HEAD AND NECK SQUAMOUS CELL CARCINOMA

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Strong evidence of an etiologic association between HPV and a distinct subset of head and neck squamous cell carcinomas, distinguished by the presence of high-risk HPV DNA in tumor cell nuclei, has recently been reported. These tumors are overwhelmingly HPV16 positive. Because viral oncoproteins E6 and E7 are consistently expressed in HPV-associated cancers and are tumor-specific antigens, patients with HPV-associated head and neck squamous cell carcinoma (HPV-HNSCC) may benefit from therapeutic strategies designed to augment the cellular immune response to HPV oncoproteins. In preclinical model systems, linkage of Mycobacterium tuberculosis heat shock protein 70 (HSP70) to the HPV16 E7 antigen was demonstrated to significantly enhanced the potency of a naked DNA vaccine. Vaccination of mice with E7/HSP70 DNA increased the frequency of HPV16 E7-specific CD8+ T cells by at least 30-fold compared to vaccination with wild-type E7 DNA and generated a significant antitumor effect against an E7-expressing tumor. This vaccine demonstrated significant potency against established E7-expressing murine tumors with down-regulation of Major Histocompatibility Complex (MHC) class I molecules, an important finding given a significant proportion of advanced stage HNSCC exhibit down-regulation of MHC class I molecules. Repeated DNA vaccinations elicited qualitatively different cytotoxic T lymphocytes (CTL) with higher avidity and improved protective anti-tumor effects. Furthermore, the addition of signal peptide to E7(detox)/HSP70 in the DNA vaccine significantly improved the efficacy of the intramuscular method of immunization. An E7 gene with mutations in the critical Rb binding residues (termed E7 detox) was generated which failed to bind Rb, had no transforming activity, and yet maintained potent immunogenicity. GMP grade Sig-E7(detox)/HSP70 in the pNGVL4a DNA backbone has been manufactured for clinical trials with support from the NIH Rapid Access to Intervention Development program. An open label, dose escalation trial to evaluate the safety, feasibility, and preliminary evidence of immunological activity of four intramuscular injections of the E7(detox)HSP70 DNA vaccine in patients with HPV16-HNSCC is proposed. Immunologic activity will be assessed by measurement of the E7 specific T cell-mediated immune response using ELISPOT, CTL, tetramer staining assays, and intracellular cytokine staining followed by flow cytometry analysis as well as the humoral immune response via measurement of HPV16 E7 antibody titers. The dose that is found to be safe, feasible, and to develop evidence of immunologic activity will be studied in a future phase II trial.