Bladder cancer is the sixth most common cancer diagnosis in the U.S. Although three-quarters of patients are diagnosed early with superficial (non-invasive) disease, bladder cancer is highly recurrent and requires long-term maintenance therapy and costly continuous surveillance. Novel therapies, capable of inducing durable anti-tumor responses, are needed to limit progressive recurrence and to improve survival. Immune-based therapies have demonstrated the potential to elicit, durable tumor-specific immunity. In particular, the pro-inflammatory cytokine, interleukin-12 (IL-12), has demonstrated remarkable anti-tumor activity and protective immunity in numerous preclinical tumor models. Previous research has demonstrated that chitosan, a natural polysaccharide derived from the exoskelatons of crustaceans, can enhance the anti- tumor efficacy of intravesically administered IL-12. Co-formulations of chitosan solution and IL-12 (chitosan/IL- 12) were found to eliminate established orthotopic bladder tumors and generate systemic tumor-specific protective immunity. The proposed project will continue the preclinical development of intravesical chitosan/IL-12 immunotherapy. Three independent aims are proposed.
Aim 1 is designed to elucidate the mechanisms by which chitosan facilitates intravesical IL-12 delivery.
Aim 2 will assess the pharmacokinetics, safety and tolerability of intravesical chitosan/IL-12 immunotherapy using clinically relevant endpoints.
Aim 3 will begin to describe how an intravesical immunotherapy can generate systemic protective immunity. The overall goal of this project is to improve our mechanistic understanding of chitosan-enhanced intravesical delivery while providing critical preclinical data in support of translation of a promising new immunotherapy for the treatment of bladder cancer. At the same time, this project will enhance the biomedical research capacity at an AREA institution, provide valuable research opportunities for 2 new graduate students and expose approximately 15-25 undergraduate students to biomedical research.

Public Health Relevance

Bladder cancer, the sixth most common non-skin cancer diagnosis in the U.S., is a highly recurrent disease that would benefit from a new therapy capable of inducing durable tumor regression. A novel immune-based therapy, comprised of a mixture of chitosan, a polysaccharide, with interleukin-12, an immune stimulating cytokine, is under development. This project will evaluate the potential of this therapy to safely provide long term cures.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Academic Research Enhancement Awards (AREA) (R15)
Project #
1R15CA176648-01A1
Application #
8626563
Study Section
Special Emphasis Panel (ZRG1-OTC-X (90))
Program Officer
Yovandich, Jason L
Project Start
2014-03-01
Project End
2017-02-28
Budget Start
2014-03-01
Budget End
2017-02-28
Support Year
1
Fiscal Year
2014
Total Cost
$416,897
Indirect Cost
$116,897
Name
University of Arkansas at Fayetteville
Department
Engineering (All Types)
Type
Schools of Engineering
DUNS #
191429745
City
Fayetteville
State
AR
Country
United States
Zip Code
72701
Jayanthi, Srinivas; Koppolu, Bhanu prasanth; Smith, Sean G et al. (2014) Efficient production and purification of recombinant human interleukin-12 (IL-12) overexpressed in mammalian cells without affinity tag. Protein Expr Purif 102:76-84