Prostate SPORE Project 5

An Immune-Based Therapeutic Approach for Prostate Cancer

Principal Investigator: Esteban Celis, M.D., Ph.D., H. Lee Moffitt Cancer Center

The primary objective of this application is to translate into the clinic the preclinical scientific achievements derived from the previous funding period. We will utilize CTL and Th cell peptide epitopes identified from prostate-associated antigens, together with a novel topical vaccination technique, to carry out a clinical study in prostate cancer patients. For these studies we have selected two CTL epitopes and two Th cell epitopes derived from the prostate-associated antigens, PSMA and TARP, which will be administered in the form of a topical vaccine. The secondary objective of this proposal will be to further optimize peptide topical vaccines by developing a vaccination strategy that takes into account the immune suppressive environment of the tumor site, which limits the effectiveness of many cancer vaccines. To accomplish these objectives, we propose the following specific aims:

1. To evaluate the safety and immunogenic effects of a topical formulation of a PSMA/TARP peptide vaccine in prostate cancer patients. We will conduct a clinical study in 30 patients who will receive a topical vaccine consisting of synthetic peptides corresponding to CTL and Th epitopes administered with Aldara™ cream, which will serve as an immunological adjuvant. Two categories of patients will be accrued and stratified into the protocol:
   • Progressive asymptomatic prostate cancer before initial androgen deprivation therapy
   • Progressive asymptomatic prostate cancer soon after initial androgen deprivation therapy
   Patients will be repetitively vaccinated and immune responses to the peptides will be measured using peripheral blood lymphocytes obtained prior to each vaccination. Anti-tumor effects of vaccination will be evaluated by assessing plasma PSA levels. Simultaneously, we will monitor the expression levels of the T-cell receptor associated CD3zeta (CD3Z) chain also known as CD247 in blood T lymphocytes, as a parameter related to immune suppressive activity commonly found in cancer patients. An additional parameter associated with immune suppressor activity that will be measured is the level of arginase activity found in peripheral blood mononuclear cells. The main hypothesis for this aim is that the topical vaccine will not only be safe but will be able to induce CTL and Th responses to the immunizing peptides. The secondary hypothesis for this aim is that immune non-responsiveness (or low responsiveness) will most likely occur in those patients exhibiting signs of immunosuppressive activity. We believe that the proposed strategy is unique due to:
   • The use of a topical vaccine formulation using a TLR-ligand (imiquimod) as an adjuvant
   • The generation of both Th cell and CTL responses to antigens expressed by the tumor cells (i.e., an integrated immune response)
   • A multi-antigen strategy that may help prevent antigen-loss variants; and
   • Immunization in the presence of androgen ablation that may to improve the overall immunity. These consider that these attributes make our approach unique, novel and worth pursuing.
2. To develop a therapeutic strategy to help overcome immune suppressing activities that limit the effectiveness of vaccination against tumors. Since it is well known that established tumors create an immunosuppressive environment that affects the anti-tumor function of T lymphocytes, it is important to study therapeutic approaches that may help overcome this barrier. Myeloid suppressor cells (MSC) constitute one of the most important factors inhibiting effector T cells in the tumor setting. Thus, we will develop an animal tumor model to design a strategy to block the activities of MSC that render the immune system inoperative against the tumor. Using this animal model will also develop a method to block the inhibitory activity of T regulatory (Treg) lymphocytes. This will allow the induction of more effective anti-tumor immune responses to topical peptide vaccination. The results from this aim should facilitate the development of improved vaccination strategies for patients whose immune systems are hampered by these immune suppressor activities.