Development of Physiologic Tissue Models to Assess Tumor Explant Response to Immune Checkpoint Blockade
Recent successes of cancer immunotherapy have identified a need for more sophisticated ex vivo diagnostic systems that mimic human tumor biology and predict the response to immune-based therapies in real-time. These systems must recognize that tumor formation and progression involves the co-evolution of cancer cells together with the extracellular matrix, vascular system, immune cells, and supportive cells (e.g. fibroblasts). Thus, a continuous interaction exists between tumor cells and non-tumor cell components through direct cell contact or by the secretion of signaling factors, which is poorly modeled by current systems.
We have developed a three-dimensional microfluidic device that contains tumor cell spheroids, which are embedded within an extracellular matrix incorporating endothelial cells, immune cells, growth factors and cytokines. This recapitulates many aspects of the tumor microenvironment, and promotes cancer cell proliferation and migration. We recently found that this system is capable of culturing primary human tumor spheroids from patient derived cancer specimens. Importantly, these spheroids not only contain tumor cells, but also bring with them their unique repertoire of infiltrating immune cells, enabling the capacity to study the phenotypes and function of these immune cell populations, cytokines, and other responses ex vivo.
Furthermore, we have demonstrated the ability of this system to measure the specific impact of anti-PD1 or anti-CTLA4 antibodies on immune cell activation, cytokine profiles, and tumor cell killing from patient derived melanoma and thyroid cancer specimens. While evaluation of responses to immunotherapies ex vivo has not been previously tractable, this 3D microfluidic model may be ideally suited for such investigation. Thus, the overarching hypothesis of this proposal is that physiologic modeling of the tumor microenvironment through microfluidic culture will enhance the ability to predict patient-derived tumor responsiveness to immune checkpoint blockade.
Our goals are:
- To refine and validate our existing microfluidic tumor culture model to assess response to immune checkpoint inhibitor therapies. Our goal is to extend our preliminary studies by analyzing ex vivo response to immune checkpoint blockade using short-term tumor spheroid culture, and to develop a longer-term culture model with a vascular network.
- to incorporate vascular flow of immune cells to monitor extravasation and expansion of immune effector cells in tumor culture. The purpose of these studies is to build a more physiologic system that accounts for immune cell trafficking into the tumor, and controls for the potential loss of immune cells that may occur with chronic tumor culture.
- To provide initial clinical validation of these assays, and develop strategies to overcome intrinsic anti-PD1 resistance. Since only a subset of cancer patients achieve a robust response to immune checkpoint blockade, these data have the potential to yield a powerful predictive tool that could impact clinical-decision making.
Dana-Farber Cancer Institute
Dr. David A. Barbie is an Assistant Professor of Medicine at Harvard Medical School and Thoracic Oncologist at the Dana-Farber Cancer Institute. He obtained an A.B. from Harvard College in 1997 and M.D. from Harvard Medical School in 2002. Following a post-doctoral fellowship in Dr. William Hahn’s lab at the Broad Institute, he received a tenure-track independent investigator position in 2010 at Dana-Farber, and a clinical position within the Lowe Center for Thoracic Oncology.
His research focuses on developing combination targeted therapies for KRAS-driven lung cancer, centering around modulation of innate immune signaling pathways. To study the impact on the more complex tumor microenvironment and the adaptive immune response, his laboratory has recently developed one of the first ex vivo systems to monitor the impact of immunotherapy combinations on murine or patient- derived tumor spheroids.
The Mechanobiology Lab
Dr. Roger Kamm is the Cecil and Ida Green Distinguished Professor of Biological and Mechanical Engineering in the MIT Departments of Biological Engineering and Mechanical Engineering. He has been a leader in bringing the fields of mechanics together with biology and chemistry; by exploring the ways in which single molecules transmit force through macromolecular networks and the resulting change in molecular binding or enzymatic activity; and by developing new cell culture methods that enable simultaneous study of multiple cell types communicating in a realistic microenvironment. Recognition for his contributions is reflected in Dr. Kamm’s election as Fellow to AIMBE, ASME, BMES, AAAS and the IFMBE. He is also the 2010 recipient of the ASME Lissner Medal and the 2015 recipient of the Huiskes Medal, both for lifetime achievements, and is a member of the National Academy of Medicine.
A primary objective of Dr. Kamm’s research has been the application of fundamentals in fluid and solid mechanics to better understand essential biological and physiological phenomena. Studies over the past 40 years have addressed issues in the respiratory, ocular and cardiovascular systems. More recently, his attention has focused on new areas such as the molecular mechanisms of cellular force sensation, cell population dynamics, and the development of new microfluidic platforms for the study of cell-cell and cell-matrix interactions, especially in the context of cancer.