The invention provides optimized methods and compositions for enhancing the immune response caused by immunostimulatory compounds used for the treatment of disease such as, but not limited to, treatment of cancer, autoimmune disorders, asthma, respiratory allergies, food allergies and infectious diseases in a patient. The optimized methods according to the invention provide synergy between the therapeutic effects of immunostimulatory oligonucleotides and immunomer compounds in accordance with the invention, and the therapeutic effect of cytokine immunotherapy and/or chemotherapeutic agents and/or radiation.