2011 Progress Report – Executive Summary
The Nanomedicine Center for Mechanobiology Directing the Immune Response strives to generate useful cellular components for immunotherapy applications. This effort builds on principles that were discovered in the preceding period using fibroblastoid, neural and immune cell systems. The addition of a clinical collaboration with the immunotherapy group of Michael Milone at U. Penn and Carl June at the Abramson Cancer Center (ACC) provided a clinical setting to test the utility of the culture systems developed in the NDC. The main tool used by the ACC group is adoptive immunotherapy- growing billions of memory and effector T cells under cGMP conditions that are infused into patients to augment and focus immunity. We have successfully shifted our focus from general mechanical biology to application of mechanobiology principles to the immune response. Every participating lab now has members fully focused on projects that are directly aligned with the immunotherapy goals.
The control of T cell characteristics is limited and the current focus of our center is to establish conditions that can better control the types of T cells generated during the production phase to optimize benefit to the patient. The production of expanded populations capable of further proliferation after transfer and the development of memory cells correlates with the best in vivo results for tumor immunotherapy in animal models and patients. We will use mechanics to tune signal transduction pathway to balance rapid expansion in vitro while maintaining the capacity to replicate further in vivo. We will use immunology and systems biology tools to evaluate these complex phenotypes using in vivo effector and memory T cells from effective immune responses as a template. The key initiating event in T cell activation and differentiation is the formation of an immunological synapse, which integrates adhesion and antigen recognition. The tissue environment defined by fibroblastic reticular cells that generate a network of ECM fibers provide a physical scaffold for immunological synapse formation and differentiation. Engineering systems that provide more physiological mechanical cues may restore the balance between replication and replicative reserve. In the past year we have made a number of advances in these areas: 1. We have demonstrated the presence of force sensing elements in the immunological synapse between T cells and engineered antigen presenting cells (1). 2. We have developed methods for multispecies gene expression network comparisons that will be scaled to allow us to combine information from mouse (Immgen) and human (NDC) datasets (2). 3. The center has generated two related technologies for directly patterning single molecules on the nanoscale to resolve the importance of global and local ligand densities (3, 4) . The center has also supported phase I clinical trials of patients with chronic lymphoid leukemia in preparation for the testing of a novel T cell culture sysyem developed by the NDC (5).
The strengths of our team are in integrating studies on the effects of biological forces on nanoscale assemblies in cells and the surrounding tissue structures including the extracellular matrix. In addition to the published progress, every member has had a key role in the past year and has made significant progress. The Milone, Kam, Hone, Wind, Geiger, Vogel and Wiggins groups are collaborating on effects of substrate rigidity. The Sheetz, Dustin Kam, Geiger and Vogel labs are defining the nanoscale molecular mechanisms that account for effects of substrate rigidity on T cell activation and differentiation. The Bonneau, Dustin and Milone groups are collaborating on gene expression studies to link ex vivo expansion to key characteristics of in vivo memory. The Dustin, Sheetz, Wind, Dunlop, Wiggins and Spatz groups are using single molecule imaging and patterning to explore fundamental requirements for T Cell Antigen Receptor and Chimeric Antigen Receptor ligands. The Hone, Wind, Vogel, Sheetz, Kam and Dunlop groups are currently testing a number of secondary candidates. The June group is preparing for the clinical trial by establishing control conditions and the technology needed to “bar code” the cellular products from the nano-engineered and standard of care culture systems. These activities will generate the data needed for key critical decision points regarding the lead and secondary candidates on our translational path.
The Nanomedicine Center for Mechanobiology Directing the Immune Response has refocused its multidisciplinary efforts on the problem of generating useful T cells for immunotherapy applications- including memory, effector and regulatory cells. The NDC funded effort has been effectively re-targeted in the last year to the immune cell focus with all groups performing T cell based experiments as of this progress report. The PIÕs have coordinated this effort with the assistance of the Scientific Program Manager. The bi-weekly video conference have been an extremely useful platform to discuss progress by each group on a monthly basis (Round-robin format), where trainees from all groups give a short presentation, alternating with a detailed presentation by one trainee, and have been helpful to exert a regular influence on the trainees in all centers - this has helped to control the activity in the center and keep the project groups on task. The increased fabrication of substrates is meeting the needs of the clinical collaborators such that in vivo experiments are now in progress both in the Dustin (mouse) and Milone (human) labs. This is a very exciting time in mechanical biology and immunotherapy and our NDC is positioned to bridge these rapidly moving areas to generate synergistic discoveries with therapeutic potential.
- Biggs MJ, Milone MC, Santos LC, Gondarenko A, Wind SJ. High-resolution imaging of the immunological synapse and T-cell receptor microclustering through microfabricated substrates. J R Soc Interface. 2011. doi: 10.1098/rsif.2011.0025. NIHMSID: 296061.
- Waltman P, Kacmarczyk T, Bate AR, Kearns DB, Reiss DJ, Eichenberger P, et al. Multi-species integrative biclustering. Genome Biol. 2010;11(9):R96. PMCID: 2965388.
- Schvartzman M, Palma M, Sable J, Abramson J, Hu X, Sheetz MP, et al. Nanolithographic control of the spatial organization of cellular adhesion receptors at the single-molecule level. Nano Lett. 2011;11(3):1306 -12. PMCID: 3061283.
- Deeg JA, Louban I, Aydin D, Selhuber-Unkel C, Kessler H, Spatz JP. Impact of local versus global lig and density on cellular adhesion. Nano Lett. 2011;11(4):1469-76.
- Kalos M, Levine BL, Porter DL, Katz S, Grupp SA, Bagg A, et al. T cells expressing chimeric receptors establish memory and potent antitumor effects in patients with advanced leukemia. Nat Med. 2011;submitted.
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