With a new targeting strategy, researchers can now change where and when therapeutic T cells are activated, making cytokine therapy more useful in clinical settings. Researchers from the National University of Singapore and Shenyang Pharmaceutical University designed a biomimetic nanovaccine by engineering dendritic cell-derived cytomembrane vesicles to enable spatiotemporally synchronous cytokine delivery.

By combining multivalent interleukin-15 (IL-15) self-transpresentation and tumor antigen presentation over time and space, this method was used to make cytotoxic T lymphocyte (CTL) immune responses safer and more effective against tumors. This targeting strategy induces broad-spectrum antigen-specific T cell responses, and promotes therapeutic benefits in multiple syngeneic tumor models, including the excellent capability of tumor recurrence inhibition, with minimal systemic side effects.

The peer-reviewed research article “Biomimetic nanovaccine-mediated multivalent IL-15 self-transpresentation (MIST) for potent and safe cancer immunotherapy” was published in Nature Communications.

MIST-vaccine enables IL-15 immunotherapy

While cytokine therapy with IL-15 is a promising strategy for cancer immunotherapy, clinical application has been limited due to severe toxicity and a relatively low immune response rate caused by the wide distribution of cytokine receptors and IL-15’s short half-life. Furthermore, conventional cytokine therapy frequently causes dose-limiting toxicity due to systemic activation of nontumor-specific T cells.

Co-first authors Kaiyuan Wang, Xuanbo Zhang, and Hao Ye led an effort to create a vaccine that only targets antigen-specific CTL, reducing the amount of damage it causes to other cells. This biomimetic nanovaccine is made up of cytomembrane vesicles derived from genetically engineered dendritic cells (DC), and it contains IL-15 as well as an antigen/major histocompatibility complex (MHC). Unlike traditional IL-15 therapy, which requires APCs to bind to the IL-15R, the biomimetic nanovaccine can directly mediate IL-15 transpresentation to CD8+ T cells via “multivalent IL-15 self-transpresentation” (MIST).

The biomimetic nanovaccine holds great promise for improving the targeted delivery of IL-15 to lymph nodes due to its excellent safety profile and well-established fabrication processes. They discover that the biomimetic nanovaccine has a nanoscale-sized structure, a longer circulation half-life and retention in lymphatic organs, a wider therapeutic window, and stronger antitumor potency. This biomimetic vaccine, when administered systemically, achieves targeted delivery of IL-15 to tumor-specific T cells, reduces non-specific systemic immune stimulation, and maximizes CTL activation to drive tumor killing and immunological memory. 

This cytokine delivery platform can prevent systemic side effects while also activating antitumor immunity. Because cytomembrane vesicles can handle the addition of natural proteins, this method can be used for any type of cytokine delivery. As a result, such biomimetic nanovaccine platform technology offers a method for the clinical application of cytokine therapy.

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