Breast cancer and its microenvironment can directly subvert cytotoxic T cell immune responses. Thus, previous efforts to induce cell-mediated anti-tumor responses in vivo by vaccination have had limited success. We propose instead to adoptively transfer T cells that are engineered ex vivo to target the tumor and the tumor environment, and are armed with countermeasures to a potent tumor immune evasion strategy. In this application we propose to: 1) generate bi-specific T cells that simultaneously target two tumor-associated antigens, Her2 and Muc1, through native and chimeric receptors, thereby minimizing the impact of antigen and MHC modulation as a means of evading T cell recognition. 2) Next, we will assess the safety and function of these adoptively-transferred binary T cells in patients with refractory breast cancer. 3) Finally, to protect these ex vivo generated bi-specific T cells from the hostile tumor microenvironment, we have developed a novel chimeric cytokine receptor (4/7R). Transgenic expression of this chimeric 4/7R molecule allows the engineered T cells to utilize the suppressive Th2 cytokine IL4, produced at the tumor site, to instead promote the T cells'expansion, persistence, and cytotoxic activity in vivo. The safety and anti-tumor activity of these tumor-resistant T cells will be tested clinically in patients with metastatic breast cancer. Our approach has a potentially outstanding pharmaco-economic profile since the clinical the benefits of T cell therapy can be sustained long-term, and should be associated with minimal toxicities. The Center for Cell and Gene Therapy (CAGT), and the Breast Cancer Center at Texas Medical Center are uniquely positioned to translate to the clinic the proposed studies given the knowledge, experience, and specialized infrastructure possessed by these centers.

Public Health Relevance

We are proposing to develop a personalized treatment by modifying the patient's own immune system to fight the cancer. We will engineer T lymphocytes to recognize two different targets expressed on the cancer cells, making it much harder for the cancer cell to escape recognition. These double-killer T cells will then be equipped with a counter measure to protect them from molecules secreted by cancer cells, generating in this way a safe and clinically effective therapy for advanced breast cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
1P50CA186784-01
Application #
8747145
Study Section
Special Emphasis Panel (ZCA1-RPRB-C (M1))
Project Start
Project End
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
1
Fiscal Year
2014
Total Cost
$263,862
Indirect Cost
$105,540
Name
Baylor College of Medicine
Department
Type
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
Yu, L; Liang, Y; Cao, X et al. (2016) Identification of MYST3 as a novel epigenetic activator of ERα frequently amplified in breast cancer. Oncogene :
Malorni, Luca; Giuliano, Mario; Migliaccio, Ilenia et al. (2016) Blockade of AP-1 Potentiates Endocrine Therapy and Overcomes Resistance. Mol Cancer Res 14:470-81
Fu, Xiaoyong; Jeselsohn, Rinath; Pereira, Resel et al. (2016) FOXA1 overexpression mediates endocrine resistance by altering the ER transcriptome and IL-8 expression in ER-positive breast cancer. Proc Natl Acad Sci U S A 113:E6600-E6609
Eedunuri, Vijay Kumar; Rajapakshe, Kimal; Fiskus, Warren et al. (2015) miR-137 Targets p160 Steroid Receptor Coactivators SRC1, SRC2, and SRC3 and Inhibits Cell Proliferation. Mol Endocrinol 29:1170-83
Nardone, Agostina; De Angelis, Carmine; Trivedi, Meghana V et al. (2015) The changing role of ER in endocrine resistance. Breast 24 Suppl 2:S60-6
Giuliano, Mario; Hu, Huizhong; Wang, Yen-Chao et al. (2015) Upregulation of ER Signaling as an Adaptive Mechanism of Cell Survival in HER2-Positive Breast Tumors Treated with Anti-HER2 Therapy. Clin Cancer Res 21:3995-4003
Shi, Aiping; Dong, Jie; Hilsenbeck, Susan et al. (2015) The Status of STAT3 and STAT5 in Human Breast Atypical Ductal Hyperplasia. PLoS One 10:e0132214
Dowst, Heidi; Pew, Benjamin; Watkins, Chris et al. (2015) Acquire: an open-source comprehensive cancer biobanking system. Bioinformatics 31:1655-62
Sine, Jessica; Urban, Cordula; Thayer, Derek et al. (2015) Photo activation of HPPH encapsulated in ""Pocket"" liposomes triggers multiple drug release and tumor cell killing in mouse breast cancer xenografts. Int J Nanomedicine 10:125-45
Sinha, Vidya C; Qin, Lan; Li, Yi (2015) A p53/ARF-dependent anticancer barrier activates senescence and blocks tumorigenesis without impacting apoptosis. Mol Cancer Res 13:231-8

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