Vaccination against oncoproteins of HPV16 for non-invasive vulvar/vaginal lesions: lesion clearance is related to the strength of the T-cell response
Mené sur 43 patientes présentant des néoplasies intraépithéliales vaginales ou vulvaires de haut grade liées au papillomavirus humain de type 16 (HPV16), cet essai multicentrique met en évidence une relation entre la disparition des lésions précancéreuses et le niveau de réponse des lymphocytes T dans le cadre d'une vaccination thérapeutique associant un vaccin à base de longs peptides synthétiques issus des protéines oncogènes E6 et E7 du HPV16 et l'imiquimod appliqué sur le site de l'injection
Purpose : Therapeutic vaccination with human papillomavirus type 16 (HPV16) E6 and E7 synthetic long peptides (SLP) is effective against HPV16-induced high-grade vulvar and vaginal intraepithelial neoplasia (VIN/VaIN). However, clinical non-responders displayed weak CD8+ T-cell reactivity. Here, we studied if imiquimod applied at the vaccine site could improve CD8+ T-cell reactivity, clinical efficacy and safety of HPV16-SLP (ISA101). Experimental Design : A multicentre open-label, randomised controlled trial was conducted in patients with HPV16+ high-grade VIN/VaIN. Patients received ISA101 vaccination with or without application of 5% imiquimod at the vaccine site. The primary objective was the induction of a directly ex-vivo detectable HPV16-specific CD8+ T-cell response. The secondary objectives were clinical responses (lesion size, histology and virology) and their relation with the strength of vaccination-induced immune responses. Results : Forty-three patients were assigned to either ISA101 with imiquimod (n=21) or ISA101 only (n=22). Imiquimod did not improve the outcomes of vaccination. However, vaccine-induced clinical responses were observed in 18 of 34 (53%; 95%CI 35.1-70.2) patients at 3 months and in 15 of 29 (52%; 95%CI 32.5-70.6) patients, 8 of whom displayed a complete histological response, at 12 months after the last vaccination. All patients displayed vaccine-induced T-cell responses, which were significantly stronger in patients with complete responses. Importantly, viral clearance occurred in all but one of the patients with complete histological clearance. Conclusion : This new study confirms that clinical efficacy of ISA101 vaccination is related to the strength of vaccine-induced HPV16-specific T-cell immunity, and is an effective therapy for HPV16-induced high-grade VIN/VaIN.