A Model-Based Index of Cognitive Fightability for Warrior Systems

The practical utility of anti-cancer immunization is limited by the poor immunogeneicity of tumor-associated antigens (TAAs) normally used for vaccination. This problem may be overcome by direct delivery of TAAs to dendritic cells (DCs), which play acentral role in the generation of the immune response, by using TAA-encoding adenovirus (Ad) vectors. The specificity and efficiency of this vaccination strategy may be improved by targeting the vectors to DCs via DC-specific markers. The goal of theproposed studies is to develop an Ad vector targeted by CD40-specific ligands to CD40 molecules expressed on the surface of DCs. These ligands, the natural CD40 ligand (CD40L) and an anti-CD40 single chain antibody, will be cross-linked to TAA-expressingAd virions by peptide zippers genetically incorporated in the structures of both the Ad vector and the ligand. The completion of the studies proposed in this application will result in the generation of an Ad vector encoding both the TAA and thezipper-tagged ligand, so that the entire targeting complex is designed to self-assemble during the propagation of the Ad vector. This vector design will result in a more efficient antigen presentation by DCs, thereby leading to significant improvements inanti-cancer immunization-based treatment strategies. The development of the improved technology for genetic immunization using dendritic cells proposed herein will have immediate practical implications for anti-cancer treatment. With the estimated marketfor immunotherapeutic drugs for cancer increasing considerably and being anticipated to reach $5 billion annually of the U.S. and more than $15 billion in the major worldwide markets within the next ten years, any significant improvement of pre-existinganti-cancer vaccination strategies will have an immediate impact on the various product development strategies. While this proposal is primarily focused on the development of a genetic immunization strategy for prostate cancer, which by itself is the mostfrequently diagnosed malignancy and the second leading cause of cancer death in American men, its utility expands well beyond this disease context. Specifically, the wide range of identified tumor-associated antigens (TAAs) and cancer type-specific targetmolecules rationalizes a broad spectrum of anti-cancer immunization approaches utilizing that approach described in this proposal as a prototype. The modification of this basic technology by employing new combinations of TAAs and cancer cell-specificsurface markers will allow for the rapid development of immunization strategies tailored to a specific cancer type, thereby making the approach proposed herein even more appealing from both the therapeutic and commercial standpoints. Furthermore, theproposed adenoviral vector-targeting strategy may find broad utility in vaccination against diseases other than cancer. For instance, the strategies presently used to treat AIDS and various forms of viral hepatitis may benefit from immunization approachesutilizing targeted adenoviral vectors. In the aggregate, the versatility of the basic technological paradigm to be developed in our studies ensures its commercial success.