Defining Microenvironmental Drivers of CAR T-Cell Exhaustion Using Human Spleen Organoids

Project Summary:

Cancer claims more than 11,000 lives annually in Wisconsin. Although CAR T-cell therapy has transformed outcomes for relapsed hematologic malignancies, access is limited to a few centers in Milwaukee and Madison. Nearly 1.5 million residents live in rural areas where travel distance and subspecialty scarcity create structural barriers to care. Relapse after CAR T therapy further worsens these inequities. Improving CAR T durability is therefore both a biological and health equity priority for Wisconsin. A major barrier to durable CAR T responses is T-cell exhaustion, driven not only by chronic antigen exposure but by suppressive immune cells within lymphoid and tumor microenvironments. Regulatory T-cells and myeloid-derived suppressor cells limit persistence through inhibitory cytokines, checkpoint signaling, and metabolic competition. Current in vitro models fail to capture this multicellular immune context, limiting rational engineering strategies. The project team developed a human spleen organoid platform from Wisconsin organ donor tissue that preserves native immune architecture. This project establishes a human immune-context platform for mechanistically guided CAR T engineering to improve durability and access for Wisconsin patients.