A major challenge for developing effective therapeutic vaccines against cancer is overcoming immunological tolerance to tumor-associated antigens. As the result of tolerance, high avidity CD8 T lymphocytes, which are the effectors capable of recognizing and killing tumor cells are not induced by conventional vaccines. We have designed a novel vaccination approach that utilizes synthetic peptides representing CD8 T cell epitopes, Toll-like receptor agonists that function as a potent immunological adjuvants and immune costimulatory monoclonal antibodies. Preliminary data in a mouse model of melanoma using this vaccine, which we call TriVax (for its 3 basic components) demonstrates that this strategy is effective in inducing tumor-reactive CD8 T cells with therapeutic effectiveness. Here we propose to carry out optimization studies of TriVax to demonstrate the clinical feasibility of this approach (specific aim 1). We will perform experiments to further optimize TriVax with the aim of developing an effective vaccine against advanced tumors (specific aim 2). Lastly, we will validate the use of the TriVax immunization strategy by studying the responses of several potential CD8 T cell epitopes to determine whether the induction of high avidity CD8 T cell responses correlates with in vitro tumor recognition, with in vivo therapeutic effects against established melanomas, and with the induction of epitope spreading and autoimmunity (specific aim 3). Our goal is that the preclinical data derived from these studies will generate sufficient enthusiasm to take this approach into the clinic.

Public Health Relevance

One of the major obstacles for developing effective vaccines for treating cancer has been producing vaccines that induce strong immune responses against tumors. Unfortunately, most current vaccine types generate minimal immune responses and have little effect against established tumors. We have designed a novel vaccination approach that utilizes 3 basic components: 1) synthetic peptides (protein fragments) derived from tumor antigens that stimulate T lymphocytes;2) potent immunological adjuvants that activate the immune system;and 3) immune stimulatory monoclonal antibodies that enhance the efficacy of T cells to react with tumor cells. Preliminary results in a mouse model of malignant melanoma using this vaccine, which we call TriVax (for its 3 basic components) demonstrates that this strategy is effective in inducing tumor-reactive T cells. Here we propose to carry out optimization studies of TriVax to demonstrate the clinical feasibility of this approach (specific aim 1). We will perform experiments to further optimize TriVax with the aim of developing an effective vaccine against advanced tumors (specific aim 2). Lastly, we will validate the use of the TriVax immunization strategy by studying the responses of several potential CD8 T cell epitopes to determine whether the induction of high avidity CD8 T cell responses correlates with in vitro tumor recognition, with in vivo therapeutic effects against established melanomas, and with the induction of epitope spreading and autoimmunity (specific aim 3). The results from these studies will serve as preclinical data that will allow us to take this approach into the clinic to treat human patients with melanoma and other types of cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA136828-04
Application #
8256543
Study Section
Transplantation, Tolerance, and Tumor Immunology (TTT)
Program Officer
Muszynski, Karen
Project Start
2009-06-01
Project End
2014-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
4
Fiscal Year
2012
Total Cost
$336,129
Indirect Cost
$134,854
Name
H. Lee Moffitt Cancer Center & Research Institute
Department
Type
DUNS #
139301956
City
Tampa
State
FL
Country
United States
Zip Code
33612
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