Low dose immune checkpoint blockade in metastatic cancer

Abstract

A method of treating cancer comprising and reducing autoimmune side effects in administration of anti-CTLA-4 antibodies. The invention provides methods for low dose immune checkpoint (IC) treatment of metastatic cancer by delivering anti-CTLA-4 and anti-PD-1 antibodies to cancer patients. Methods also provide for IL-2 stimulation for the activation of T cells against tumor cells. The invention further provides methods for daily cyclic high fever response (hyperthermia) during IL-2 therapy. The methods provide treatment of metastatic cancer without unacceptable autoimmune side effects.

1 . A method for reducing autoimmune side effects by administering an effective amount of anti-PD-1 antibody to a patient anticipating or experiencing anti-CTLA-4 autoimmune side effects or by administering an effective amount of anti-CTLA-4 antibody to a patient anticipating or experiencing anti-PD-1 autoimmune side effects. 
     
     
         2 . The method of  claim 1  for reducing autoimmune side effects in administration of anti-CTLA-4 antibodies by administering an effective amount of anti-PD-1 antibody to a patient anticipating or experiencing anti-CTLA-4 autoimmune side effects. 
     
     
         3 . The method of  claim 1  for reducing autoimmune side effects in administration of anti-PD-1 antibodies by administering an effective amount of anti-CTLA-4 antibody to a patient anticipating or experiencing anti-PD-1 autoimmune side effects. 
     
     
         4 . The method of  claim 1 , further comprising administering Taurolidine to the patient, wherein the patient is being treated with HD IL-2. 
     
     
         5 . The method of  claim 1 , wherein the patient is being treated with hyperthermia. 
     
     
         6 . The method of  claim 1 , comprising administering to the patient in need 0.5 mg/kg or lower dose of anti-PD-1 antibody with co-administration of 0.3 mg/kg or lower dose of anti-CTLA-4 antibody. 
     
     
         7 . The method of  claim 1 , comprising administering to the patient in need 300 mg/m 2  or lower dose of cyclophosphamide. 
     
     
         8 . A method for enhancing cancer immunity in a patient while reducing autoimmunity in said patient comprising administering anti-PD-1 antibody and anti-CTLA-4 antibody in effective amounts to a patient in need of treatment. 
     
     
         9 . The method of  claim 8 , further comprising administering Taurolidine to the patient, wherein the patient is being treated with HD IL-2. 
     
     
         10 . The method of  claim 8 , wherein the patient is being treated with hyperthermia. 
     
     
         11 . The method of  claim 8 , comprising administering to the patient in need 0.5 mg/kg or lower dose of anti-PD-1 antibody with co-administration of 0.3 mg/kg or lower dose of anti-CTLA-4 antibody. 
     
     
         12 . The method of  claim 8 , comprising administering to the patient in need 300 mg/m 2  or lower dose of cyclophosphamide. 
     
     
         13 . The method of  claim 8 , wherein the anti-PD-1 antibody and anti-CTLA-4 antibody are administered simultaneously. 
     
     
         14 . The method of  claim 8 , wherein the anti-PD-1 antibody and anti-CTLA-4 antibody are administered at different times. 
     
     
         15 . The method of  claim 8  comprising administering to a patient in need anti-PD-1 antibody and anti-CTLA-4 antibody in amounts effective to produce an anti-cancer effect, wherein the administration of anti-PD-1 antibody and anti-CTLA-4 antibody results in a lower level of autoimmunity as compared to administration of either anti-CTLA-4 or anti-PD-1 antibody alone. 
     
     
         16 . The method of  claim 15 , wherein the anti-cancer effect is an effect chosen from decreased tumor burden, decreased metastasis, decreased tumor growth, and reduction in new tumor formation. 
     
     
         17 . (canceled) 
     
     
         18 . (canceled) 
     
     
         19 . A composition for treating cancer comprising 0.5 mg/kg or lower dose of anti-PD-1 antibody and 0.3 mg/kg or lower of dose of anti-CTLA-4 antibody, and at least one pharmaceutically acceptable excipient. 
     
     
         20 . The composition of  claim 19  wherein the antibodies in the composition produce a lower level of autoimmunity as compared to a composition of either antibody alone.