Development of vaccine technologies with therapeutic efficacy against cancer has been an elusive goal. Conventional adjuvants induce weak levels of cytotoxic CD8+ T lymphocyte (CTL) responses, while accumulating evidence suggests that simultaneous CTL and antibody (Ab) responses are needed for effective therapy. Therefore, there is a critical need for alternative approaches that can achieve strong anti-tumor immune responses. Our long-term research goal is to develop new material-based strategies that can achieve immune stimulation with potent therapeutic efficacy against cancer. Our objective in this R01 application is to delineate the key nanomaterial criteria for designing effective nano-vaccines and to utilize knowledge gained from these studies to develop a powerful vaccine technology for treatment of primary and metastatic melanomas. To that end, we have developed a novel nano-vaccine system that can (a) efficiently transport antigen (Ag) to dendritic cells (DCs); (b) promote Ag cross-presentation and cross-priming of T-cells; (c) generate significantly stronger Ag-specific CD8+ T-cell responses than conventional vaccines based on DCs, other nano-formulations, and experimental adjuvants in clinical trials; (d) enhance accumulation of anti-tumor T-cells in tumor microenvironment; and (e) induce anti-tumor immunity against primary and metastatic melanomas, in a biocompatible and safe manner. In this application, we propose to address the following questions: what are unique characteristics of our nano-vaccines that evoke such strong anti-tumor immunity, compared with other traditional cancer vaccines? Can we in turn modulate these parameters to further optimize our nano-vaccine technology and amplify anti-tumor immunity? We will evaluate outcomes of our strategy in murine models of locally and systemically disseminated melanomas. Our innovative approach employing interdisciplinary principles of materials science, bioengineering, and immunology will lead to a new vaccine nanotechnology that may eliminate primary and metastatic melanomas and improve cancer immunotherapy.

Public Health Relevance

The proposed research is relevant to public health as these studies will generate new fundamental knowledge in vaccine development, address current technical limitations in vaccine technologies, and may lead to a new form of immunotherapy that can elicit robust levels of T-cell and IgG immune responses.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA210273-04
Application #
9829551
Study Section
Nanotechnology Study Section (NANO)
Program Officer
Perloff, Marjorie
Project Start
2016-12-15
Project End
2021-11-30
Budget Start
2019-12-01
Budget End
2020-11-30
Support Year
4
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Kuai, Rui; Yuan, Wenmin; Son, Sejin et al. (2018) Elimination of established tumors with nanodisc-based combination chemoimmunotherapy. Sci Adv 4:eaao1736
Park, Hyun-Ji; Kuai, Rui; Jeon, Eun Je et al. (2018) High-density lipoprotein-mimicking nanodiscs carrying peptide for enhanced therapeutic angiogenesis in diabetic hindlimb ischemia. Biomaterials 161:69-80
Kuai, Rui; Sun, Xiaoqi; Yuan, Wenmin et al. (2018) Subcutaneous Nanodisc Vaccination with Neoantigens for Combination Cancer Immunotherapy. Bioconjug Chem 29:771-775
Ochyl, Lukasz J; Bazzill, Joseph D; Park, Charles et al. (2018) PEGylated tumor cell membrane vesicles as a new vaccine platform for cancer immunotherapy. Biomaterials 182:157-166
Nam, Jutaek; Son, Sejin; Ochyl, Lukasz J et al. (2018) Chemo-photothermal therapy combination elicits anti-tumor immunity against advanced metastatic cancer. Nat Commun 9:1074
Kuai, Rui; Sun, Xiaoqi; Yuan, Wenmin et al. (2018) Dual TLR agonist nanodiscs as a strong adjuvant system for vaccines and immunotherapy. J Control Release 282:131-139
Bailey, Brittany A; Desai, Kashappa-Goud H; Ochyl, Lukasz J et al. (2017) Self-encapsulating Poly(lactic-co-glycolic acid) (PLGA) Microspheres for Intranasal Vaccine Delivery. Mol Pharm 14:3228-3237
Kuai, Rui; Ochyl, Lukasz J; Bahjat, Keith S et al. (2017) Designer vaccine nanodiscs for personalized cancer immunotherapy. Nat Mater 16:489-496
Bailey, Brittany A; Ochyl, Lukasz J; Schwendeman, Steven P et al. (2017) Toward a Single-Dose Vaccination Strategy with Self-Encapsulating PLGA Microspheres. Adv Healthc Mater 6:
Tang, Jie; Kuai, Rui; Yuan, Wenmin et al. (2017) Effect of size and pegylation of liposomes and peptide-based synthetic lipoproteins on tumor targeting. Nanomedicine 13:1869-1878

Showing the most recent 10 out of 15 publications