Human papillomavirus (HPV) is one of the most common sexually transmitted infections. Although the usual manifestation of HPV infection in normal individuals is subclinical, HPV is an important HIV-related malignancy that causes cancer. Recently, an FDA-approved HPV prophylactic vaccine has shown significant clinical efficacy in prevention of HPV infection, but it exhibits no efficacy in treatment of infected patients. Thus, the development of safe and effective immunotherapeutic vaccines against HPV-associated cancers, particularly in the setting of HIV-infected patients, is necessary. A major immune arm of immunotherapeutic vaccines is cellular immunity. Studies have shown that the HPV oncoproteins, E6 and E7, are constitutively expressed in HPV-infected cells and tumor cells. Thus, several types of vaccine models carrying peptides derived from E6/7 proteins have been tested, but these vaccines have drawbacks either in efficacy or safety in immunodeficient patients. This gap necessitates developing safe and potent immunotherapeutic vaccines against HPV-associated cancer. To develop novel and potent immunotherapeutic vaccines against broad ranges of cancer and infections, BIIR has established a platform technology for targeting antigens directly to human DC subsets via anti-DC receptor antibody vehicles. Mouse model, human in vitro, and NHP in vivo studies show that vaccines based on DC-targeting elicit potent and broad immune responses at low antigen doses. Based upon the recent progresses made in DC biology, we intend to develop vaccines that target Langerhans cells (LCs). LCs and interstitial DCs (intDCs) in human skin differ in their capacity to activate lymphocytes. IntDCs induce the differentiation of naove B cells into immunoglobulin-secreting plasma cells. In contrast, LCs are particularly efficient inducers/activators of cytotoxic CD8+ T lymphocytes (CTLs), the major immune arm against cancer. Thus, vaccines that target LCs will elicit potent cellular immunity against HPV-associated cancer. Fundamental to the induction of immunity is concomitant antigen-uptake and activation by DCs. Thus, to maximize the potency of vaccines, we also propose to test vaccine adjuvants. In a close collaboration with scientists at the University of Texas M. D. Anderson Cancer Center, we will test our immunotherapeutic approach in a non-human primate (NHP) model. This study fulfills the premises of the GO grant by developing safe and potent immunotherapeutic vaccines against HIV-related malignancies (NIAID RFA-OD-09-0004). This grant will allow us to preserve two research assistants and create employment for one technician.
The final outcome of this study will be the development of effective and safe immunotherapeutic vaccines that can bring significant clinical benefit to patients who have HPV-associated cancer. The results of this study will also have immediate implications for the rational design and development of vaccines against other cancers and infections. Importantly, this work will allow preservation and creation of jobs.
|Duluc, Dorothee; Gannevat, Julien; Joo, Hyemee et al. (2013) Dendritic cells and vaccine design for sexually-transmitted diseases. Microb Pathog 58:35-44|