Combination immunotherapy with synthetic long peptides and chemotherapy or PD-1 blocker for cancers caused by human papilloma virus type 16.

Therapeutic vaccination of premalignant conditions and of different stages of cancer can be accomplished with several platforms including DNA vaccines, RNA vaccines, synthetic long peptides (SLP), and recombinant viruses. We successfully used a therapeutic vaccine composed of SLP covering the complete sequence of the two oncogenic proteins E6 and E7 of human papillomavirus type 16 (HPV16) as monotherapy in patients with premalignant disease. However, combination treatment might be required in patients with (advanced) cancer because of the hostile cancer microenvironment for T cells in established HPV16+ cancer, often associated with systemic immunosuppression. In patients with late-stage recurrent or metastatic HPV16+ cancers, we have therefore combined treatment with the SLP vaccine, called ISA101b, with either standard-of-care chemotherapy or with immune checkpoint inhibition with anti-PD-1 monoclonal antibody. A strong vaccine-induced interferon gamma-producing T cell response to HPV16 E6/E7 was associated with significantly better survival. In a second phase 1/2 study, patients with recurrent or metastatic HPV16+ oropharyngeal cancer were treated with the combination of ISA101b and anti-PD-1 (nivolumab). In this trial, the clinical overall response rate (ORR) in 22 patients was 36%, twice the ORR in the nivolumab registration trial for this category of patients, and 2/22 patients had a complete clinical response that is ongoing after 4 1/2 years. Other promising strategies for late-stage cancer recipients are the infusion of expanded tumor-infiltrating lymphocytes or the infusion of T cell receptor transduced T cells, both directed against HPV16.