Circular Bispecific Aptamer-Mediated Artificial Intercellular Recognition for Targeted T Cell Immunotherapy

Adoptive T cell immunotherapy, such as chimeric antigen receptor (CAR) T cell therapy, has proven to be highly efficient in the treatment of hematologic malignancies. However, it is challenged by complicated ex vivo engineering, systemic side effects, and low expression of tumor-specific antigen, especially in solid tumors. In this paper, we present a "recognition-then-activation" strategy, which first assists naïve T cells to recognize and adhere to cancer cells and then activates the accumulated T cell in situ to specifically kill cancer cells. In this way, we could unleash the antitumor power of the T cell without complicated and time-consuming cell engineering. To this end, circular bispecific aptamers (cb-aptamers), a class of chemically cyclized aptamers with improved stability and molecular recognition ability which can simultaneously bind to two different types of cells, were first constructed to form artificial intercellular recognition between naïve T cells and tumor cells. After T cell accumulation in the tumor mediated by cb-aptamers, T cells in the tumor site were subsequently activated in situ via commercial CD3/CD28 T cell activator beads to induce tumor-specific killing. Furthermore, by simply choosing different anticancer aptamers, the application of this "recognition-then-activation" strategy can be expanded for targeted treatment of various types of cancer. This may represent a simple T cell immunotherapy that is useful for the treatment of multiple cancers.