T-Cell Defined Oral Carcinoma Antigens

University Of Pittsburgh At Pittsburgh, Pittsburgh PA

Investigators

Linked publications & trials

Abstract

DESCRIPTION: (provided by applicant) T-cell mediated Th1-type responses are known to play a key role in the host defense against cancer. Therapeutic vaccines for oral squamous cell carcinoma (OSCC) aim at inducing T-cell mediated specific anti-tumor immunity in patients with cancer. Studies indicate that the induction of T-cell immunity or stimulation of pre-existing immunity is likely to be optimal when immunogenic epitomes are presented to CD8+ or CD4+ T cells by MHC class I or class II molecules, respectively, expressed on dendritic cells (DC). These professional APC can be used in vitro or in vivo to present tumor-derived epitopes/antigens to T cells, thus inducing anti-tumor responses. The goal of this project is to evaluate the potential of the T cell-defined cytotoxic and helper epitopes, identified by the investigator?s OSCC antigen discovery program, as components of a therapeutic anti-tumor vaccine. To select the components of the vaccine that are most likely to generate a robust Th1-type anti-tumor response, the investigators will first determine immunogenicity of the epitopes in a series of ex vivo experiments. In specific aim 1, the investigators will finalize the identification of CTL and HTL epitopes that are recognized by tumor-reactive T cells they have generated. In aim 2 the investigators will determine whether the antigens identified in aim 1 are overexpressed on tumor cells and are present on normal tissues. Specific aim 3 will compare the ability of the T-cell epitopes, or the tumor protein from which they derive, to generate tumor-specific cytotoxic (CD8+) or helper (CD4+) T cells from peripheral blood mononuclear cells (PBMC) of normal donors or patients with OSCC. The frequency of epitope-specific precursor T cells in the circulation of these patients will be determined using tetramers and correlated with functional T cell responses. These responses generated by in vitro sensitization of the patient's PBMC with epitope-pulsed DC or DC processing the intact protein will be measured in ELISPOT for IFN-gamma and IL-5 or epitope-driven proliferation assays. The immunodominant vs. subdominant epitopes of the intact protein will be identified. The criteria for the selection of components of the vaccine will be based on capabilities of the epitopes or intact protein(s) to promote Th1-type responses ex vivo. A phase I clinical vaccination trial proposed for aim 4 will then be designed and implemented in the last year of the project, in which autologous DC pulsed with the selected epitopes or proteins will be transferred to patients with OSCC in the presence of adjuvant cytokine. Safety and immunogenicity will be the endpoints. Overall, in this translational project, a preclinical phase of establishing immunogenicity of T-cell defined epitopes in OSCC will be followed by a pilot/phase I clinical trial to determine the safety and potential of the vaccine to up-regulate auto-tumor responses in vivo.