin; Jazirehi, Ali; Vega, Mario I et al. (2013) Roles Each of Snail, Yin Yang 1 and RKIP in the Regulation of Tumor Cells Chemo-immuno-resistance to Apoptosis. For Immunopathol Dis Therap 4:|
|Jazirehi, Ali R; Torres-Collado, Antoni X; Nazarian, Ramin (2013) Epigenetic regulation of melanoma tumor suppressor miRNA-124a. Epigenomics 5:251-52|
|Jazirehi, Ali R; Economou, James S (2012) Proteasome inhibition blocks NF-?B and ERK1/2 pathways, restores antigen expression, and sensitizes resistant human melanoma to TCR-engineered CTLs. Mol Cancer Ther 11:1332-41|
|Masood, Aisha; Shahshahan, Mohammad A; Jazirehi, Ali R (2012) Novel approaches to modulate apoptosis resistance: basic and clinical implications in the treatment of chronic lymphocytic leukemia (CLL). Curr Drug Deliv 9:30-40|
|Jazirehi, Ali R (2012) Editorial: Functional complementation, molecular targeted strategies, and chemo/immuno-sensitization in cancer treatment: hurdles and solutions. Curr Drug Deliv 9:1-4|