Abstract
French Human papillomavirus (HPV) infections are the cause of all cervical and numerous oropharyngeal and anogenital cancers. The currently available HPV vaccines, which induce neutralizing antibodies, have no therapeutic effect on established tumors. Here, we developed an immuno-oncotherapy against HPV-induced tumors based on a non-integrative lentiviral vector encoding detoxified forms of the Early E6 and E7 oncoproteins of HPV16 and 18 genotypes, namely, "Lenti-HPV-07". A single intramuscular injection of Lenti-HPV-07 into mice bearing established HPV-induced tumors resulted in complete tumor eradication in 100% of the animals and was also effective against lung metastases. This effect correlated with CD8+ T-cell induction and profound remodeling of the tumor microenvironment. In the intra-tumoral infiltrates of vaccinated mice, the presence of large amounts of activated effector, resident memory, and transcription factor T cell factor-1 (TCF-1)+ "stem-like" CD8+ T cells was associated with full tumor eradication. The Lenti-HPV-07-induced immunity was long-lasting and prevented tumor growth after a late re-challenge, mimicking tumor relapse. Lenti-HPV-07 therapy synergizes with an anti-checkpoint inhibitory treatment and therefore shows promise as an immuno-oncotherapy against established HPV-mediated malignancies. A lentiviral vector‐based immuno‐oncotherapy, used in mice bearing Human PapillomaVirus (HPV)‐induced tumors, triggers a T‐cell immunity able to fully eradicate tumors in 100% of experimental animals. A single intramuscular injection of this vector deeply remodels the tumor microenvironment and favors the actions of anti‐tumor immune effectors.The available prophylactic HPV vaccines mainly induce neutralizing antibodies which prevent viral infection but have no therapeutic effect on HPV‐induced tumors.A lentiviral vector‐based immuno‐oncotherapy (Lenti‐HPV‐07) encodes antigens from HPV16 and HPV18 genotypes.A single administration of Lenti‐HPV‐07 is enough to eradicate small or large HPV‐induced tumors in 100% of animals in a preclinical model.Lenti‐HPV‐07 treatment induces a long‐term protective immunity which avoids tumor relapse.Lenti‐HPV‐07 immuno‐oncotherapy can be combined to other immunotherapies to potentiate their actions.