A NANOPARTICLE-BASED APPROACH FOR BREAST CANCER IMMUNOTHERAPY

T cells can recognize tumor antigens presented by tumor cells. However, most antigenic tumors are not efficiently rejected by these T cells. The critical mechanisms that prevent T cell meditated tumor rejection include lack of strong antigenic and co-stimulatory signals from tumors and suppression of the tumor-specific T cell response by TGF-beta and regulatory T cells. Thus, a challenging task in tumor immunotherapy is to develop a strategy that may bypass these obstacles to activate CD8+ T cells with minimal damage to the normal tissues.In this collaborative effort between Dr. Hua Gu's and Xudong Yuan's laboratories, we propose to generate Cbl-b-/- CD8+ T cells using CD8+ T specific nanoparticles and explore the possibility of using Cbl-b-/- CD8+ T cells as the 'super killer' T cells for breast cancer therapy. This proposal stems from recent findings from our laboratories and others showing that: (1) Cbl-b-/- T cells respond to antigen stimulation independent of co-stimulation and the response is not inhibited by TGF-beta. (2) Cbl-b-/- mice efficiently reject inoculated tumors with strong or weak antigeneicity. (3) Adoptive transfer of Cbl-b-/- CD8+ T cells eradicates established tumors. (4) Introduction of Cbl-b-/- mutation into tumor-prone ataxia telangiectasia-mutated deficient (ATM-/-) or BRCA1-/-p53+/- mice prevents spontaneous lymphomas or breast cancers, respectively. (5) We have established a biodegradable nanoparticle-based gene delivery system and successfully used this system to silence gene expression. These results thus support the idea that ablation of Cblb in T cells by nanoparticle-mediated siRNA delivery can be used as an effective therapeutic approach against tumors. In this study, we propose to optimize a targeted nanoparticle delivery system we developed that may specifically inactivate Cbl-b in CD8+ T cells in vivo. We will then test the hypothesis that ablation of Cbl-b in CD8+ T cells may render them responsive against tumors and use this approach to treat spontaneous breast cancer in BRCA1-/- p53+/- mice. The specific aims are the following:Aim 1: To prepare and characterize biodegradable multifunctional nanoparticles that can efficiently deliver siRNA specifically into CD8+ T cells.Aim 2: To determine the efficiency and specificity of CD8-nanoparticle-mediated siRNA delivery and test whether in vivo ablation of Cbl-b in CD8+ T cells prevents and cures spontaneous breast cancer in BRCA1-/- p53+/- mice.This study may bring a new avenue to the prevention and treatment of breast cancers.