It has been well established that the immune system possesses strong tumor surveillance mechanisms and anti-tumor responses. Treatments utilizing engineered T cells have the potential to offer long-term protection, through memory, but it is unclear which T cell subset should be used. Our lab focuses on modulating invariant natural killer T (NKT) cells for cancer immunotherapy. NKT cell-based therapy offers the possibility of inducing an initial cytotoxic tumor response, in addition to activating NK cells and the adaptive immune system to produce tumor-directed cytotoxic T cells with long-lived memory. Thus NKT cells can mediate direct anti-tumor effects and also activate other immune pathways. We hypothesize that transducing NKT cells with anti- CD19 chimeric antigen receptors (CAR) will enhance their cytotoxic functions and will be more efficient than transducing bulk T cells. In order to test this hypothesis we will transduce NKT cells and bulk T isolated from the peripheral blood of healthy donors and lymphoma patients. We will characterize our CAR expressing NKT/T cells by assessing their phenotype, proliferative capacity, and function. We will compare their anti-tumor effector functions utilizing in vitro T cell assays and cytotoxicity studies, as wll as using mouse xenograft models. The information gained in these studies will serve to help understand and design NKT cell based immunotherapeutic approaches for the treatment of cancer.
Hematological malignancies, like lymphomas, remain incurable because of the high risk of relapse. Most lymphomas are B cell in origin, and are primarily divided into Hodgkin's and non-Hodgkin's lymphomas (NHL). NHL is the second fastest rising cancer in incidence and death rates in the United States, therefore the development of novel treatment strategies is essential. In this application, we propose an innovative method to generate natural killer T (NKT) cells expressing anti-CD19 chimeric antigen receptor and to assess its ability to enhance anti-tumor immune responses specifically by NKT cells. This work is important because it could lead to the development of new therapeutic strategies for the treatment of lymphoma.
| Shissler, Susannah C; Webb, Tonya J (2018) The ins and outs of type I iNKT cell development. Mol Immunol 105:116-130 |
| Bates, Joshua P; Derakhshandeh, Roshanak; Jones, Laundette et al. (2018) Mechanisms of immune evasion in breast cancer. BMC Cancer 18:556 |
| Shissler, Susannah C; Lee, Michael S; Webb, Tonya J (2017) Mixed Signals: Co-Stimulation in Invariant Natural Killer T Cell-Mediated Cancer Immunotherapy. Front Immunol 8:1447 |
| Bollino, Dominique; Webb, Tonya J (2017) Chimeric antigen receptor-engineered natural killer and natural killer T cells for cancer immunotherapy. Transl Res 187:32-43 |
| Shissler, Susannah C; Bollino, Dominique R; Tiper, Irina V et al. (2016) Immunotherapeutic strategies targeting natural killer T cell responses in cancer. Immunogenetics 68:623-38 |
| Tiper, Irina V; East, James E; Subrahmanyam, Priyanka B et al. (2016) Sphingosine 1-phosphate signaling impacts lymphocyte migration, inflammation and infection. Pathog Dis 74: |
| Webb, Tonya J; Carey, Gregory B; East, James E et al. (2016) Alterations in cellular metabolism modulate CD1d-mediated NKT-cell responses. Pathog Dis 74: |
| Tiper, Irina V; Webb, Tonya J (2016) Histone deacetylase inhibitors enhance CD1d-dependent NKT cell responses to lymphoma. Cancer Immunol Immunother 65:1411-1421 |
| Tiper, Irina V; Webb, Tonya J (2016) Targeted attack: mechanisms by which ovarian cancers suppress the immune system. Transl Cancer Res 5:S1305-S1306 |
