Human Papillomavirus-Directed Therapeutics for Human Papillomavirus-Associated Oropharyngeal Cancer

Abstract

Despite the availability of prophylactic human papillomavirus (HPV) vaccines, there is a growing incidence of HPV-associated head and neck squamous cell carcinomas (HPV-HNSCC) worldwide. The viral etiology of HPV-HNSCC provides an opportunity to develop personalized immune-based therapies, which target the unique viral- or tumor-specific proteins. Novel HPV-targeted immunotherapeutic approaches in clinical development are reviewed. Early results from these trials highlight new opportunities and potential challenges ahead. Immunotherapies for HPV-associated HNSCCs will require a tailored combinatorial approach based on preexisting mechanisms of host immune resistance. As the field continues to identify the relevant HPV types 16 and 18 immunogenic epitopes that are presented by diverse HLA class I alleles, improved HPV-targeted biologics and clinical monitoring tools can be developed and applied to a broader cancer patient population.

Figure 1:. Opportunities for Targeted Immunotherapy in HPV-associated Head and Neck Cancers.

Both viral and non-viral antigens are immunotherapeutic targets in HPV-associated head and neck cancers. HPV-infected epithelial cells express the viral associated proteins, E6, E7, E2 and E5, which support viral replication and cellular transformation. Antigen presenting cell populations, such as dendritic cells, in the tumor microenvironment (TME) (left) phagocytose apoptotic/necrotic HPV-infected cells and present HPV viral epitopes to CD4+ and CD8+ T cells that then get activated to recognize and kill HPV-infected cells (right, upper arrow). Viral-induced cellular transformation can result in genetic instability leading to cellular re-expression of cancer testis antigens (CTA) and increase the tumor mutational burden (TMB) leading to neoantigen (Neo) expression. These non-HPV antigens can also serve as immunotherapeutic targets. Based on the expression of multiple immunogenic antigens, both foreign and mutated, by the HPV-transformed cell, multiple tumor resistance mechanisms are activated in HPV-associated head and neck cancers (right, lower arrow), including the downregulation of antigen presenting and processing machinery (red X) and recruitment of immune suppressive immune cells, such as myeloid suppressor cells and FoxP3⁺ CD4⁺ (Tregs).