Immunoswitch particles: A new approach to cancer immunotherapy
Alyssa K. Kosmides, John-William Sidhom, Andrew Fraser, Qiongman Kong, Jonathan P. Schneck
Johns Hopkins University School of Medicine, USA
One of the largest obstacles in cancer immunotherapy involves overcoming the immunosuppressive tumor microenvironment. Monotherapies that initiate T cell activation or block immunosuppressive pathways have led to exciting results, although a significant population still does not respond. Here, we develop a novel nanomedicine, termed Immunoswitch particles, which simultaneously activate tumor-specific T cells and target the immunosuppressive tumor microenvironment.
Immunoswitch particles are synthesized by functionalizing 80nm particles with antagonistic antibodies against PD-L1 and agonistic antibodies against 4-1BB. These particles can thus simultaneously bind PD-L1 on the tumor cell and 4-1BB on the T cell to switch an inhibitory signal into a co-stimulatory one. Immunoswitch particle treatment but not soluble antibody is able to delay or eliminate tumor growth in two different murine tumor models by activating an endogenous anti-tumor response without a priori knowledge of the target antigen. We have demonstrated that the presence of both antibodies on the surface of the same particle increases effector-target cell conjugation and that CD8+ T cell activation is dependent on the expression of a cognate signal 1 by the target cell. Mechanistically, Immunoswitch particles increase CD8+ T cell infiltration and alter the T cell receptor (TCR) repertoire used to recognize a model tumor antigen. The changes in the TCR repertoire are conserved, indicating that treatment facilitates shaping of the repertoire and results in an effective anti-tumor response without altering the antigen being recognized.
Here, we have developed a new nanomedicine for cancer immunotherapy using an immuno-engineering approach where synthetic therapeutics are developed in novel ways to further synergize biological activity. Immunoswitch particles represent a new genre of nanoparticle signal-switching immunotherapies that can be utilized in multiple cancer models and disease states.