PROVIDED.Self antigens are recognized on cancers by the immune system of patients with cancer. Immune responsesto self antigens can lead to rejection of cancer in laboratory models. Immunization against these antigenspresents problems, however, because these are weak antigens. This proposal addresses limitations of thepresent molecularly defined cancer vaccines targeting self-antigens: 1) insufficient potency, 2) specificity foronly individual epitopes or determinants, and 3) a need to modulate the immune system to favor response tovaccination. Using prototypical differentiation antigens of the tyrosinase family for models, creation ofmultiple heteroclitic epitopes and manipulation of protein stability and trafficking will be studied to increasepotency of active immunization against cancer self-antigens. In the first Aim, DNA vaccines are designed tointroduce multiple heteroclitic epitopes and to enhance antigen processing and presentation, followed bytesting in laboratory treatment models for induction of antibody and T-cell responses and for antitumoractivity.
The second Aim i nvestigates strategies to increase immune responses to vaccination throughmodulation of homeostatic immune cell recovery. Another strategy is explored to immunological target bothcancer self-antigens and tumor stroma through active immunization or combination of active and passiveimmunization.
The third Aim i nvestigates immune modulation in combination with DNA vaccination in aclinical study. Finally, the last Aim explores DNA vaccination against cancer self-antigens in combinationwith vaccination against tumor stroma in a clinical study.
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