Immunoswitch Particles for the Conversion of Inhibitory Signals to Co-stimulatory Signals for Enhanced Immune-mediated Tumor Cell Killing

Unmet Need:
One of the largest obstacles to overcome in cancer immunotherapy is the suppressive actions of the tumor microenvironment. Combination therapies that activate an immune response as well as block inhibitory pathways have potential in creating a prolonged and effective anti-tumor response.
 
Technology Overview:
Johns Hopkins researchers develop an immunoswitch nanoparticle that combines an inhibitory checkpoint signal, PD-L1, in the tumor microenvironment with a co-stimulatory, 4-1BB, signal to T cells for efficient stimulation. By combining antibodies against both molecules on a single platform, the particles physically link effector and target cells and switch off the inhibitory PD-L1 pathway on tumor cells while simultaneously switching on the stimulatory 4-1BB pathway on murine CD8 cells. These particles bypass the requirement for a priori selection of tumor antigens to activate T cells against by utilizing tumor-derived peptide-MHC during stimulation. The immunoswitch particles increase activation of CD8 cells in vitro in the presence of cognate target cells, and enhance effector-target cell conjugation. Immunoswitch particles significantly delay tumor growth and extend survival in two in vivo models of murine melanoma and colon cancer over soluble antibody or isotype particles. Their effectiveness is dependent on the presence of both antibodies on the same nanoparticle, as separating them onto distinct particles diminishes the in vivo effect. This novel approach to combination therapy results in a single, all-encompassing injectable therapeutic for cancer immunotherapy
 
Stage of Development:
The inventors have developed a novel immunoswitch particle that link checkpoint blockade with T cell costimulation on a single platform and studied its efficacy in an in vitro model developed to mimic tumor-specific T cells within the tumor microenvironment. Preclinical in vivo studies were performed in murine melanoma and colon cancer model. The researchers have shown proof of concept of a novel signal-switching approach that links two signaling pathways.
 

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