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.
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.
| Ravindranathan, Sruthi; Nguyen, Khue G; Kurtz, Samantha L et al. (2018) Tumor-derived granulocyte colony-stimulating factor diminishes efficacy of breast tumor cell vaccines. Breast Cancer Res 20:126 |
| Jayanthi, Srinivas; Koppolu, Bhanu Prasanth; Nguyen, Khue G et al. (2017) Modulation of Interleukin-12 activity in the presence of heparin. Sci Rep 7:5360 |
| Smith, Sean G; Baltz, John L; Koppolu, Bhanu Prasanth et al. (2017) Immunological mechanisms of intravesical chitosan/interleukin-12 immunotherapy against murine bladder cancer. Oncoimmunology 6:e1259050 |
| Smith, Sean G; Zaharoff, David A (2016) Future directions in bladder cancer immunotherapy: towards adaptive immunity. Immunotherapy 8:351-65 |
| Ravindranathan, Sruthi; Koppolu, Bhanu Prasanth; Smith, Sean G et al. (2016) Effect of Chitosan Properties on Immunoreactivity. Mar Drugs 14: |
| Smith, Sean G; Koppolu, Bhanu Prasanth; Ravindranathan, Sruthi et al. (2015) Intravesical chitosan/interleukin-12 immunotherapy induces tumor-specific systemic immunity against murine bladder cancer. Cancer Immunol Immunother 64:689-96 |
| 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 |
| Kurtz, Samantha L; Ravindranathan, Sruthi; Zaharoff, David A (2014) Current status of autologous breast tumor cell-based vaccines. Expert Rev Vaccines 13:1439-45 |
