Full eradication of pre‐clinical human papilloma virus‐induced tumors by a lentiviral vaccine

Abstract

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.

Differential predictive value of resident memory CD8+T cell subpopulations in non-small-cell lung cancer patients treated by immunotherapy

“…In infectious and oncological models, other groups have also documented a correlation between the preferential ability of mucosal immunization to induce T RM expansion and protection against the development of cancers and viral infections (Jeyanathan, Fritz et al, 2022, Stewart, Counoupas et al, 2022, Sun, Peng et al, 2016). However, other studies based on vaccinations using systemically administered recombinant viral vectors have shown that T RM can be induced in the lungs (Douguet, Fert et al, 2023). This result may be explained by the use of viruses that enable vaccine dissemination in the pulmonary or head and neck compartments.…”

T-cell immunity induced and reshaped by an anti-HPV immuno-oncotherapeutic lentiviral vector

“…HPV16 and HPV18 have respectively a prevalence of 80% and 3% in oropharyngeal cancers 3 . We have recently developed an anti-HPV16/18 immunotherapy based on a non-integrative lentiviral vector 4 , 5 , known as “Lenti-HPV-07”, which encodes a polyprotein composed of the detoxified sequences of the Early (E)6 and E7 oncoproteins of HPV16 and HPV18 6 . One of the main advantages of the lentiviral vectors as a vaccine platform is their ability to transduce dendritic cells in vivo.…”

“…The protective efficacy of Lenti-HPV-07 results from the induction of robust CD8 + T cell-based immunity 6 . Lenti-HPV-07 treatment induces a profound remodeling of immune infiltrates and a conversion of the tumor microenvironment to a pro-inflammatory state, which is a highly favorable factor for the success of immuno-oncotherapy 10 .…”

“…We showed that the T cells induced by this vaccine have the required characteristics Programmed cell Death protein (PD)1 + and T cell factor-1 (TCF-1) + to be re-invigorated by anti-PD1 treatment. A synergistic anti-tumor effect of anti-PD1 treatment and Lenti-HPV-07 vaccination has been well established 6 . The strong efficacy of Lenti-HPV-07 treatment in the preclinical model led us to set up the preparation of a phase I/IIa clinical trial.…”

“…In the preclinical model, a single intramuscular (i.m.) injection of Lenti-HPV-07 is capable of completely eradicating solid tumors in 100% of individuals 6 . However, for clinical use, given the often-weakened immune system of cancer patients, more than one injection may be required to induce a sufficient anti-tumor immunity.…”