Hespecta Vaccination in HPV+ Tumors or Malignant Lesions

Human papillomavirus (HPV) has been found to be associated with several types of premalignant lesions and cancer. HPV16 is the far most common HPV type detected in these tumors and premalignant lesions. HPV16 encodes the two tumor-specific oncoproteins E6 and E7. In most humans the virus is cleared. However, in some individuals, infection results in an uncontrolled persistent HPV16 infection that due to expression of the viral oncoproteins E6 and E7 may lead to the formation of malignancies. Moreover, these oncoproteins maintain the malignant state of the transformed cells. The virus-specific interferon-γ (IFNγ)-producing cluster of differentiation 4 (CD4+) helper T cells (Th1 cells) and cluster of differentiation 8 (CD8+) cytotoxic T-lymphocytes (CTL) are able to recognize peptides processed from the highly immunogenic E6 and play a critical role in the elimination and/or control of the virus. Studies in patients with HPV associated tumors showed that the spontaneous HPV-specific T-cell responses, are weak and fail to sufficiently control tumor outgrowth. Preexisting specific T-cell responses against E6 and E7 in patients with HPV related tumors such are associated with better outcome after treatment. Since the HPV16-transformed tumor cells constitutively express the two HPV16 encoded E6 and E7 oncoproteins, these viral antigens are considered to be excellent targets for immunotherapeutic vaccine strategies aiming at reinforcing the tumor-specific T-cell response. Previous vaccination studies showed that the use of our first generation HPV16 synthetic long peptides vaccine (HPV16-SLP) was safe and highly immunogenic in patients with HPV-induced ano-genital lesions. Vaccination of patients with cervical cancer (CxCa) also resulted in the induction of HPV16-specific T-cell responses but the nature and strength of the induced T cell responses was not sufficient for the regression of these tumors. Specifically, it was concluded that the polarization of the T cell response to Th1 (IFNγ-response) was not optimal and a much stronger CD8+ T cell response was required for clinical efficacy. These results initiated the development of new HPV16 vaccination strategies that are able to polarize the induced Th1 response and obtain strong CD8+ T-cell cytotoxicity. One of these developments consists of conjugating two of the HPV16 E6 SLP to Amplivant® a synthetic Toll-like receptor (TLR) 2 ligand. These two peptides cover the most immunodominant regions of the overlapping HPV16-SLP set and contain both Th and CTL epitopes. Peptide conjugated Amplivant® has been selected because it is acknowledged for its capacity to strongly enhance antigen presentation by dendritic cells (DCs), enhance T-cell priming and cause superior induction of effective anti-tumor CTL responses in mouse tumor models, compared to a mixture of free TLR ligand and peptide. In preclinical murine studies, Amplivant®-conjugated SLP showed 10 to 100 times higher bioactivity compared to unconjugated SLP, in terms of induced immune responses. In addition, the quantity and quality of human T-cell responses, and especially the HPV16-specific CD8+ T-cell response, in cancer patients could be markedly enhanced by ex vivo stimulation with Amplivant®-conjugated SLPs.