CAREER: Engineering Therapeutic Immune Responses with Artificial Antigen-Presenting Cells

Yale University, New Haven CT

Investigators

Abstract

0747577 Fahmy This CAREER project will develop a new class of artificial antigen presenting cell-like devices (aAPC) that enhance immune system responses against disease. Enhancing the capacity of the immune response to pathogens and even tumors is a major goal in immunotherapy. Because T lymphocytes play a central role in this enhancement, progress towards that goal is accomplished by stimulating the antigen-specific T cell immune response in vivo through antigen immunization, or by re-transfer of large numbers of T cells expanded outside the body in a process called adoptive immunotherapy. In both active and adoptive therapy, there is a critical need for a reliable and effective antigen-presentation strategy to stimulate sufficient numbers of T cells. While natural antigen-presenting cells are the most potent cells in the body for antigen-presentation, their utility for these applications are limited by their availability, quality of isolated cells, quantity and labor associated with their isolation. Yet much has been learned about their strategies for antigen-display to T cells and this new biological information should be instructive for designing new, rational technologies for artificial antigen-presentation. The PI's approach incorporates signals important for T cell stimulation in biocompatible polymer particulates. These systems integrate all the signals needed for efficient T cell stimulation. Devices as such offer ease and flexibility over targeting different types of T cells enabling their expansion for a variety of disease states. The proposed work will lead to improvements in the state of the art in the preparation of a new generation of therapeutic systems. By recapitulating the biological requirements needed to engineer an artificial antigen-presenting device, this project will facilitate a systematic dissection of the interactions of polymer particles with T cells and their effect in modulating immune responses. The proposed research program will explore new methods for creation of biomimetic degradable particles that impact immune system function. Much is known about immunity in health and disease, yet integration of this understanding with new materials technology has been lacking. The project will facilitate a key opportunity to synergize biology and engineering for the purpose of restoring immune competence in challenging diseases. The studies proposed will lead to a better understanding and better design of materials needed to address important challenges in biology. Unlike approaches relying on the use of engineered recombinant antibodies or drugs the strategies here should produce a stable, easy to fabricate product that might be useful as an off-the-shelf device for cancer immunotherapy. The project team will approach an important technological problem within the context of an educational and outreach program that seeks to train young scientists and engineers in a new area of interdisciplinary science that is of immediate societal relevance and public interest: engineering immunity. In addition, this science project, which addresses a problem of biomedical significance, provides an opportunity to attract the attention of young people as well as educators in the greater New Haven area through well-established and successful outreach and education programs.