PT  - JOURNAL ARTICLE
AU  - Laura Arribillaga
AU  - Iciar Echeverria
AU  - Viriginia Belsue
AU  - Timothy Gomez
AU  - Teresa Lozano
AU  - Noelia Casares
AU  - Lorea Villanueva
AU  - Sonia Domingos-Pereira
AU  - Pedro J Romero
AU  - Denise Nardelli-Haefliger
AU  - Sandra Hervás-Stubbs
AU  - Pablo Sarobe
AU  - María Josefa Rodriguez
AU  - José L Carrascosa
AU  - Thomas Zürcher
AU  - Juan José Lasarte
TI  - Bivalent therapeutic vaccine against HPV16/18 genotypes consisting of a fusion protein between the extra domain A from human fibronectin and HPV16/18 E7 viral antigens
AID  - 10.1136/jitc-2020-000704
DP  - 2020 Jun 01
TA  - Journal for ImmunoTherapy of Cancer
PG  - e000704
VI  - 8
IP  - 1
4099  - http://jitc.bmj.com/content/8/1/e000704.short
4100  - http://jitc.bmj.com/content/8/1/e000704.full
SO  - J Immunother Cancer2020 Jun 01; 8
AB  - Background In vivo targeting of human papillomavirus (HPV) derived antigens to dendritic cells might constitute an efficient immunotherapeutic strategy against cervical cancer. In previous works, we have shown that the extra domain A from murine fibronectin (mEDA) can be used to target antigens to toll-like receptor 4 (TLR4) expressing dendritic cells and induce strong antigen-specific immune responses. In the present study, we have produced a bivalent therapeutic vaccine candidate consisting of the human EDA (hEDA) fused to E7 proteins from HPV16 and HPV18 (hEDA-HPVE7-16/18) and evaluate its potential as a therapeutic vaccine against cervical cancer.Materials and methods Recombinant fusion proteins containing HPV E7 proteins from HPV16 and HPV18 virus subtypes fused to hEDA were produced and tested in vitro on their capacity to bind TLR4 and induce the production of tumor necrosis factor-α or interleukin (IL)-12 by human monocytes and dendritic cells. The immunogenicity and potential therapeutic activity of the vaccine in combination with cisplatin or with the TLR3 agonist molecules polyinosinic‐polycytidylic acid (Poly IC) or Poly ICLC was evaluated in mice bearing subcutaneous or genital orthotopic HPV16 TC-1 tumors.Results hEDA-HPVE7-16/18 prototype vaccine binds human TLR4 and stimulate TLR4-dependent signaling pathways and IL-12 production by human monocyte-derived dendritic cell. Vaccination with hEDA-HPVE7-16/18 induced strong HPVE7-specific Cytotoxic T lymphocyte (CTL) responses and eliminated established tumors in the TC-1-based tumor model. The antitumor efficacy was significantly improved by combining the fusion protein with cisplatin or with the TLR-3 ligand Poly IC and especially with the stabilized analog Poly ICLC. Moreover, hEDA-HPVE7-16/18+Poly ICLC induced full tumor regression in 100% of mice bearing orthotopic genital HPV tumors.Conclusion Our results suggest that this therapeutic vaccine formulation may be an effective treatment for cervical tumors that do not respond to current therapies.