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Principal Investigator: Zhongchao Zhao
Organization: UNIVERSITY OF CALIFORNIA, SAN DIEGO
Fiscal Year: 2024
Award: $130,350
Funding agency: National Cancer Institute
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.
Terms: <Adjuvant><Advisory Committees><Agonist><Antigens><Biochemical><Biochemistry><Biological Chemistry><Biology><Biomedical Engineering><Cancer Patient><Cancer Treatment><Cancers><Capsid><Cell Body><Cells><Checkpoint inhibitor><Chemotactic Cytokines><Clinical><Clinical Oncology><Clinical Research><Clinical Study><Clinical Trials><Co-Stimulator><Combination Drug Therapy><Combination immunotherapy><Combined Modality Therapy><Costimulator><Cowpea Mosaic Viruses><Debulking><Development><Diagnosis><Disease><Disease remission><Disorder><Edodekin Alfa><Educational workshop><Encapsulated><Engineering><Enrollment><Epidermal Thymocyte Activating Factor><FDA approved><Faculty><Female Reproductive Cancer><Future><Genetic><Genetic Engineering><Genetic Engineering Biotechnology><Genetic Engineering Molecular Biology><Goals><Grant><Gynecologic Cancer><Gynecological Cancer><HBV><Hepatitis B Virus><Homologous Chemotactic Cytokines><Homologous Serum Hepatitis Virus><IL-12><IL-2><IL12><IL2 Protein><Immune><Immune checkpoint inhibitor><Immune mediated therapy><Immunes><Immunity><Immunologically Directed Therapy><Immunology><Immunomodulation><Immunooncology><Immunotherapy><Impairment><In Vitro><Inflammatory><Innate Immune System><Innate Immunity><Intercrines><Interleukin 2><Interleukin 2 Precursor><Interleukin II><Interleukin-12><Interleukin-2><Interleukine 2><Interleukine 2 Precursor><Interleukine II><Investigators><Knowledge><Learning><Liposomal><Liposomes><Lymphocyte Mitogenic Factor><Macrophage><Malignant Cell><Malignant Female Reproductive System Neoplasm><Malignant Gynecologic Neoplasm><Malignant Gynecologic Tumor><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasms><Malignant Ovarian Neoplasm><Malignant Ovarian Tumor><Malignant Tumor><Malignant Tumor of the Female Reproductive System><Malignant Tumor of the Ovary><Malignant neoplasm of ovary><Mentors><Messenger RNA><Mitogenic Factor><Modality><Modeling><Multimodal Therapy><Multimodal Treatment><Mφ><NKSF><Nanoplatform><Nanotechnological platform><Native Immunity><Natural Immunity><Natural Killer Cell Stimulatory Factor><Non-Specific Immunity><Nonspecific Immunity><Operative Procedures><Operative Surgical Procedures><Ovary Cancer><Patients><Peptides><Ph D student><Ph D. student><Ph. D. student><Ph.D student><Ph.D. student><PhD student><PhD. student><Phase><Plant Viruses><Pliability><Polychemotherapy><Position><Positioning Attribute><Postdoc><Postdoctoral Fellow><Production><Protein Engineering><Reagent><Receptor Activation><Receptor Protein><Recombinant DNA Technology><Recurrence><Recurrent><Recurrent Malignant Neoplasm><Recurrent Malignant Tumor><Recurrent disease><Relapsed Disease><Remission><Reporting><Research><Research Associate><Research Institute><Research Personnel><Research Technics><Research Techniques><Researchers><SIS cytokines><Secure><Structure><Surgical><Surgical Interventions><Surgical Procedure><Survival Rate><System><T cell growth factor><T-Cell Growth Factor><T-Cell Stimulating Factor><TIL4><TLR protein><TLR2><TLR2 gene><TLR2 receptor><Task Forces><Therapeutic><Thymocyte Stimulating Factor><Toll-Like Receptor 2><Toll-Like Receptor Family Gene><Toll-like receptors><Toll/Interleukin 1 Receptor-Like 4><Toll/Interleukin 1 Receptor-Like 4 Gene><Toll/Interleukin 1 Receptor-Like Protein 4><Training><Translational Research><Translational Science><Tumor Antigens><Tumor Cell><Tumor Debulking><Tumor Immunity><Tumor-Associated Antigen><Woman><Workshop><advisory team><anti-cancer immunotherapy><anti-cancer therapy><anti-tumor immune response><anti-tumor immunity><anticancer immunotherapy><antitumor immunity><bio-engineered><bio-engineers><bioengineering><biological engineering><cancer antigens><cancer cell><cancer immunity><cancer immunology><cancer immunotherapy><cancer microenvironment><cancer recurrence><cancer therapy><cancer-directed therapy><career development><chemical conjugate><chemoattractant cytokine><chemokine><chemotherapy><clinical translation><clinically translatable><combination chemotherapy><combination pharmacotherapy><combination therapy><combinatorial immunotherapy><combined modality treatment><combined treatment><cowpea virus><cytokine><cytoreductive surgery><deliver mRNA><deliver messenger RNA><delivery system for mRNA><design><designing><develop a vaccine><develop vaccines><development of a vaccine><developmental><doctoral student><dual immunotherapy><effective therapy><effective treatment><efficacy study><enroll><genetic protein engineering><genetically engineered><gynecologic malignancy><gynecological malignancy><immune check point inhibitor><immune microenvironment><immune modulation><immune regulation><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based cancer therapies><immune-based therapies><immune-based treatments><immune-oncology><immuno oncology><immuno therapy><immunogen><immunogenic><immunologic reactivity control><immunology oncology><immunomodulatory><immunoregulation><immunoregulatory><immunosuppressive microenvironment><immunosuppressive tumor microenvironment><immunotherapy for cancer><immunotherapy of cancer><improved><in situ anti-tumor vaccine><in situ antitumor vaccine><in situ cancer vaccine><in situ tumor vaccine><in situ vaccine><in vivo><insight><mRNA><mRNA delivery><malignancy><messenger RNA delivery><mouse model><multi-modal therapy><multi-modal treatment><murine model><nano medicinal><nano medicine><nano meter scale><nano meter sized><nano particle><nano-sized particle><nanomaterials><nanomedicinal><nanomedicine><nanometer scale><nanometer sized><nanoparticle><nanoscale><nanosized particle><nanotechnology platform><neoplasm immunology><neoplasm/cancer><neoplastic cell><novel><oncoimmunology><ovarian cancer><pliable><post-doc><post-doctoral><post-doctoral trainee><prevent><preventing><programs><protein design><receptor><research associates><skills><standard of care><success><surgery><surgical cytoreduction><synergism><tenure process><tenure track><translation research><translational investigation><treatment strategy><tumor><tumor cytoreduction><tumor immune microenvironment><tumor immunology><tumor microenvironment><tumor-immune system interactions><tumor-specific antigen><vaccine development><viral nanoparticle>