Numerous pre-clinical and clinical studies, including our own, demonstrate that DC-based tumor immunotherapies can induce potent tumor specific immunologic and clinical responses. However, complete clinical responses have been rare, and the improvement of DC-based immunotherapies is the focus of considerable effort. Increasing evidence suggests that tumor induced immunosupression, and the presence or induction of regulatory T-cells (Tregs), may limit the efficacy of anti-tumor immunization strategies. Our hypothesis is that Tregs play a critical role in limiting DC-based immunization against tumors, and that the reduction/removal of Tregs prior to immunotherapy may result in enhanced anti-tumor immunity and improved therapeutic efficacy. The studies we propose here will provide the experimental foundation for this approach and enable a direct test of this hypothesis through clinical trials designed to evaluate combined immunization/Treg depletion approaches for the immunotherapy of patients with advanced stage cutaneous T-cell lymphoma (CTCL). In our preliminary studies, we have developed and evaluated a DC-based immunization strategy for the immunotherapy of patients with CTCL. To construct an autologous tumor vaccine, we have utilized patientderived matured and """"""""polarized"""""""" DCs loaded with autologous circulating tumor cells from leukemic CTCL Patients. Our preliminary data demonstrates that immunization of a patient with end-stage Sezary Syndrome SzS resulted in significant anti-tumor immune responses and a complete clinical response. The studies we propose here are designed to continue the logical progression of the development of this immunization strategy by identifying and obviating immunosuppressive mechanisms in the host that are likely to limit vaccine efficacy. Our preliminary data demonstrate that CTCL patients have elevated levels of Tregs compared to normal controls. In this project we will evaluate and characterize Treg populations in CTCL patients, and will develop strategies to reduce or eliminate Tregs prior to immunization using already approved chemotherapeutic agents. These studies will provide the basis for the in vivo evaluation of the effectiveness of combined immunization and Treg depletion therapies for CTCL, and future analogous approaches for the treatment of human cancers.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
5P50CA121973-05
Application #
8379334
Study Section
Special Emphasis Panel (ZCA1-RPRB-M)
Project Start
Project End
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
5
Fiscal Year
2012
Total Cost
$201,874
Indirect Cost
$74,767
Name
University of Pittsburgh
Department
Type
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Mathers, A R; Carey, C D; Killeen, M E et al. (2017) Electrophilic nitro-fatty acids suppress allergic contact dermatitis in mice. Allergy 72:656-664
Davar, Diwakar; Ding, Fei; Saul, Melissa et al. (2017) High-dose interleukin-2 (HD IL-2) for advanced melanoma: a single center experience from the University of Pittsburgh Cancer Institute. J Immunother Cancer 5:74
Booth, Laurence; Roberts, Jane L; Sander, Cindy et al. (2017) The HDAC inhibitor AR42 interacts with pazopanib to kill trametinib/dabrafenib-resistant melanoma cells in vitro and in vivo. Oncotarget 8:16367-16386
Najjar, Yana G; Ding, Fei; Lin, Yan et al. (2017) Melanoma antigen-specific effector T cell cytokine secretion patterns in patients treated with ipilimumab. J Transl Med 15:39
Butterfield, Lisa H (2017) The Society for Immunotherapy of Cancer Biomarkers Task Force recommendations review. Semin Cancer Biol :
Lemchak, David; Banerjee, Swati; Digambar, Shaunak S et al. (2017) Therapeutic and prognostic significance of PARP-1 in advanced mycosis fungoides and Sezary syndrome. Exp Dermatol :
Ferris, Laura K; Saul, Melissa I; Lin, Yan et al. (2017) A Large Skin Cancer Screening Quality Initiative: Description and First-Year Outcomes. JAMA Oncol 3:1112-1115
Scharping, Nicole E; Menk, Ashley V; Whetstone, Ryan D et al. (2017) Efficacy of PD-1 Blockade Is Potentiated by Metformin-Induced Reduction of Tumor Hypoxia. Cancer Immunol Res 5:9-16
Overacre-Delgoffe, Abigail E; Chikina, Maria; Dadey, Rebekah E et al. (2017) Interferon-? Drives Treg Fragility to Promote Anti-tumor Immunity. Cell 169:1130-1141.e11
Kalinsky, Kevin; Lee, Sandra; Rubin, Krista M et al. (2017) A phase 2 trial of dasatinib in patients with locally advanced or stage IV mucosal, acral, or vulvovaginal melanoma: A trial of the ECOG-ACRIN Cancer Research Group (E2607). Cancer 123:2688-2697

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