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 beenproducing vaccines that induce strong immune responses against tumors. Unfortunately;most current vaccine types generate minimal immune responses and have little effectagainst established tumors. We have designed a novel vaccination approach that utilizes3 basic components: 1) synthetic peptides (protein fragments) derived from tumorantigens that stimulate T lymphocytes; 2) potent immunological adjuvants that activatethe immune system; and 3) immune stimulatory monoclonal antibodies that enhance theefficacy of T cells to react with tumor cells. Preliminary results in a mouse model ofmalignant melanoma using this vaccine; which we call TriVax (for its 3 basiccomponents) demonstrates that this strategy is effective in inducing tumor-reactive Tcells. Here we propose to carry out optimization studies of TriVax to demonstrate theclinical feasibility of this approach (specific aim 1). We will perform experiments tofurther optimize TriVax with the aim of developing an effective vaccine against advancedtumors (specific aim 2). Lastly; we will validate the use of the TriVax immunizationstrategy by studying the responses of several potential CD8 T cell epitopes to determinewhether the induction of high avidity CD8 T cell responses correlates with in vitro tumorrecognition; with in vivo therapeutic effects against established melanomas; and with theinduction of epitope spreading and autoimmunity (specific aim 3). The results from thesestudies will serve as preclinical data that will allow us to take this approach into the clinicto 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 #
7R01CA136828-06
Application #
8796766
Study Section
Transplantation, Tolerance, and Tumor Immunology (TTT)
Program Officer
Muszynski, Karen
Project Start
2009-06-01
Project End
2015-04-30
Budget Start
2014-02-12
Budget End
2015-04-30
Support Year
Fiscal Year
2014
Total Cost
$258,324
Indirect Cost
$86,108
Name
Georgia Regents University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
966668691
City
Augusta
State
GA
Country
United States
Zip Code
30912
Ramakrishnan, Rupal; Tyurin, Vladimir A; Tuyrin, Vladimir A et al. (2014) Oxidized lipids block antigen cross-presentation by dendritic cells in cancer. J Immunol 192:2920-31
Nagato, Toshihiro; Lee, Young-Ran; Harabuchi, Yasuaki et al. (2014) Combinatorial immunotherapy of polyinosinic-polycytidylic acid and blockade of programmed death-ligand 1 induce effective CD8 T-cell responses against established tumors. Clin Cancer Res 20:1223-34
Cho, Hyun-Il; Barrios, Kelly; Lee, Young-Ran et al. (2013) BiVax: a peptide/poly-IC subunit vaccine that mimics an acute infection elicits vast and effective anti-tumor CD8 T-cell responses. Cancer Immunol Immunother 62:787-99
Kumai, T; Matsuda, Y; Oikawa, K et al. (2013) EGFR inhibitors augment antitumour helper T-cell responses of HER family-specific immunotherapy. Br J Cancer 109:2155-66
Cho, Hyun-Il; Reyes-Vargas, Eduardo; Delgado, Julio C et al. (2012) A potent vaccination strategy that circumvents lymphodepletion for effective antitumor adoptive T-cell therapy. Cancer Res 72:1986-95
Barrios, Kelly; Celis, Esteban (2012) TriVax-HPV: an improved peptide-based therapeutic vaccination strategy against human papillomavirus-induced cancers. Cancer Immunol Immunother 61:1307-17
Cho, Hyun-Il; Lee, Young-Ran; Celis, Esteban (2011) Interferon ? limits the effectiveness of melanoma peptide vaccines. Blood 117:135-44
Hayashi, Satoshi; Kumai, Takumi; Matsuda, Yoshiya et al. (2011) Six-transmembrane epithelial antigen of the prostate and enhancer of zeste homolog 2 as immunotherapeutic targets for lung cancer. J Transl Med 9:191
Lu, Tangying; Ramakrishnan, Rupal; Altiok, Soner et al. (2011) Tumor-infiltrating myeloid cells induce tumor cell resistance to cytotoxic T cells in mice. J Clin Invest 121:4015-29
Cho, Hyun-Il; Celis, Esteban (2010) Overcoming doubts and other obstacles in the development of effective peptide-based therapeutic vaccines against cancer. Expert Rev Vaccines 9:343-5

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