Many pathogens and diseased cells undergo dynamic changes in vivo but standard-of-care drugs are only designed to target the state of disease present at the time of diagnosis. Additionally, no cure exists for many emerging diseases. Several host-defense peptides from non-human origin have been identified to exert therapeutic response towards the microenvironment created by such cell-based malignancies. However, the challenge is to effectively deliver these therapeutic peptides to the disease cells without undergoing immune degradation and without causing toxicity to the normal cells. This can be achieved by the T cells because they can actively traffic to the disease sites through multiple solid tissues and identify the target cells with molecular specificity. These T cells can therefore be engineered for a broad range of effector functions following their interaction with antigens on their target cells. The investigator's long-term goal is to develop new treatments by targeting underlying molecular principles in disease pathology. The objective of this project, toward the long- term goal, is to develop the T cell into a broadly applicable drug synthesis vehicle that will actively seek out the disease microenvironments and autonomously synthesize non-human therapeutic peptides directly at the disease site. To achieve this objective, the investigator will test his central hypothesis that antigen-specific transmembrane chimeric antigen receptors can be engineered to control the T-cell-activation transcriptional machinery for self-assembly of non-human therapeutic peptides upon stimulation by the target cells. The foundation of this project rests upon the investigator's capability to upregulate the T-cell activation cascade and finding the compounds that suppress this activation. The feasibility of this plan is further supported by the well- studied biology of T cells and host-defense peptides of non-human origin. The rationale for this project is that it will break the status quo in passive delivery of static drugs and replace it with the one that actively searches for the disease and autonomously synthesizes complex biologic drugs in situ. The project is significant due to its broad applicability against the diseases that evade the immune function or involve it malfunction. While the investigator proposes to use dengue as a disease model, T cells can also be engineered to target other cell- based malignancies through their surface molecular antigens. The innovation lies in engineering different components of multiple pathways in the T cell so that it autonomously triggers the self-assembly of therapeutics in situ only when stimulated by its target disease microenvironment.
This research is relevant to public health because it will open new horizons in the treatments for many diseases where human immune system fails e.g. emerging pathogens, autoimmune disorders, cancers, etc. The project will direct this technology against dengue that is exhibiting global spread and for which no cure exists. This effort is relevant to NIH's mission as this platform can be used for self-assembly of complex therapeutics at the disease site thereby circumventing their degradation and toxicity to healthy cells.
