In order to facilitate analysis of the complex immune response to cancer cells, a well-defined tumor model systems have been established in our group. In this model the metastatic mouse breast cancer 4T1.2 or the mouse renal carcinoma Renca have been transfected with the viral protein hemagglutinin (4T1.2-HA, Renca-HA) as a surrogate tumor antigen. The transfer of the viral HA gene provides a tumor that is much more immunogenic, due to response by CD 8 cytotoxic T cells of the mouse to the viral protein. In addition transgenic mice have been generated where the T cell receptor (TCR) transgene specifically recognizes a single dominant peptide of the viral HA protein (TCR-HA), thus allowing for this antigen-specific T cell population to be accurately followed and monitored in vivo. These mice have been crossed onto strains which lack some of the cytotoxic effector molecules of T cells such as perforin and FasL important for killing tumor cells in vitro. Using such a pre-clinical model system we have demonstrated that the proteasome inhibitor bortezomib, when administered a with an optimal dose and timing can be combined with adoptive T cell transfer to improve therapeutic outcome. This seems to be due to both the sensitization of the cancer cells by bortezomib to undergo immune-mediated apoptosis as well as the unexpected enhancement of an ongoing anti-cancer response. More recently we have identified specific members of the withanolide family of natural products that sensitize cancer cells to apoptosis in response to TNF family death ligands. Therefore in current ongoing studies we are assessing if these active withanolides can be combined with adoptive T cell transfer, checkpoint (anti-PD-1) inhibition and immune adjuvant (poly (I:C) therapies in preclinical models of melanoma, renal cancer and breast cancer

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC010012-22
Application #
9556239
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
22
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
Shanker, Anil; Pellom Jr, Samuel T; Dudimah, Duafalia F et al. (2015) Bortezomib Improves Adoptive T-cell Therapy by Sensitizing Cancer Cells to FasL Cytotoxicity. Cancer Res 75:5260-72
Pellom Jr, Samuel Troy; Dudimah, Duafalia Fred; Thounaojam, Menaka Chanu et al. (2015) Modulatory effects of bortezomib on host immune cell functions. Immunotherapy 7:1011-22
Weiss, Jonathan M; Subleski, Jeff J; Back, Tim et al. (2014) Regulatory T cells and myeloid-derived suppressor cells in the tumor microenvironment undergo Fas-dependent cell death during IL-2/?CD40 therapy. J Immunol 192:5821-9
Mathews, Lesley A; Keller, Jonathan M; Goodwin, Bonnie L et al. (2012) A 1536-well quantitative high-throughput screen to identify compounds targeting cancer stem cells. J Biomol Screen 17:1231-42
Zaritskaya, Liubov; Shurin, Michael R; Sayers, Thomas J et al. (2010) New flow cytometric assays for monitoring cell-mediated cytotoxicity. Expert Rev Vaccines 9:601-16
Shanker, Anil; Brooks, Alan D; Jacobsen, Kristen M et al. (2009) Antigen presented by tumors in vivo determines the nature of CD8+ T-cell cytotoxicity. Cancer Res 69:6615-23
Salcedo, Rosalba; Hixon, Julie A; Stauffer, Jimmy K et al. (2009) Immunologic and therapeutic synergy of IL-27 and IL-2: enhancement of T cell sensitization, tumor-specific CTL reactivity and complete regression of disseminated neuroblastoma metastases in the liver and bone marrow. J Immunol 182:4328-38