Biochemical Engineering of Cancer Immunotherapeutics
Susan Thomas, Postdoctoral Researcher, École Polytechnique Fédérale de Lausanne
Friday, January 21, 2011
This seminar is part of the Jones Seminars on Science, Technology, and Society series
Cancer progression is tightly linked to the ability of malignant cells to exploit the immune system to promote survival. Herein I will present how insight into immune function can therefore be gained from understanding how tumors exploit immunity through the application of engineering fundamentals. Conversely, I will highlight how this interplay makes the concept of harnessing the immune system to combat cancer using biomaterial methodologies an intriguing approach. The transport of fluids, cancer cells and immune cells plays a pivotal role in regulating both metastasis and adaptive immunity. First, circulating tumor cells promote their extravasation from the vasculature by co-opting host immune cells. By enabling high kon and koff selectin-dependent interactions that are required for immune cell homing to sites of inflammation in the high shear environment of the vasculature, sialofucosylated O-linked glycans on colon carcinoma-expressed selectin ligands confer pro-metastatic function. The demonstration of selectin binding function possessed by carcinoma-expressed CD44v, carcinoembryonic antigen and podocalyxin-like protein brings a unifying perspective to the enhanced metastatic potential associated with tumor cell over-expression of these molecules and the critical role of selectins in metastasis. Next, lymphatic drainage is well appreciated to promote tumor metastasis and control the initiation of adaptive immune response. However, contrary to the prevailing hypothesis, peripheral lymphatic drainage of antigen presenting cells and soluble antigen to the lymph node is critical to B cell and tolerogenic T cell immunity, but not effector T cell function. These findings implicate the lymph node as a prime target for immunotherapies inducing neutralizing antibodies (e.g., anti-viral vaccines), immune tolerance (e.g., transplantation) or for reversing tumor-induced immune tolerance. Biomaterial strategies in immune modulation warrant development to meet clinical interest in cancer immunotherapeutics. Furthermore, there is a great clinical demand for adjuvants capable of initiating potent immune responses, especially in mounting an immune attack against tumors in the case of cancer vaccines, but that are not too potent as to cause systemic inflammation. Nanobiotechnology-based approaches using biomaterials can address these issues by providing improved delivery of immune modulators (adjuvants and antigen) to enhance or stem immune stimulation. First, design of polymeric vaccine nanoparticle surface chemistry can harness a biomaterials' inherent biological activity via complement activation and regulation to direct immunological responses in vivo. Next, given the critical role of lymphatic drainage to lymph nodes in tolerogenic T cell immunity, the tumor-draining lymph node is an attractive tissue target for therapies aimed at reversing tumor-induced tolerance. By encapsulating immune stimulatory chemotherapeutics in lymphatic-draining, polymeric nanoparticles, potent, local immune responses are achieved in vivo. Furthermore, treatment of tumor-draining lymph nodes with chemotherapeutic-encapsulating nanoparticles redirects immune response towards anti-tumor immunity and decreases tumor burden. These studies suggest that an approved-for-human-use chemotherapeutic may be reappropriated for use in a novel biomaterials-based immunomodulation scheme.
About the Speaker
Susan N. Thomas received her B.S. in Chemical Engineering from the University of California, Los Angeles in 2003, and her Ph.D. in Chemical and Biomolecular Engineering from The Johns Hopkins University in 2008 under the direction of Konstantinos Konstantopoulos studying the fluid mechanic and molecular underpinnings of cancer metastasis. She is currently a postdoctoral researcher and Whitaker Scholar at EPFL in the groups of Drs. Melody Swartz and Jeffrey Hubbell studying the role of lymphatic transport in immunity and developing biomaterial strategies for cancer immunotherapy.