Nanomedicine Center for Mechanobiology Directing the Immune Response
Michael Dustin, Ph.D., New York University
Michael Milone, M.D., Ph.D., University of Pennsylvania
Carl June, M.D., University of Pennsylvania
The Nanomedicine Center for Mechanobiology Directing the Immune Response strives to generate useful cellular components for immunotherapy applications.
This center began with a strong team of basic scientists investigating the effects of biological forces on nanoscale assemblies in cells and surrounding tissue structures. The long-term goal of the center was to use their deep understanding of how cells respond to nanoscale forces to manipulate such forces for clinical use. The foundation of the center’s current translational effort is the discovery that substrate rigidity regulates human T cell activation and proliferation. The current translational studies build on principles that were discovered during early years of the NDC award using fibroblastoid, neural and immune cell systems. For example, the center developed an approximation of cell spreading in stromal cells which also applies to T cells, and findings in rigidity sensing and regulation of polarization in cultured fibroblasts are now being applied to T cells.
The NDC is developing culture systems to improve adoptive immunotherapy, which involves growing billions of memory and effector T cells under current good manufacturing practices (cGMP) conditions, and then infusing them into patients to augment and focus immunity. Collaboration with the immunotherapy group of Michael Milone at U. Penn and Carl June at the Abramson Cancer Center provides a clinical setting to test the utility of the culture systems developed by the NDC. Although the June group has already seen success in treating patients with chronic lymphocytic leukemia (CLL), there are some patients for whom adoptive immunotherapy does not work due to poor T cell expansion. The NDC’s work opens up the possibility of curing more patients, and improving treatment overall.
The center aims to establish conditions that can better control the types and number of T cells generated during the production phase to optimize benefit to the patient. The production of expanded populations of cells capable of further proliferation after transfer into the patient, and the development of memory cells correlate with the best in vivo results for tumor immunotherapy in animal models and patients. The investigators coat beads with activating antibodies, and then culture T cells on the surface of the beads. By growing T cells on soft surfaces, the investigators are able to manipulate cell signaling in such a way to cause increased activation and rapid expansion of cells in vitro, while maintaining the capacity of the cells to replicate further in vivo. Experiments testing new culture systems are now underway in both mouse and human.