Despite increased understanding of the molecular pathogenesis of cancer, the treatment of squamous cell carcinoma of the oral activity (OSCC) cancer remains a formidable problem. Studies of the immunobiology of OSCC have revealed profound suppression of local immune function in these tumors and trials of biologic agents including Interleukin-2 (IL-2) have shown limited benefit because of systemic toxicities. The impaired immune reactivity observed in patients with OSCC could be due to alterations in antigen presenting cells (APC) or their response to cytokines. IL-12 is a heterodimeric cytokine which plays a role in the induction of a TH1 response which is though to be critical for the immune response to tumors. IL-12 has been shown in pre clinical and clinical studies with tumors of several different histologies to have potent anti-tumor effects. Given the success we have had treating squamous cell carcinoma and other tumors in syngeneic murine models (and recently in a single patient with advanced squamous cell carcinoma of the head and neck) we plan to examine the efficiency of IL-12 gene therapy and recombinant human IL-12 in the treatment of squamous cell carcinoma in human subjects and to investigate the molecular and cellular mechanism of this cytokine's anti tumor activities. Since IL-12 is produced by dendritic cells, the most potent APCs, we plan to evaluate the effects of recombinant IL-12 AND IL-12 gene therapy on dendritic cells in OSCC tumors. To examine these issues, we envision three specific aims:
Aim 1. To determine clinical efficacy and the biologic effects on tumor derived dendritic cells in patients with advanced squamous cell carcinoma of the oral cavity treated with IL-12 gene therapy.
Aim 2. To conduct a Phase 1B study of IL-12 (to determine the optimal dose for inducing biologic/immunologic effects) as well as a Phase II study of IL-12 in patients with oral cavity carcinoma.
Aim 3. To determine he ability of peripheral blood dendritic cells isolated from patients with OSCC to elicit a primary and secondary immune response to autologous tumor in vitro and in vivo alone, and when transfected with the gene for IL-12.

Project Start
1997-09-01
Project End
2002-08-31
Budget Start
Budget End
Support Year
5
Fiscal Year
2001
Total Cost
$90,362
Indirect Cost
Name
University of Pittsburgh
Department
Type
DUNS #
053785812
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
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