Methods for treating renal cell carcinoma

Abstract

Methods for treating renal cell carcinoma using low doses of IL-2 are disclosed. In particular, the invention relates to methods of treating metastatic renal cell carcinoma in patients who are renally impaired and/or intolerant of high dose IL-2 therapy. The therapeutic regimen described herein significantly inhibits tumor growth with reduced toxicity and adverse side effects compared to high dose IL-2 therapy.

1 . A method for treating a human patient having renal cell carcinoma, wherein the patient is renally impaired, the method comprising: 
 a) administering a dose of 1-52 MIU of IL-2 per day, in 1-3 doses a day, for 3-6 days a week, repeated for 1-24 weeks; and    b) administering no IL-2 for 1-4 weeks.    
     
     
         2 . A method for treating a human patient having renal cell carcinoma, wherein the patient is renally impaired, the method comprising: 
 a) administering a dose of 1-52 MIU of IL-2 every 5 days to 1 month, repeated for 1-24 weeks, wherein the IL-2 is covalently conjugated to polyethylene glycol or polyoxyethylated polyol; and    b) administering no IL-2 for 1-4 weeks.    
     
     
         3 . A method for treating a human patient having renal cell carcinoma, the method comprising: 
 a) administering a dose of 9-18 MIU of IL-2 per day, in 1-3 doses a day, for 3-6 days a week, repeated for 1-24 weeks;    b) administering no IL-2 for 1-4 weeks;    c) administering a dose of 9 MIU of IL-2 per day, in 1-3 doses a day, for 3-6 days a week, repeated for 1-24 weeks; and    d) administering no IL-2 for 1-4 weeks.    
     
     
         4 . The method of  claim 3 , wherein the method comprises: 
 a) first, administering a dose of 18 MIU of IL-2 per day for 5 days during one week;    b) second, administering a dose of 9 MIU of IL-2 per day for 2 days followed by administering a dose of 18 MIU of IL-2 per day for 3 days during each week, repeated for 5 weeks;    c) third, administering no IL-2 for 3 weeks;    d) fourth, administering a dose of 9 MIU of IL-2 per day for 5 days of each week, repeated for 6 weeks; and    e) fifth, administering no IL-2 for 3 weeks.    
     
     
         5 . The method of  claim 1 , wherein said IL-2 is recombinantly produced IL-2 comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of human IL-2.  
     
     
         6 . The method of  claim 2 , wherein said IL-2 is recombinantly produced IL-2 comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of human IL-2.  
     
     
         7 . The method of  claim 3 , wherein said IL-2 is recombinantly produced IL-2 comprising an amino acid sequence having at least 70% sequence identity to the amino acid sequence of human IL-2.  
     
     
         8 . The method of  claim 3 , wherein said IL-2 comprises an amino acid sequence having at least 80% sequence identity to the amino acid sequence of human IL-2.  
     
     
         9 . The method of  claim 3 , wherein said IL-2 comprises an amino acid sequence having at least 90% sequence identity to the amino acid sequence of human IL-2.  
     
     
         10 . The method of  claim 3 , wherein said IL-2 comprises an amino acid sequence having at least 95% sequence identity to the amino acid sequence of human IL-2.  
     
     
         11 . The method of  claim 1 , wherein said IL-2 is an IL-2 mutein.  
     
     
         12 . The method of  claim 2 , wherein said IL-2 is an IL-2 mutein.  
     
     
         13 . The method of  claim 3 , wherein said IL-2 is an IL-2 mutein.  
     
     
         14 . The method of  claim 11 , wherein said IL-2 is des-alanyl-1, serine-125 human interleukin-2 (aldesleukin).  
     
     
         15 . The method of  claim 12 , wherein said IL-2 is des-alanyl-1, serine-125 human interleukin-2 (aldesleukin).  
     
     
         16 . The method of  claim 13 , wherein said IL-2 is des-alanyl-1, serine-125 human interleukin-2 (aldesleukin).  
     
     
         17 . The method of  claim 11 , wherein said IL-2 is selected from the group consisting of Ala 104  Ser 125  IL-2; des-Ala 1  des-Pro 2  des-Thr 3  des-Ser 4  Ala 104  Ser 125  IL-2; and des-Ala 1  des-Pro 2  des-Thr 3  des-Ser 4  des-Ser 5  des-Ser 6  IL-2.  
     
     
         18 . The method of  claim 12 , wherein said IL-2 is selected from the group consisting of Ala 104  Ser 125  IL-2; des-Ala 1  des-Pro 2  des-Thr 3  des-Ser 4  Ala 104  Ser 125  IL-2; and des-Ala 1  des-Pro 2  des-Thr 3  des-Ser 4  des-Ser 5  des-Ser 6  IL-2.  
     
     
         19 . The method of  claim 13 , wherein said IL-2 is selected from the group consisting of Ala 104  Ser 125  IL-2; des-Ala 1  des-Pro 2  des-Thr 3  des-Ser 4  Ala 104  Ser 125  IL-2; and des-Ala 1  des-Pro 2  des-Thr 3  des-Ser 4  des-Ser 5  des-Ser 6  IL-2.  
     
     
         20 . The method of  claim 2 , wherein the IL-2 is conjugated to a polyethylene glycol.  
     
     
         21 . The method of  claim 20 , wherein the polyethylene glycol has an average molecular weight of 1,000 to 40,000 daltons.  
     
     
         22 . The method of  claim 20 , wherein the polyethylene glycol has an average molecular weight of 2,000 to 20,000 daltons.  
     
     
         23 . The method of  claim 20 , wherein the polyethylene glycol has an average molecular weight of 3,000 to 12,000 daltons.  
     
     
         24 . The method of  claim 2 , wherein the IL-2 is covalently conjugated to a polyoxyethylated polyol.  
     
     
         25 . The method of  claim 24 , wherein the polyoxyethylated polyol is a member selected from the group consisting of polyoxyethylated sorbitol, polyoxyethylated glucose and polyoxyethylated glycerol.  
     
     
         26 . The method of  claim 25 , wherein the polyoxyethylated polyol is polyoxyethylated glycerol.  
     
     
         27 . The method of  claim 26 , wherein the polyoxyethylated glycerol has an average molecular weight of 1,000 to 40,000.  
     
     
         28 . The method of  claim 1 , wherein said renal cell carcinoma is metastatic.  
     
     
         29 . The method of  claim 2 , wherein said renal cell carcinoma is metastatic.  
     
     
         30 . The method of  claim 3 , wherein said renal cell carcinoma is metastatic.  
     
     
         31 . The method of  claim 3 , wherein multiple cycles of the method of treatment are administered to said subject for a time period sufficient to effect at least a partial tumor response.  
     
     
         32 . The method of  claim 3 , further comprising multiple cycles of a treatment comprising: 
 a) administering a dose of 9 MIU of IL-2 per day, in 1-3 doses a day, for 3-6 days a week, repeated for 1-24 weeks; and    b) administering no IL-2 for 1-4 weeks;    administered to said subject for a time period sufficient to effect at least a partial tumor response.    
     
     
         33 . The method of  claim 31 , wherein the time period is at least 6 months.  
     
     
         34 . The method of  claim 32 , wherein the time period is at least 6 months.  
     
     
         35 . The method of  claim 31 , wherein the time period is at least 12 months.  
     
     
         36 . The method of  claim 32 , wherein the time period is at least 12 months.  
     
     
         37 . The method of  claim 31 , wherein a complete tumor response is effected.  
     
     
         38 . The method of  claim 32 , wherein a complete tumor response is effected.  
     
     
         39 . The method of  claim 1 , wherein said IL-2 is administered by subcutaneous, intraperitoneal, intramuscular, intravenous, oral, pulmonary, nasal, topical, or transdermal administration, or by infusion or suppositories.  
     
     
         40 . The method of  claim 2 , wherein said IL-2 is administered by subcutaneous, intraperitoneal, intramuscular, intravenous, oral, pulmonary, nasal, topical, or transdermal administration, or by infusion or suppositories.  
     
     
         41 . The method of  claim 3 , wherein said IL-2 is administered by subcutaneous, intraperitoneal, intramuscular, intravenous, oral, pulmonary, nasal, topical, or transdermal administration, or by infusion or suppositories.  
     
     
         42 . The method of  claim 41 , wherein said IL-2 is administered subcutaneously.  
     
     
         43 . The method of  claim 3 , wherein said patient is renally impaired.  
     
     
         44 . The method of  claim 3 , wherein said patient is intolerant of high dose IL-2 treatment.