Combinational therapies for treatment of cancer comprising a bacteriochlorophyll derivative

Abstract

An anti-myeloid-derived suppressor cells agent (“anti-MDSCs agent”) and a bacteriochlorophyll derivative (hereinafter”Bchl-D) for use in combination therapy for cancer. wherein the anti-MDSC agent and the Bchl-D are administered sequentially and the administration of the Bchl-D is followed by photodynamic therapy (PDT) or vascular targeted PDT (VTP).

1 . A method for treatment of a primary cancer solid tumor or a metastasis thereof by combination therapy, comprising administering sequentially to a patient in need thereof: (i) an anti-myeloid-derived suppressor cells (MDSCs) agent (hereinafter “anti-MDSCs agent treatment”); and (ii) a therapeutically effective amount of an anionic bacteriochlorophyll derivative (Bchl-D), optionally conjugated to an RGD-containing peptide or RGD-peptidomimetic residue, followed by photodynamic therapy (PDT) (hereinafter “PDT treatment”),
 wherein 
 said anti-MDSCs agent treatment is carried out according to a metronomic chemotherapy regimen comprising from 4 to 10 administrations of the anti-MDSCs agent at determined time intervals of 5 to 12 days, wherein an interval between two such determined intervals may be longer than each determined interval, and reduces the MDSCs load; 
 said PDT treatment comprises a sole administration of the Bchl-D followed by illumination of the localized solid tumor to be treated; and 
 said anti-MDSCs agent treatment and said PDT treatment are synchronized such that the outcome of said PDT treatment and the increase in the anti-tumor immunity caused thereby, in combination with the reduction in the MDSCs load caused by said anti-MDSCs agent treatment, lead to ablation of said solid tumor and elimination of micrometastases thereof. 
 
     
     
         2 . The method of  claim 1 , wherein the anionic Bchl-D optionally conjugated with an RGD-containing peptide or R6D-peptidomimetic residue has the formula 
       
         
           
           
               
               
           
         
         wherein 
         M represents 2H or Pd; 
         R 1  is O—R 4  or —NHR 5 , wherein R 4  is H, H +  an ammonium group or a monovalent metal cation selected from Na +  and K + , and R 5  is an RGD-containing peptide or RGD peptidomimetic residue; 
         R 2  is —O—C 1 —C 6  alkyl; 
         R 3  is —NH—(CH 2 ) n —SO 3   − R 6   + , wherein n is 2 or 3, and R 6+  is a monovalent metal cation selected from Na +  and K + ; and 
         pharmaceutically acceptable salts and optical isomers thereof. 
       
     
     
         3 . The method of  claim 2 , wherein the anionic Bchl-D of formula I is not conjugated to an RGD-containing peptide or RGD peptidomimetic residue. 
     
     
         4 . The method of  claim 3 , wherein M represents Pd. 
     
     
         5 . The method of  claim 4 , wherein said anionic. Bchl-D is palladium 3 1 -oxo-15-methoxycarbonylmethyl-rhodobacteriochlorin 13 1 -(2-sulfoethyl)amide, or a salt of palladium 3 1 -oxo-15-methoxycarbonylmethyl-rhodobacteriochlorin 13 1 -(2-sulfoethyl)amide with ammonium or a monovalent alkaline metal selected from the group consisting of potassium and sodium. 
     
     
         6 . The method of  claim 5 , wherein said anionic Bchl-D is palladium 3 1 -oxo-15-methoxycarbonylmethyl-rhodobacteriochlorin 13 1 -(2-sulfoethyl)amide dipotassium salt, herein designated. WST11. 
     
     
         7 . The method of  claim 3 , wherein the anionic Bchl-D of formula I is selected from the Bchl-Ds herein designated WST11 and STL-7012. 
     
     
         8 . The method of  claim 7 , wherein the PDT is vascular-targeted PDT (VTP) and the area to be treated is illuminated 0-30 min. after the administration of the non-conjugated Bchl-D is completed. 
     
     
         9 . The method of  claim 2 , wherein the anionic Bchl-D of formula I is conjugated to an RGD-containing peptide or RGD peptidomimetic residue. 
     
     
         10 . The method of  claim 9 , wherein the anionic Bchl-D of formula I is selected from the Bchl-Ds herein designated STL-6014, STL-6033. STL-6038, and STL-6068. 
     
     
         11 . The method of  claim 10 , wherein the PDT is tissue-targeted and the localized solid tumor for treatment is illuminated at least 4 h after the conjugated Bchl-D is administered. 
     
     
         12 . The method of  claim 11 , wherein the localized solid tumor for treatment is illuminated 6 h after the conjugated Bchl-D is administered. 
     
     
         13 . The method of claim I, wherein the PDT is VTP that is performed with the Bchl-D WST11. 
     
     
         14 . The method of  claim 13 , wherein the area to be treated is illuminated 0-30 min after the administration of the non-conjugated Bchl-D is completed. 
     
     
         15 . The method of  claim 1 , wherein the PDT is performed with the Bchl-D STL-6014. 
     
     
         16 . The method of  claim 15 , wherein the localized solid tumor for treatment is illuminated at least 4 h after the conjugated Bchl-D is administered. 
     
     
         17 . The method of  claim 1 , wherein the PDT treatment comprises a sole administration of the Bchl-D followed by illumination of the localized solid tumor to be treated. 
     
     
         18 . The method of  claim 1 , wherein the anti-MDSC agent is administered in a dose 3 or 4 times lower than the conventional dose of the agent in conventional monochemotherapy. 
     
     
         19 . The method of  claim 1 , wherein the anti-MDSCs agent is selected from the group consisting of 5-fluorouracyl (5-FU), cisplatin, paclitaxel, cyclophosphamide, sunitinib, a cyclooxygenase 2 (COX-2) inhibitor such as SC-58236 and SC-58125, a bisphosphonate such as zoledronic acid or an aminobisphosphonate such as alendronate, all-trans retinoic acid (ATRA), vitamin D3, vitamin A, a KIT-specific antibody, a nitroaspirin derivative, a synthetic triterpenoid derivative such as bardoxolone methyl (known as CDDO-Me), and a phosphodiesterase-5 (PDE-5) inhibitor such as sildenafil and taladafil. 
     
     
         20 . The method of  claim 9 , wherein the anti-MDSCs agent is cyclophosphamide.