Introduction Bladder cancer is a significant healthcare problem. According to the National Cancer Institute, bladder cancer is the 6th most common type of cancer and represents 4.5% of total cancer patients in the U.S. Intravesical therapy with Bacillus Calmette-Guerin (BCG) vaccine is the gold standard for treating non-muscle invasive bladder cancer. However, BCG has several drawbacks. First, BCG is a tuberculosis vaccine, which often fails to trigger immune response against bladder cancer. This leads to low therapeutic efficacy and high recurrence rates. Secondly, intravesical injection is painful and causes urinary side effects, including burning sensation and increased frequency of urination. Therefore, a therapeutic regimen that can specifically treat bladder cancer and can be administered through other routes is highly needed. Immunotherapeutic strategy using nanoparticle can fulfill these needs. Polymeric nanoparticles encapsulating an immune adjuvant and co-injected with a tumor-associated antigen can trigger robust immune response against bladder cancer. Moreover, nanoparticles formulated using the FDA approved polymer poly (lactide-co-glycolide) (PLGA) is approved for human use and can be injected subcutaneously.
Methods Nanoparticles encapsulating a novel imidazoquinoline derivative that activates both Toll-Like Receptor (TLR) 7 and 8 was used as vaccine adjuvants. These novel nanoparticle-encapsulated TLR agonists were used in combination with a model antigen, ovalbumin, to create the vaccine. This is referred to as nanovaccine in this study. C57BL/6 mice were vaccinated subcutaneously with 1-5 doses of the nanovaccine or various control treatments. Two days after the final vaccination dose, mice were sacrificed and organs were harvested. Splenocytes and lymphocytes were analyzed using flow cytometry.
Results Nanovaccine improved dendritic cell activation in the lymph node. Frequency of co-stimulatory molecule CD80+ dendritic cells was two fold higher in the lymph node of vaccinated group. Greater activation of T cells and increased frequency of antigen-specific T cells were found in the spleen of vaccinated group. Antigen-specific CD44+ CD8 Tcell frequency was two fold higher in the vaccinated group. Nanovaccine elevated the frequency of both antigen-specific CD4 T cells and antigen-specific CD44+ CD4 T cells by ten fold.
Conclusion Nanovaccine generated antigen-specific immune response that can maximize the efficacy of immunotherapy. Moreover, nanoparticles were physically stable and remained active after subcutaneous injection, which can overcome the administration difficulties of current BCG therapy. Next step is to generate nanovaccine with bladder tumor-specific antigen or using whole cell lysate and test the therapeutic efficacy in tumor bearing mice. Generation of a bladder cancer-specific immune response will allow stronger and durable inhibition of tumor growth and diminished risk of progression.
Citation Format: Hyunjoon Kim, Lin Niu, Peter Larson, Katherine Murphy, Tamara Kucaba, David Ferguson, Thomas Griffith, Jayanth Panyam. Nanovaccine : A novel immunotherapeutic strategy to treat bladder cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2348.