Prodrug Lipid Nanoparticles for Synergistic Cancer Immunotherapy

Prodrug lipid nanoparticle (LNP) with a mRNA encoding for a therapeutic cytokine for solid tumor immunotherapy.</brief>
Problem:
Approximately 2 million people are diagnosed with cancer each year in the United States. Messenger RNA (mRNA)-based cancer immunotherapy has emerged as a potential cancer treatment using cytotoxic T cells to eliminate cancer cells. However, this treatment is associated with T cell exhaustion, which limits the effectiveness of immunotherapy. Recently, mRNA-based cancer therapies have been combined with immune checkpoint blockade therapies to inhibit T cell exhaustion, but this has only been successful in a limited number of patients due to treatment resistance and low response rates. These limitations have driven interest in developing immunotherapy platforms that simultaneously target various immunosuppressive pathways.
Solution:
Prodrug ionizable lipid nanoparticles (PLNPs) simultaneously deliver cytokine-encoded mRNA to activate T cells and an inhibitor to prevent T cell exhaustion. This therapy showed a long-lasting immune response and protected against subsequent tumors. This prodrug LNP platform can be used with diverse mRNA and small-molecule drugs as a combination cancer immunotherapy.
Technology:
Prodrug ionizable lipids (PILs) were synthesized to contain a T cell exhaustion inhibitor and an enzymatic cleavage site. These PILs were then used to formulate prodrug lipid nanoparticles (PNLPs) encapsulating mRNA encoding for interleukin-12 (IL-12), a cytokine used for T cell stimulation. in vitro studies showed that the lead PIL had stronger mRNA transfection than the FDA-approved ionizable lipid. In a subcutaneous tumor mouse model, PLNPs cleared primary tumors to increase survival compared to control mice. In addition, the PLNP immunotherapy induced a memory T cell response associated with long-term protection against the tumor and cleared distal tumors.
Advantages:

Provided 44-fold greater extracellular IL-12 protein and 8.6-fold greater intracellular IL-12 protein levels compared to FDA-approved ionizable lipid.
PLNP treatment exerted in vivo therapeutic synergistic effects, suppressed tumor growth, and cleared all tumors within 30 days in tumor mouse model.
PLNPs elicited effective long-term anti-tumor responses and drove regression of distal tumors.

Stage of Development:

Preclinical Discovery

A) Depiction of prodrug lipid nanoparticle (PLNP) formulated with engineered prodrug ionizable lipid and mRNA encoding for interleukin 12 (IL-12) to inhibit T cell exhaustion while also activating cytotoxic T cells to kill cancer cells. B) Tumor did not grow in mice treated with PLNP (red, “Treated”) compared to control (black, “Control”) in a subcutaneous tumor mouse model. C) Mice treated with PNLP (red, “Treated”) survived to the study endpoint (> 60 days) following tumor implantation, while control mice (black, “Control”) succumbed to the tumor within 40 days.
Intellectual Property: