HPV VACCINE THERAPY AND CORRELATES OF RESPONSE IN HEAD AND NECK SQUAMOUS CELL

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The association between the high-risk type-16 of the human papillomavirus (HPV-16) and a subset of head and neck squamous cell carcinomas (HNSCC) has recently been established. Given the causative role of HPV-16 in a subset of head and neck cancers, both prophylactic and therapeutic vaccines targeted to HPV- 16 are accepted as highly relevant for the prevention and treatment of HPV-HNSCC. The HPV viral oncoproteins, E6 and E7, are constitutively expressed in HPV-associated cancers; therefore, they represent ideal target tumor antigens for the development of antigen-specific vaccines. In preclinical studies, we have found that a DMA vaccine comprised of a model tumor antigen (HPV-16 E7) which is physically linked to the immunomodulatory protein calreticulin (CRT), results in potent E7-specific CD8+ T cell immune responses and anti-tumor effects against an E7-expressing tumor model in vaccinated mice. This vaccine has also been proved effective against E7-expressing murine tumors with down-regulated Major Histocompatibility Complex (MHC) class I molecules; an important finding, given a significant proportion of advanced stage HNSCC down-regulate MHC class I molecules as a means of immune evasion. In addition, we found that the combination of CRT/E7 DMAvaccination and a mild chemotherapeutic agent, Epigallocatechin-3-Gallate (EGCG), a compound found in green tea, acted synergistically to enhance tumor-specific T cell immune responses, as well as enhance anti-tumor effects, resulting in a higher cure rate than either DNA vaccination or EGCG alone. These findings have prompted us to investigate whether the combination of intradermal administration of CRT/E7 DNA vaccine via gene gun and oral EGCG administration is safe and able to generate E7-specific CD8+ T cell immune responses in patients with advanced HPV-associated head and neck cancers.