In early April 2019, the Institute for Systems Biology (ISB, Settle WA) hosted its 18th annual symposium. This year's theme focused on translational biology, which is the practice of commercializing research discovery. Over the two-day symposium, the audience was informed about the latest in the research and development of new products for fighting cancer with immunotherapy and combating research to improve global health.
Meeting Highlights - Immunotherapy
One of ISB's strong values is communicating science to public. This meeting was no exception; much of it was recorded and the video's are posted on the ISB YouTube channel.
The first day focused on immunotherapy. Digital World Biology has a keen interest in immunotherapy because it is a major area of employment that needs many technicians and is a driver for our collaboration with Shoreline Community College in developing an immuno-bioinformatics course. To learn more about companies working in immunology and immunotherapy check out the listing of immunology companies on Biotech-Careers.org
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Dr. Phil Greenberg (head of immunology at the Fred Hutch) kicked off the first session. Much of his talk focused on the reasons why T cell therapies do not always work in fighting cancer and how we can improve immunotherapy for solid tumors. While immunotherapy has shown great promise, it is not a panacea. A large number of patients still do not respond and these therapies thus far have worked best for blood-based cancers (aka leukemia). Using single cell RNA-Seq (scRNA-Seq) the Greenberg lab has identified several reasons why immunotherapies fail. First, T cells die, which limits their ability to expand. Second, tumors suppress T cell growth. Some of this suppression is related to a lack of CD8 (T cell) activation.
Dr. Wei Zhang (Wake Forest School of Medicine) shared a doctors' perspective. His lab focuses on using genomic methods to understand glioma - a deadly form of brain cancer. Through his talk, we were reminded of the challenges in precision oncology from extreme tumor heterogeneity, to expensive treatments that offer too little life extension, to physician fatigue.
On an optimistic note, Dr. Zhang shared results from mining TCGA (The Cancer Genome Atlas) data to find that mutations in CTNNB1 (Catenin Beta 1) can predict cancer outcomes. CTNNB1 encodes a protein that is part of a complex of proteins that constitute adherens junctions (AJs). AJs are necessary for the creation and maintenance of epithelial cell layers by regulating cell growth and adhesion between cells. CTNNB1 is also an oncogene, which makes sense given its role in cell growth.
Zhang also discussed findings from liquid biopsy work that show a high prevalence of TP53 mutations in African Americans, and conjectured that this may be correlated with higher rates of smoking menthol cigarettes. As to the physician fatigue, Zahng made the point that a challenge in precision oncology, where DNA sequencing is used to define treatments, is that physicians have not yet been trained to interpret the data. The full talk was captured in the ISB videos.
Dr. Lili Yang (Molecular Biology Institute, Los Angeles) presented work on invariant natural killer T cells (iNKT cells). These are the special forces of the immune system and are rare. If we look at the cells in a single drop of blood, we find only 10 iNKT cells, 10 million red blood cells, 100,000 white blood cells and 5000 conventional T cells. The invariant in iNKT cells is because they also contain a specific T cell receptor (TCR) rearrangement (Vα24Jα18).
The iNKTCR recognizes lipid antigens on CD1d (an MHC class I like molecule, that is NOT polymorphic), so they can target multiple types of cancer (by recognizing tumor-derived glycolipids) using multiple mechanisms that are independent of protein tumor antigen and MHC restrictions. Thus, they can be a powerful immunotherapy if they are present in a high enough concentration. Thus, Dr. Yang's research group is working on ways to increase iNKT cells in cancer by feeding in alpha galacto-ceramide, or trying to expand iNKT cells in vitro and transfuse back into patients, or engineer hematopoietic stem cells to develop into iNKT cells. In the stem cell engineering approach, Yang's lab has had success by adding a transgene that over expresses the Vα24Jα18 TCR. The over expression blocks normal TCR rearrangement and many iNKT cells can be grown and infused back into the patient. So far, this has only been tested in mice, but they are learning the details about production and managing iNKT cell growth.
For more on iNKT cells checkout Discovery of NKT cells and development of NKT cell-targeted anti-tumor immunotherapy for history and background and the video of Dr. Yang's talk.
Other talks by Dr. Bernard Fox (UbiVac) continued the theme of cancer immunotherapy. Fox, CEO of UbiVac and the Harder Family Chair for Cancer Research, at the Earle A Chiles Research Institute, Providence Portland Cancer Center, discussed work in understanding how cell surface markers can be used as biomarkers in defining how immunotherapies are used. While very effective at killing cancer cells, immunotherapies can also kill patients by stimulating the release of cytokines that further stimulate killer T cell growth. His teams are exploring how to identify cell surface markers in conventional blood tests, and also by looking at tumor sections under microscopes because their data indicate that spacial relationships between markers on cells can also matter. To learn more check out the video of Dr. Fox's presentation.
Dr. Alex Fanzusoff (CEO PACT Pharma) closed the session on immunotherapy. PACT Pharma develops immunotherapies that target neoantigens. Neoantigens (new antigens) have always been present and for a long time and have been speculated to be a driver in how the immune system plays a role in preventing cancer. The concept of neoantigens as potential targets of immunotherapy did not fully develop until high throughput DNA sequencing systems became available and large surveys of cancer mutations could be studied. Dr. Fanzusoff shared PACT Pharma's methods for mapping T cell / neoantigen recognition. Their experiments utilize microfluidic devices that mix T cells with nanoparticles containing DNA barcode sequences with fluorescent molecules. The system captures T cells that bind tumor specific neoantigens, and their machine learning algorithms then determine which T cells are involved in interactions will have the greatest therapeutic benefit for further engineering and reintroduction into patients.