414 VACCINATION WITH RAD5 CARRYING A FUSION CONSTRUCT OF PROSTATE-SPECIFIC ANTIGENS GENERATES EFFECTOR T CELLS

Abstract

INTRODUCTION AND OBJECTIVES: Immunotherapy has emerged as a promising approach in the development of novel therapies for prostate cancer. While most currently approved vaccines are targeted toward a single antigen, the heterogeneity of prostate cancer may create a limitation toward achieving a maximal effector response with this approach. Our goal is to expand the range of anti-tumor responses by creating a multi-antigenic T cell response utilizing a single immunization with a recombinant viral construct containing a fusion of two known prostate cancer antigens. METHODS: A fusion construct (PSPA) containing prostatespecific antigen (PSA) and prostate stem cell antigen (PSCA) was created and combined with a recombinant adenovirus type 5 (rAd5) vector and injected into mice. Following immunization, spleen cell suspensions were processed to analyze the production of IFNin the vaccinated mice compared to control. In vivo cytotoxic T cell assays and tumor growth challenge studies were compared in the vaccinated group compared to control mice. Student’s t-test was used to determine levels of significance among groups studied. RESULTS: Average immune responses of anti-PSA (p 0.037) and anti-PSCA (p 0.026) CD8 T cells following Ad5PSPA immunization were significantly higher as compared to controls. A reduced level of anti-PSA IFNwas noted in comparison to anti-PSCA following immunization (p 0.056). Immunized mice showed a strong cytotoxic response, being able to lyse 80% and 100% of PSA or PSCA coated target cells, respectively (p 0.034 and 0.005, respectively). Immunized mice demonstrated a significant inhibition of tumor outgrowth derived from PSA-expressing murine tumor cell lines with a total survival rate of 60%. CONCLUSIONS: Immunization of mice with rAd5 vector carrying a fusion construct of PSA and PSCA simultaneously induces the expansion of anti-PSA and anti-PSCA CD8 T cells. The developed antigen-specific T cell responses were efficient in eliminating target cells expressing cognate antigens, and strong anti-tumor immunity was elicited when challenged with prostate tumor cell lines. The effector response caused by the use of multiple antigens may have a synergistic effect to significantly reduce tumor burden and have important implications for human clinical trials targeted at prostate cancer.