LIGAND-DIRECTED DELIVERY OF ANTI-CANCER DRUGS

DESCRIPTION: (Applicant's Description) We have recently discovered a novel mechanism for the down-regulation of expression of a tumor-associated antigen. Such down-regulation, which we call "antigen silencing", exemplifies one route by which a tumor can escape immune destruction in the presence of tumor specific, cytotoxic T-cells. This Phase I project has as one of its goals the isolation and characterization of the tumor-secreted protein that induces "antigen-silencing." Isolation of this protein factor represents the first step toward our objective of developing therapeutics whose use will result in the maintenance of, or reversal of the loss of, antigens recognized by cytotoxic T lymphocytes. Such therapeutics would restore tumor susceptibility to immune-mediated destruction. Determination of the sequence of the factor, in addition to providing clues to its mechanism of action (and therefore a roadmap to future therapeutic approaches), will allow us to produce cDNA for it, and recombinant protein for antibody and other reagent development. Factor-specific antibodies will allow us to evaluate patient samples for the in vivo appearance of the factor, and to demonstrate that reversal of antigen down-regulation can be accomplished. Phase II will develop drug screens for compounds that up-regulate antigen expression. PROPOSED COMMERCIAL APPLICATION: We propose the development of a therapy which will prevent the escape of tumors from immune destruction. Although preliminary evidence has been limited to a single tumor type, future implementation on a variety of tumors could make the proposed strategy a part of general cancer therapy designed to enhance the host's ability to control tumor growth.