Professor Massachusetts Institute of Technology, United States
Introduction:: The majority of high-grade serous ovarian cancer (HGSOC) patients are diagnosed at late stages in disease progression (stage III/IV), which leads to extremely low cure rates with current surgical and chemotherapy interventions. Further, of the meager surviving patient population, over 80% will experience relapse due to the persistence of a small, clinically undetectable population of chemotherapy-resistant cancer cells known as minimal residual disease (MRD), and in this event, the disease is considered incurable. In many other types of cancer, chemoresistance has been overcome with the introduction of immunotherapies, but HGSOC has yet to see the impact of these emerging therapies as their tumor environment is considered “cold” with limited immune cell infiltration.
However, recent work has shown the potential of type I interferon as a means to recruit immune cells to HGSOC tumor sites, allowing these cells to then target and eliminate the cancer cells. In the case of MRD, the delivery of type I interferon is limited by the cytokine’s high toxicity and poor pharmacokinetics while attempting to target such a small cell population. Thus, in this work, we engineer polymeric layer-by-layer nanoparticles (LbL NPs) for the targeted delivery of immunotherapies to ovarian cancer at the MRD stage.
Materials and Methods:: Here, we utilize the LbL NP platform to deliver interferon-β (IFN-β) in two ways: One by directly conjugating the cytokine to the NP, and one by encapsulating an IFN-β-inducing small molecule CARM I inhibitor, EZM 2302 in the NP.
For the IFN-β-loaded NP, the cytokine is directly tethered to a liposome core, and for the EZM 2302-loaded NP, the drug is encapsulated in the bilayer of a liposome. Both NPs are then layered with a polymeric coating that yields potent HGSOC-specific delivery. The synthesis and modification of each therapeutic-loaded NP is thoroughly characterized and optimized. Both NPs are assessed in vitro for bioactivity and efficacy in relevant cancer cell lines.
Results, Conclusions, and Discussions:: These LbL NPs are thoroughly characterized and evaluated for their ability to induce inflammatory responses in the HGSOC tumor microenvironment. In all, this LbL NP platform provides a novel approach to targeting ovarian cancer cells at the MRD stage as promising strategy for improving the efficacy of immunotherapies in HGSOC.
