The long-term goal of this study is the development of a gene therapy protocol for patients with head and neck squamous cell carcinoma (HNSCC). The proposal is based on the applicants' hypothesis that (a) all tumors are potentially immunogenic by virtue of a mutated gene product and/or excess synthesis of self protein(s); (b) various non-immunogenic or weakly immunogenic tumor phenotypes reflect different degrees of suppression of the immune cells; (c) the immune suppression is reversible by modulation of the microenvironment of the tumor; and (d) the tumor microenvironment can be modulated by in situ delivery of cytokines or co-stimulatory molecules. Antitumor immunity is likely to be invoked by up regulation of the antitumor activities of effector cells in situ. This proposal will explore our hypothesis by using a murine model of HNSCC (SCC VII/SF). The actual anatomical site and the initial locoregional aggressiveness of SCC VII, with early direct extension into the neck, later extension into the cervical lymph node and pulmonary metastasis resemble the biological behavior of tumor progression seen in HNSCC. Moreover, as seen in HNSCC patients, tumor-bearing mice show general immune suppression. SCC VII/SF, thus, provides an excellent model for evaluation of cancer vaccines in HNSCC patients.
In Specific Aim 1, they will construct recombinant vaccinia virus (rvv) expressing various cytokines and co-stimulatory molecules for use as tumor vaccines.
In Specific Aim 2, they will study the mechanism of immune suppression observed in this model and explore ways to reverse the suppression. The tumor will be implanted into the floor of the mouth and vaccinations will be performed by intratumoral injection (Specific Aim 3). A number of cytokines (GM-CSF, IL-2, IL-12) and co-stimulatory molecules (B7-1 and B7-2) will be delivered in situ by replication competent rvv as vector.
In Specific Aim 4, they will study the mechanism of the antitumor immunity. Based on their earlier studies with rvv and reports from a number of other laboratories, they predict the following: (1) Rvv will cause tumor regression by cell lysis and will release tumor specific and tumor associated antigenic proteins; (2) Antigen presenting cells in the tumor periphery will engulf the antigens, process and present them to effector cells; (3) The cytokines produced by the virus will induce the expansion of helper and cytolytic T cells as well as memory cells; (4) This cascade of events will result in the reversal of immune suppression and development of systemic antitumor immunity.
