Engineering viral nanoparticles for TLR agonist-based multi-functional cancer immunotherapies

PROJECT SUMMARY/ABSTRACT Ovarian cancer is the most lethal gynecologic malignancy for women; standard of care surgery and chemotherapy treatment can provide a short period of remission but cannot eradicate the disease and prevent recurrence. Cancer immunotherapy has shown great potential in treating cancers, but no clinical

success has been reported for ovarian cancer. One major hurdle for cancer immunotherapy that is needed to overcome is to convert the immunosuppressive tumor microenvironment (TME). The goal of this proposal is to develop effective nanomedicines that are capable of reprogramming and converting the suppressive

TME for ovarian cancer treatment. To achieve this goal, I will utilize viral nanoparticles (VNPs) to incorporate various functionalities targeting different aspects of the TME through bioengineering approaches. The two VNPs that will be used in this proposal are cowpea mosaic virus (CPMV) and hepatitis B virus capsid (HBVc),

which both have well-characterized and stable structures for in vitro bioengineering. Toll-like receptor (TLR) agonists have been demonstrated to be potent to activate the innate immune system and modulate the TME. CPMV is a triple TLR 2, 4, and 7 agonist and is effective to reprogram the TME of ovarian cancer. In the

mentored K99 phase, I will focus on using CPMV as a triple TLR agonist to develop an adjuvant and antigen combination in-situ vaccine for ovarian cancer treatment (Aim 1) and developing multi-TLR agonists to investigate the mechanism of action (MOA) of CPMV and multi-TLRs activation in cancer treatment to design

potent TLR agonists combination for downstream applications (Aim 2). During my independent R00 phase, I will use HBVc as a nanotechnology platform to develop multiple functional therapeutic nanomaterials aiming to reprogram the suppressive TME to treat ovarian cancer and investigate the MOA. First, I will

develop HBVc-based TLR agonist and pro-inflammatory cytokine combination therapies, which can exert the functions of reprograming the TME and killing cancer cells concurrently (Aim 3). Secondly, I will develop HBVc into a “smart” nanoparticle that functions as a TLR agonist and targets and converts the pro-tumor M2

macrophages into anti-tumor M1 macrophages (Aim 4). During my graduate study, I have been trained in manipulating HBVc in vitro assembly and genetic engineering of HBVc to design novel structures. In the past two and a half years as a postdoc in Dr. Steinmetz’s lab at UCSD, I have been trained systematically

in the bioengineering of VNPs and the application of engineered VNPs for cancer treatment. A further two years of training in Dr. Steinmetz’s lab will allow me to enrich my background in cancer immunology, immune-oncology, and tumor modeling. With the help and guidance from my advisory committee, by the

end of my mentored phase, I will be able to secure a tenure-track faculty position in a top-tier research institute to establish my independent research program focusing on using HBVc as a nanotechnology platform to develop novel and effective multi-functional nanomedicines for cancer patients.