Immune checkpoint inhibitors have revolutionized the treatment of cancer because they yield dramatic responses and long-lasting therapeutic benefits in previously untreatable cancers (e.g. metastatic melanoma). Despite this promise, the responses to immune checkpoint inhibitors have been restricted to small subsets of patients and are associated with toxic, and potentially fatal immune-related adverse events. In response to this urgent need to devise novel therapeutic strategies that dramatically increase the response rate to immune checkpoint inhibitors, we have engineered an ensemble nanoimmunotherapy that combine the advantages of nanotechnology and immunotherapy. Specifically, our ensemble comprises: Prussian blue nanoparticles (PBNPs) biofunctionalized with immune adjuvants and administered in combination with systemically administered checkpoint inhibitors. We utilize the PBNPs for photothermal therapy, which ablates tumor cells, releasing tumor antigens, and damage-associated molecular patterns that increase tumor immunogenicity. The loss of immunogenicity is one of the key immune escape mechanisms in cancer. Additionally, the PBNPs are biofunctionalized to serve as a depot for local delivery of exogenous immune adjuvants, particularly toll-like receptor agonists that play an important role in breaking tolerance to tumor antigens and improving tumor antigen presentation, which is impaired in immunosuppressive tumors. These effects are complemented by systemically administered checkpoint inhibitors (anti-PD-1 and anti-CTLA-4) that reverse suppression of immune cell responses (particularly T cells) and unleash their potent antitumor effects. We believe that this ensemble approach of targeting tumor cells, antigen presenting cells, and T cells may hold the key in converting a non-responsive ?cold? tumor to a responsive ?hot? tumor.
In Aim 1, we seek to determine whether the PBNPs biofunctionalized with toll-like receptor agonists and used for photothermal therapy elicits immunogenic cell death and improves antigen presentation.
In Aim 2, we test the efficacy of the ensemble nanoimmunotherapy on tumor eradication and preventing relapse.
In Aim 3, we evaluate the efficacy of the nanoimmunotherapy in treating disseminated cancer. The successful completion of the project will provide critical insight into the use of multifunctional nanoparticles in combination with immunotherapies to overcome tumor immune evasion mechanisms and improve therapeutic outcomes. Importantly, it will provide the impetus for clinical translation of our nanoimmunotherapy, thereby extending its lasting benefits to a larger proportion of cancer patients.

Public Health Relevance

This project is relevant to public health because it could make available an effective and safe therapeutic regimen that dramatically increases the response rates of cancer patients to immune checkpoint inhibitors, immunotherapies that have revolutionized cancer therapy because they elicit robust treatment responses in previously untreatable tumors. It will also advance insight into the scientific merit and feasibility of engineering ensemble nanoimmunotherapies by combining biofunctionalized nanoparticle-based photothermal therapy with immune checkpoint inhibition for treating cancer, and the immunological basis for the observed treatment responses. Successful completion of the project will provide the impetus for clinical translation of our nanoimmunotherapy, thereby extending lasting benefits to a larger proportion of cancer patients.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA226171-01A1
Application #
9659958
Study Section
Nanotechnology Study Section (NANO)
Program Officer
Henderson, Lori A
Project Start
2018-12-03
Project End
2022-11-30
Budget Start
2018-12-03
Budget End
2019-11-30
Support Year
1
Fiscal Year
2019
Total Cost
Indirect Cost
Name
George Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
043990498
City
Washington
State
DC
Country
United States
Zip Code
20052