Novel RNA-based anti-cancer therapeutic for sustained immunotherapy by combined pattern recognition receptor (PRR) activation and anti-microRNA therapy (AMT)
Unmet Need
Cancer is incredibly prevalent and current therapies are insufficient. Globally, lifetime prevalence is 1 in 5, and mortality is 1 in 9 in men and 1 in 12 in women. Solid tumors account for approximately 90% of adult cancers yet are difficult to treat owing to the immunosuppressive tumor microenvironment (TME). A growing strategy to sensitize solid tumors is activation of pattern recognition receptors (PRRs). Agonism of PRRs drives production of anti-tumor factors and recruitment of immune cells. This de-suppression of the TME increases the efficacy of immunotherapies, such as immune checkpoint blockade (ICB), as well as other treatment modalities like chemotherapy. However, PRR agonism loses efficacy with repeated dosing and can even lead to a transiently compromised immune system with chronic administration. This is because PRR signaling is regulated by immune regulatory microRNAs (miRNAs) such as miR-21 and miR-146a. There is a need for PRR activators that retain efficacy with chronic administration.
Technology
Duke inventors have created a novel PRR agonist with retains anti-tumor efficacy with repeated administration. RigantmiR-21 activates a cytoplasmic RNA-sensing PRR called retinoic acid-inducible gene I (RIG-I, also known as DDX58) and also inhibits miR-21. It is intended to be administered to patients with solid tumors, including late-stage patients who have not responded well to other therapies and patients who need multiple treatments over time, to achieve anti-cancer therapeutic effects through the stimulation of the patients' innate immune response. Specifically, activation of RIG-I and inhibition of miR-21 leads to the production of type I interferons (IFNs) and inflammatory cytokines in both cancer and immune cells. Among the immune cells, dendritic cells are stimulated, T cells are recruited, and the population of immuno-suppressive myeloid-derived suppressor cells (MDSCs) is reduced. These responses induce immunogenic cell death (ICD) in the cancer cells. This has been demonstrated in vivo in the mouse model system. Intra-tumoral injection of RigantmiR-21 significantly increased cancer cell death and improved the survival of tumor-bearing mice compared with conventional RIG-I agonists. Repeated treatments continued to be effective, unlike conventional RIG-I agonists. Additionally, the combination of RigantmiR-21 and IFN-b priming improved anti-cancer responses in the particularly stubborn P53-/-, Rb-/- mouse head and neck cancer cells, which are resistant to conventional RIG-I agonists. Furthermore, RigantmiR-21 synergized with the anti-PD-1 antibody in the treatment of mouse sarcoma, demonstrating that RigantmiR-21 sensitizes tumors to checkpoint blockade immunotherapy.
Other Applications
The inventors' PRR agonist and miRNA antagonist hybrid design can target other PRRs besides RIG-I, including Stimulator of Interferon Genes (STING), Melanoma Differentiation Associated Protein -5 (MDA5), Laboratory of Genetics and Physiology 2 (LPG2), RNA-activated Protein Kinase (PKR), Nucleotide-binding Oligomerization Domain-containing Protein 2 (NOD2), and Nacht Leucine-rich Protein 3 (NALP3), as well as other miRNAs besides miR-21, including miR-146a.
RigantmiR-21 could potentially treat liquid tumors, since miR-21 has been shown to be the most commonly upregulated miRNA in solid and hematological malignancies.
The inventors' design could also be used as anti-infection, anti-viral agents.
Advantages
- First-in-class therapeutic that combines both PRR activation and anti-microRNA therapy for sustained efficacy across repeated treatment
- Stability: resistant to nuclease degradation
- Safety: few noncancerous cells are sensitive to RIG-I agonists
- Broadly effective: on a variety of solid and hematological cancers including those resistant to conventional RIG-I agonists
- Synergistic with other immunotherapies and treatment modalities