Humans and mice have a highly conserved population of T cells that recognizes the nonpolymorphic MHC class I-like CD1d protein. These T cells are distinguished by their expression of several cell surface proteins otherwise found largely on natural killer (NK) cells and by a conserved invariant TCR alpha chain. These invariant NK T cells appear to have an immunoregulatory function based upon their ability to produce large amounts of IL-4and IFN-gamma within hours of activation in vivo. The loss of invariant NK T cells has been linked to the development of autoimmune disease in humans and mice, but other studies show critical roles in anti-viral and anti-tumor responses, and indicate that these cells mediate the anti-tumor effects of IL-2. Data in humans further indicate that invariant NK T cells are decreased in patients with advanced cancer and we have shown marked decreases in their INF-gamma production. These findings strongly suggest that expansion and activation of human invariant NK T cells to produce INF-gamma could yield anti-tumor responses and enhance the effects of IL-2 and tumor vaccines. To test this hypothesis we would like to conduct a phase 1 clinical trial of in vitro expanded autologous invariant NK T cells. We have shown that human invariant NK T' cells can be readily expanded in vitro and that their INF-gamma production can be restored with IL-12. The primary objective of this proposal is to establish optimal methods for the in vitro expansion of invariant NK T cells from cancer patients for use in clinical trials (Aim I). We will also take advantage of ongoing IL-12 clinical trials to determine whether IL-12 treatment in vivo augments invariant NK T cell function (Aim 2). These pre-clinical studies will then be used to design of a phase I clinical trial of invariant NK T cells in cancer.
The specific aims are to: 1) Establish optimal methods for the in vitro expansion and activation of human Invariant NK T cells; 2) Determine whether IL-12 treatment in vivo enhances in vitro expansion or INF production by invariant NK T cells.
| Exley, Mark A; Wilson, Brian; Balk, Steven P (2010) Isolation and functional use of human NKT cells. Curr Protoc Immunol Chapter 14:Unit 14.11 |
| Balk, Steven P; Ko, Yoo-Joung; Bubley, Glenn J (2003) Biology of prostate-specific antigen. J Clin Oncol 21:383-91 |
