The principle that adoptively transferred T lymphocytes have therapeutic promise for a variety of infections and cancers is established. Recent data from our laboratory and others indicates that human T cell subsets have distinct growth requirements, yet there are no clinically scalable and FDA compliant culture systems for many of the various T cell subsets. For example, it would be desirable to have T cell culture systems that are dedicated to efficient generation of central memory T cells (TCM) or effector T cells (TEM) for cancer and HIV. Similarly, there are no dedicated T cell culture systems to grow regulatory T cells (TREG) to evaluate them as potential therapy for autoimmunity or to prevent organ allograft rejection. Here we assert that limitations in T cell culture technology serve as a barrier to the field of investigators that are developing T cell based immunotherapy strategies. Studies conducted in our laboratory have focused on developing strategies to develop T cell culture systems to mimic the functions of dendritic cells. Our approach has been to develop artificial antigen presenting cells (aAPC) to circumvent the time, expense and sub-optimal reproducibility of dendritic cell cultures. In this project, our overall strategy is to develop novel culture systems based on the concept of artificial antigen presenting cells (aAPC) that we have pioneered. The central hypothesis of this application is that aAPC can be created with efficiency equal to or better than dendritic cells for vaccines and to generate T cell subsets for immunotherapy. In the following three specific aims we will: (1) develop enhanced cell based aAPC by engineering second generation aAPC based on the K562 cell line. (2) test the hypothesis that novel aAPC culture systems will reveal distinct costimulatory and cytokine requirements for long term growth and effector function by human T cell subsets. The culture systems developed in Aim 1 will be used to determine the replicative lifespans of na?ve T cells, TCM, and TEM and (3) adapt cell-based aAPC for clinical use. In preparation for future clinical trials, and so that other laboratories may have access to the cell based aAPC reagents, we will carry out the scale up experiments required to render the cell based aAPC compliant with FDA regulations.
Showing the most recent 10 out of 29 publications
