Abstract B108: Combining Notch immunostimulation and bortezomib with adoptive immunotherapy in breast cancer

Abstract

Abstract Breast cancer mortality occurs primarily due to invasive metastasis and takes a disproportionately heavy toll in African American women. Clinical immunotherapy efforts prove largely ineffective, partly due to the numerous immune-regulatory circuits influenced by cancers, which alter the differentiation and function of immune cells, including T cells. The long-term objective of this study is to enhance immune mechanisms of cancer rejection to provide durable clinical benefits against breast cancer. Our recent work using mouse models has revealed the therapeutic potential of combinatorial adoptive cell transfer regimens along with immunostimulatory and tumor cell-death-sensitizing treatments. We found that the proteasome inhibitor bortezomib selectively sensitized mammary tumor cells to apoptosis by amplifying caspase-8 activation in the death-inducing signaling complex. This resulted in reduced lung metastases in mice. In addition, bortezomib could be combined with adoptive T cell transfer with no adverse effects on the antigen-specific T cell proliferative or cytolytic functions in vivo. However, no long-term survival benefits could be observed, likely due to immunosuppressive effects of tumor. More recently, we observed that Delta-like ligand (DLL1)-specific immune Notch activation could enhance antitumor T cell immunity by overcoming tumor-associated immunosuppression. These data predict the potential of combining immunostimulatory Notch activation by soluble clustered DLL1 ligand treatment and bortezomib-induced sensitization of breast tumor cells to apoptosis with T cell adoptive transfers. This could prevent tumor metastasis and significantly improve breast cancer therapy. Citation Information: Cancer Epidemiol Biomarkers Prev 2011;20(10 Suppl):B108.