Dendritic cell targeting vaccines for HPV-associated malignancies and prostate cancer.

Abstract

Dendritic cells (DCs) are major antigen-presenting cells (APCs) that are able to capture, process and cross-present antigens to CD8+ T cells. CD8+ T cells play key roles in host immunity to cancers by efficiently killing tumor cells. DC-based immunotherapeutic strategies against cancers have thus been well rationalized. The first generation of DC vaccine, reinfusion of tumor-associated antigen (TAA)-loaded autologous in vitro generated DCs, is safe, but the clinical efficacy of this type of vaccine has been limited. In addition to cost, most importantly, in vitro generated DCs are not the same as the DCs in vivo. We have thus employed a DC-targeting vaccine strategy, in the form of recombinant fusion proteins composed of TAA and monoclonal antibody (mAb) specific to DC surface receptors. However, critical questions have remained for the rational design of DC targeting vaccines against cancers. First, we need to determine which targeted receptors can result in the greatest CD8+ T cell responses. Second, we have to demonstrate that prototype vaccines designed to target selected receptors meet the requirements to be tested in patients. In this study, we compared antigen-specific CD4+ and CD8+ T cell responses elicited by DCs targeted with mAb-antigen fusion proteins via 11 different DC surface receptors. We found that targeting antigens to DCs via CD40 primed and activated the greatest levels of antigen-specific naïve and memory CD8+ T cells, respectively. We then generated prototype DC-targeting vaccines for human papilloma virus (HPV)-associated cancer, αCD40-HPV16.E6/7, and for prostate cancer, αCD40-PSA (prostate-specific antigen). We demonstrated that αCD40-HPV16.E6/7 could activate HPV16.E6/7-specific CD4+ and CD8+ T cells from HPV16+ head-and-neck cancer patients. αCD40-HPV16.E6/7 was also immunogenic in human CD40 transgenic (hCD40Tg) mice and could thus prevent and suppress the growth of TC-1 tumor cells expressing HPV16.E6/7 protein. In addition, αCD40-PSA was also able to prime and activate PSA-specific T cells from prostate cancer patients. We demonstrated that αCD40-PSA could induce PSA-specific CD4+ and CD8+ T cell responses in hCD40Tg mice. Therefore, this dissertation offers a proof-of-concept that tumor antigen delivery to DCs through CD40 can be an effective immunotherapeutic strategy for cancer patients.