Oral Microparticulate Prostate Cancer Vaccine: A Promising Immunotherapeutic Approach

Abstract

Prostate cancer is one of the leading causes of cancer-related deaths among men in the United States. Currently, there are 5 new agants approved in the United States against prostate cancer which include Sipuleucel-T, cabazitaxel, abiraterone acetate, enzalutamide and radium-223. Introduction of these agents into the clinic are important strides; however, resistance to chemotherapeutic agents is still a significant challenge, Furthermore, when patients suffer from recurrence of prostate cancer, survival is less than five months. Hence, there is an urgent need to investigate alternative approaches to treat castration resistant prostate cancer and prevent relapse. Immunotherapeutic approaches to treat cancer are under intense investigation owing to their specificity and potency to eliminate tumors. One of the most intensely studied areas in the cancer research is identification of cancer antigens that can help indicate progression of cancer, in certain scenarios these antigens may also serve as vaccines for cancer immunotherapy. These cancer antigens are important because they boost the immune system to specifically recognize and kill tumors. In our studies, we have investigated two different antigens to combat prostate cancer. Sperm protein-17 and tumor associated antigens extracted from TRAMP C2 murine prostate cancer cell line were investigated as potential therapeutic vaccines. The above mentioned antigens are proteins and protein antigens themselves have poor bioavailability and absorption thus making it difficult to initiate immune response against the cancer. Particulate delivery systems encapsulating protein antigens have been proved to improve the delivery and efficacy of vaccine responses. Thus, particulate delivery systems are crucial in improving the delivery of these potent cancer antigens for a sustained and systemic anti-cancer activity, Another important aspect of vaccine delivery is the route of vaccination owing to its patient compliance and ease of administration. However, several challenges such as harsh gastric environment and tolerance induction has hindered successful clinical effectiveness of oral vaccines. Adjuvants have always been administered along with vaccines for decades. FDA approved vaccines such as Gardasil and Cerverix both have adjuvants to boost immunity. Thus, identifying appropriate adjuvants that will help boost anti-tumor activity is paramount. In order to increase the potency of our vaccine, several toll-like receptor (TLR) and non-TLR adjuvants were also studied.

In this study, we have developed an oral microparticulate vaccine encapsulating two distinct antigens against prostate cancer. SP17 and antigens extracted from murine prostate cancer cell line were encapsulated separately in microparticles. Microparticulate vaccines were characterized for their physiochemical properties in vitro and evaluated for their antigenicity on murine dendritic cells. In order to protentiate vaccine efficacy, we also included adjuvants in microparticulate formulations and evaluated their potential to enhance the antigenicity of our vaccine formulations. SP17 administration. Several adjuvants such as R848, MPL, MF59 and alum were selected for future studies in vivo studies.

The second part of this project focuses on formulation of a microparticulate vaccine encapsulating tumor associated antigens extracted from a murine prostate cancer cell line (TRAMP C2). We investigated the potential of our formulated vaccine along with two adjuvant microparticles, ALUM and MF59, to boost anti-tumor response against prostate cancer. Finally, to prove the effectiveness of our vaccine and overcome the tumor "immune escape" mechanism in cancer, we also performed a therapeutic in vivo study on a murine prostate cancer model. Encouraging results from the in vivo study demonstrate excellent anti-tumor activity of our therapeutic vaccine. We observed a significant reduction in tumor volume and sustained anti-tumor T-cell activity in vivo. Thus, we could also demonstrate , in our experiments, the importance of combination therapy which inhibits cancer "immune escape" mechanisms and improves vaccine efficacy.