CXCR4/CXCR7 Blockade and Treatment of Human Papilloma Virus-Associated Disease

Abstract

The present invention relates to methods and compositions for treating human papilloma virus (HPV)-associated diseases using an inhibitor of CXCL12 signaling. The invention further relates to methods and compositions for treating immune checkpoint blockade resistant diseases using an inhibitor of CXCL12 signaling. The invention further relates to methods and compositions for enhancing the immune response against an HPV-associated disease using an inhibitor of CXCL12 signaling.

That which is claimed is: 
     
         1 . A method of treating a human papilloma virus (HPV)-associated disease in a subject in need thereof, comprising delivering to the subject a therapeutically effective amount of an inhibitor of CXCL12 signaling, thereby treating the HPV-associated disease. 
     
     
         2 . A method for enhancing an immune response against a human papilloma virus (HPV)-associated disease in a subject in need thereof, comprising delivering to the subject a therapeutically effective amount of an inhibitor of CXCL12 signaling, thereby enhancing the immune response against the HPV-associated disease. 
     
     
         3 . A method of treating an immune checkpoint blockade resistant disease in a subject in need thereof, comprising delivering to the subject a therapeutically effective amount of an inhibitor of CXCL12 signaling, thereby treating the immune checkpoint blockade resistant disease. 
     
     
         4 . The method of any one of  claims 1 - 3 , wherein the inhibitor of CXCL12 signaling is a CXCR4 antagonist. 
     
     
         5 . The method of  claim 4 , wherein the CXCR4 antagonist is AMD3100 (plerixafor). 
     
     
         6 . The method of any one of  claims 1 - 5 , wherein the HPV-associated disease is a HPV positive tumor and/or lesion. 
     
     
         7 . The method of  claim 6 , wherein the HPV positive tumor and/or lesion is cervical intraepithelial neoplasia 1, cervical intraepithelial neoplasia 2, cervical intraepithelial neoplasia 3, cervical cancer (in situ and/or invasive), head and neck cancer, HPV papillomatosis, anal papillomatosis, anal cancer, vaginal cancer, vulvar cancer, and/or penile cancer. 
     
     
         8 . The method of  claim 7 , wherein the head and neck cancer is squamous cell carcinoma. 
     
     
         9 . The method of  claim 7 , wherein the cervical cancer is adenocarcinoma of the cervix and/or squamous cell carcinoma of the cervix. 
     
     
         10 . The method of  claim 7 , wherein the HPV papillomatosis is recurrent respiratory papillomatosis (RRP) and/or laryngeal papillomatosis. 
     
     
         11 . The method of  claim 3 , wherein the immune checkpoint blockade resistant disease is a tumor or a lesion that is unresponsive to a programmed cell death-1 (PD-1) inhibitor, to a programmed cell death-ligand 1 (PD-L1) inhibitor, and/or to a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor. 
     
     
         12 . The method of any one of  claims 1 - 11 , further comprising delivering to the subject an additional therapeutic agent. 
     
     
         13 . The method of  claim 12 , wherein the additional therapeutic agent is an immunotherapeutic agent. 
     
     
         14 . The method of  claim 13 , wherein the immunotherapeutic agent is a vaccine for inducing an immune response against HPV in the subject. 
     
     
         15 . The method of  claim 13 , wherein the immunotherapeutic agent is an immune checkpoint inhibitor. 
     
     
         16 . The method of  claim 15 , wherein the immune checkpoint inhibitor is an inhibitor of PD-1 or PD-L1. 
     
     
         17 . The method of  claim 15  or  claim 16 , wherein, wherein the immune checkpoint inhibitor is an antibody that specifically binds PD-1 or PD-L1. 
     
     
         18 . The method of any one of  claims 15 - 17 , wherein the immune checkpoint inhibitor is nivolumab, pembrolizumab, ipilimumab, durvalumab, or atezolizumab. 
     
     
         19 . The method of any one of  claims 15 - 17 , wherein the immune checkpoint inhibitor is nivolumab. 
     
     
         20 . The method of  claim 13 , wherein the immunotherapeutic agent is a natural killer cell. 
     
     
         21 . The method of  claim 13 , wherein the immunotherapeutic agent is a T cell. 
     
     
         22 . The method of  claim 13 , wherein the immunotherapeutic agent is an antibody specific for the HPV-associated disease. 
     
     
         23 . The method  claim 12 , wherein the additional therapeutic agent is a chemotherapeutic agent. 
     
     
         24 . The method of  claim 12 , wherein the additional therapeutic agent is a radiotherapeutic agent. 
     
     
         25 . The method of any one of  claims 12 - 24 , wherein the inhibitor of CXCL12 signaling and additional therapeutic agent are delivered to the subject in the same composition. 
     
     
         26 . The method of any one of  claims 12 - 22 , wherein the inhibitor of CXCL12 signaling and the additional therapeutic agent are delivered to the subject in separate compositions. 
     
     
         27 . The method of any one of  claims 12 - 24 , wherein the inhibitor of CXCL12 signaling and the additional therapeutic agent are delivered to the subject sequentially. 
     
     
         28 . The method of  claim 27 , wherein the sequential delivery is repeated. 
     
     
         29 . The method of any of  claims 1 - 28 , wherein the HPV is an HPV type 6, 11, 16, 18, 26, 31, 33, 35, 39, 42, 44, 45, 51, 52, 53, 56, 58, 59, 66, 68, 73, and/or 82. 
     
     
         30 . A composition comprising an inhibitor of CXCL12 signaling and a vaccine for inducing an immune response against HPV in a subject. 
     
     
         31 . The composition of  claim 30 , further comprising an additional therapeutic agent. 
     
     
         32 . A kit of parts comprising a first container comprising an inhibitor of CXCL12 signaling and a second container comprising a vaccine for inducing an immune response against HPV in a subject. 
     
     
         33 . The kit of parts of  claim 32 , comprising a third container comprising an additional therapeutic agent. 
     
     
         34 . The composition or kit of parts of  claim 31  or  claim 33 , wherein the additional therapeutic agent is an immunotherapeutic agent, a chemotherapeutic agent, and/or a radiotherapeutic agent. 
     
     
         35 . The composition or kit of parts of any one of  claims 30 - 34 , wherein the HPV is an HPV type 6, 11, 16, 18, 26, 31, 33, 35, 39, 42, 44, 45, 51, 52, 53, 56, 58, 59, 66, 68, 73, and/or 82. 
     
     
         36 . The composition or kit of parts of any one of  claims 30 - 35 , wherein the inhibitor of CXCL12 signaling is a CXCR4 antagonist. 
     
     
         37 . The composition or kit of parts of  claim 36 , wherein the CXCR4 antagonist is AMD3100 (plerixafor). 
     
     
         38 . The composition or kit of parts of  claim 34 , wherein the immunotherapeutic agent is an immune checkpoint inhibitor. 
     
     
         39 . The composition or kit of parts of  claim 38 , wherein the immune checkpoint inhibitor is an inhibitor of PD-1 or PD-L1. 
     
     
         40 . The composition or kit of parts of any one of  claim 38  or  39 , wherein the immune checkpoint inhibitor is an antibody that specifically binds PD-1 or PD-L1. 
     
     
         41 . The composition or kit of parts of any one of  claims 38 - 40 , wherein the immune checkpoint inhibitor is nivolumab, pembrolizumab, ipilimumab, durvalumab, or atezolizumab. 
     
     
         42 . The composition or kit of parts of any one of  claims 38 - 40 , wherein the immune checkpoint inhibitor is nivolumab.