Methods and means for the treatment of hpv induced intraepithelial neoplasias

Abstract

The current invention provides improved methods and means for the treatment of virally induced intraepithelial neoplasias of the anogenital tract, such as HPV induced vulvar, cervical, vaginal, penile and anal intraepithelial neoplasias (VIN, CIN, VAIN, PIN and AIN). The invention provides a method of treatment of a subject suffering from an anogenital intraepithelial neoplasia comprising at least the steps of first determining whether the subject has a T-cell reactivity for viral early antigens, in particular high risk type HPV antigens; and subsequently a local treatment of the neoplasia with immune modulating compounds eliciting local inflammation if the subject scores positive for the T-cell reactivity, preferably a CD4+ response against HPV early antigens. The invention also comprises methods and means to induce or further stimulate a cellular immune response against HPV antigens, prior to or during treatment with the immune modulating compound capable of eliciting a local inflammatory response.

1 . A method for treating neoplasia induced by human papillomavirus (HPV) in a subject, comprising administering imiquimod, R848/resiquimod, loxoribine and/or bropirimine to a subject who scores positive for a CD4+ T cell response against a HPV viral antigen. 
     
     
         2 . The method according to  claim 1  wherein the HPV is selected from the group of HPV types consisting of HPV-16, HPV-18, HPV-31, HPV-33, HPV-35, HPV-39, HPV-45, HPV-51, HPV-52, HPV-56, HPV-58, HPV-59 and HPV-68. 
     
     
         3 . The method according to  claim 1 , wherein the HPV-induced neoplasia is in epithelial tissue. 
     
     
         4 . The method according to  claim 2 , wherein the HPV induced neoplasia is cervical intraepithelial neoplasia of any grade, vaginal intraepithelial neoplasia, anal intraepithelial neoplasia or penile intraepithelial neoplasia. 
     
     
         5 . The method according to  claim 1  wherein the HPV causes genital warts. 
     
     
         6 . A method for treating intraepithelial neoplasia of a subject's anogenital tract and/or area which neoplasia is caused by an infectious agent, comprising administering imiquimod, R848/resiquimod, loxoribine and/or bropirimine to a subject scoring positive for a CD4+ T cell response against an antigen of said neoplasia. 
     
     
         7 . The method according to  claim 6 , wherein the infectious agent is a virus, a bacterium, and/or a fungus. 
     
     
         8 . The method according to  claim 7 , wherein the bacterium is a mycobacterium. 
     
     
         9 . The method according to  claim 7 , wherein the virus is a herpesvirus, a human immunodeficiency virus (HIV) and/or a cytomegalovirus. 
     
     
         10 . The method according to  claim 9 , wherein the herpesvirus is herpes simplex virus-1 or herpes simplex virus-2. 
     
     
         11 . The method according to  claim 1 , further comprising administering to the subject an interferon, a cytokine or a chemokine that is directly involved in inflammatory pathways. 
     
     
         12 . The method according to  claim 1  wherein the detectable CD4+ T cell response against said HPV viral antigen is the result of prior or concurrent administration of said antigen to the subject. 
     
     
         13 . The method according to  claim 6  wherein the detectable CD4+ T cell response against said neoplasia antigen is the result of prior or concurrent administration of said antigen to the subject. 
     
     
         14 . The method according to  claim 12  wherein the HPV antigen was/is a peptide antigen of 12 to 45 amino acids in length which comprises an HPV early antigen from HPV E2, E6 or E7 protein. 
     
     
         15 . The method according to  claim 14 , wherein the peptide:
 comprises a T cell epitope; and   (ii) is capable of eliciting an interferon-γ response.   
     
     
         16 . The method according to  claim 15  wherein the peptide is one or more of:
 (a) a sequence corresponding to residues 1-22, 31-52, 41-62, 43-77, 51-72 or 77-98 of SEQ ID NO:1; 
 (b) a sequence corresponding to residues 31-75, 91-120, 151-195, 271-300, 286-315, 301-330, 316-345 or 331-365 of SEQ ID NO:2; or 
 (c) a sequence corresponding to residues 31-52, 81-102, 91-112, 111-132, 121-158 and 131-152 of SEQ ID NO:3. 
 
     
     
         17 . The method according to  claim 1  further comprising administering to the subject a CD40 receptor-activating and/or a 4-1-BB receptor-activating compound or agonist. 
     
     
         18 . The method according to  claim 6  further comprising administering to the subject a CD40 receptor-activating and/or a 4-1-BB receptor-activating compound or agonist. 
     
     
         19 . The method according to  claim 3 , wherein the imiquimod, R848/resiquimod, loxoribine and/or bropirimine is:
 (A) formulated in an ointment or a cream for topical administration, or   (B) applied in a transdermal patch, or   (C) injected in, around or nearby a lesion of the epithelial neoplasia.   
     
     
         20 . The method according to  claim 6 , wherein the imiquimod, R848/resiquimod, loxoribine and/or bropirimine is:
 (A) formulated in an ointment or a cream for topical administration, or   (B) applied in a transdermal patch, or   (C) injected in, around or nearby a lesion of the intraepithelial neoplasia.