Reprogramming human T cell function and specificity with non-viral genome targeting July 11, 2018 | Nature Theodore L. Roth, Cristina Puig-Saus, Ruby Yu, Eric Shifrut, Julia Carnevale, P. Jonathan Li, Joseph Hiatt, Justin Saco, Paige Krystofinski, Han Li, Victoria Tobin, David N. Nguyen, Michael R. Lee, Amy L. Putnam, Andrea L. Ferris, Jeff W. Chen, Jean-Nicolas Schickel, Laurence Pellerin, David Carmody, Gorka Alkorta-Aranburu, Daniela del Gaudio, Hiroyuki Matsumoto, Montse Morell, Ying Mao, Min Cho, Rolen M. Quadros, Channabasavaiah B. Gurumurthy, Baz Smith, Michael Haugwitz, Stephen H. Hughes, Jonathan S. Weissman, Kathrin Schumann, Jonathan H. Esensten, Andrew P. May, Alan Ashworth, Gary M. Kupfer, Siri Atma W. Greeley, Rosa Bacchetta, Eric Meffre, Maria Grazia Roncarolo, Neil Romberg, Kevan C. Herold, Antoni Ribas, Manuel D. Leonetti and Alexander Marson PubMed Article More Summary of work Parker Institute scientists at UCSF and UCLA developed a potentially more cost-effective and rapid way of performing gene editing, with significant applications for cell therapy and CAR-T immunotherapy treatments. The new method involves CRISPR and avoids the use of expensive viruses that can often create a bottleneck in cell therapy production. In this paper, PICI researcher Alexander Marson, MD, PhD, first used the technology to correct single disease-causing mutations in human cells. In a second application done in collaboration with Antoni Ribas, MD, PhD, Parker Institute director at UCLA, the researchers demonstrated it was possible to use the gene editing to insert large amounts of DNA into T-cells, altering them to more effectively target and kill tumor cells. Why this is impactful to patients “This is a huge advance for the cell therapy and CAR-T field, opening the door for us to create more robust, personalized cancer immunotherapy treatments in less time,” said Fred Ramsdell, PhD, vice president of research at the Parker Institute. “What takes months or even a year may now take a couple weeks using this new technology. If you are a cancer patient, weeks versus months could make a huge difference.”
Epigenomic-Guided Mass Cytometry Profiling Reveals Disease-Specific Features of Exhausted CD8 T Cells May 15, 2018 | Immunity Bertram Bengsch, Takuya Ohtani, Omar Khan, Manu Setty, Sasikanth Manne, Shaun O’Brien, Pier Federico Gherardini, Ramin Sedaghat Herati, Alexander C. Huang, Kyong-Mi Chang, Evan W. Newell, Niels Bovenschen, Dana Pe’er, Steven M. Albelda, and E. John Wherry PubMed Article More Summary of work During cancer and chronic infections, T-cells that fight off disease can become exhausted, preventing the body from being able to control the disease effectively. In this paper, Parker Institute researchers at the University of Pennsylvania developed a method to better identify and characterize exhausted T-cells in cancer and HIV patients, using an approach that incorporates epigenetic and gene expression screens followed by mass cytometry. E. John Wherry, PhD, Parker Institute co-director at the University of Pennsylvania, is senior author and PICI project member Bertram Bengsch, PhD, is first author. Co-authors include Parker Bridge Scholar Alexander Huang, MD, PhD, and Pier Federico Gherardini, PhD, Parker Institute associate director of technology development. Why this is impactful to patients Understanding more about exhausted T-cells could prove helpful when creating new therapies that could aid cancer or HIV patients. “Interestingly, in this paper the scientists identify combinations of immunotherapy targets on exhausted T-cell populations that could lead to novel combinations of immuno-oncology drugs for testing in clinical trials,” said Nicholas Bayless, PhD, a Parker Institute research scientist on the informatics team.
Transcript-Indexed ATAC-seq for Precision Immune Profiling April 23, 2018 | Nature Medicine Ansuman T. Satpathy, Naresha Saligrama, Jason D. Buenrostro, Yuning Wei, Beijing Wu, Adam J. Rubin, Jeffrey M. Granja, Caleb A. Lareau, Rui Li, Yanyan Qi, Kevin R. Parker, Maxwell R. Mumbach, William S. Serratelli, David G. Gennert, Alicia N. Schep, M. Ryan Corces, Michael S. Khodadoust, Youn H. Kim, Paul A. Khavari, William J. Greenleaf, Mark M. Davis and Howard Y. Chang PubMed Article More Summary of work Only a small fraction of human T-cells recognize and destroy tumors. How do you separate the signals in these few T-cells from the rest? Parker Bridge Scholar Ansuman Satpathy, MD, PhD, PICI member Howard Chang, MD, PhD, co-director Mark Davis, PhD, and their colleagues teamed up to create a new method called T-ATAC-seq to analyze the underlying genetic mechanisms of single T-cells to identify which cells are most capable of killing a tumor. Why this is impactful to patients Understanding T-cell biology is fundamental to the development of more effective immunotherapy treatments. “T-ATAC-seq is a useful technology that will help us better characterize T-cells, the dynamics of their response to tumors and how their function changes in response to immunotherapy,” says Pier Federico Gherardini, PhD, associate director of technology development at the Parker Institute. With this method, scientists can “link the identity of a T-cell, defined by the unique sequence of its T-cell receptor (TCR), with the T-cell’s functional state or capacity, as revealed by its epigenomic profile.”
Nivolumab plus Ipilimumab in Lung Cancer with a High Tumor Mutational Burden April 16, 2018 | New England Journal of Medicine Matthew D. Hellmann, Tudor-Eliade Ciuleanu, Adam Pluzanski, Jong Seok Lee, Gregory A. Otterson, Clarisse Audigier-Valette, Elisa Minenza, Helena Linardou, Sjaak Burgers, Pamela Salman, Hossein Borghaei, Suresh S. Ramalingam, Julie Brahmer, Martin Reck, Kenneth J. O’Byrne, William J. Geese, George Green, Han Chang, Joseph Szustakowski, Prabhu Bhagavatheeswaran, Diane Healey, M.S., Yali Fu, Faith Nathan and Luis Paz-Ares PubMed Article More Summary of work Parker Institute’s Matthew Hellmann, MD, and colleagues at Memorial Sloan Kettering Cancer Center found that the odds of progression-free survival among advanced non-small cell lung cancer (NSCLC) patients with a high tumor mutational burden (TMB) was nearly three times higher when patients were treated with nivolumab and ipilimumab compared to chemotherapy-only (43% vs. 13% after one year, respectively). This work built off previous research that indicated TMB could predict response to this particular combination of immunotherapies, and it was the first phase III clinical trial to evaluate TMB as a predictive biomarker. Why this is impactful to patients “This study is a win for patients with metastatic lung cancer,” says Theresa LaVallee, PhD, vice president of translational medicine and regulatory affairs for the Parker Institute. Non-small cell lung cancer is the most common form of lung cancer and the leading cause of cancer deaths globally. For patients without a targetable mutation, the standard of care is chemotherapy, which is not only toxic but does not have a long-lasting effect. This study demonstrates that combining immunotherapies nivolumab and ipilimumab can be an effective and possibly durable first-line treatment option for patients; and tumor mutation burden can be a predictive biomarker to identify patients who would benefit from combination immunotherapy. “These are significant advances that can have an immediate impact on how we treat lung cancer moving forward,” says LaVallee.
Genetic Mechanisms of Immune Evasion in Colorectal Cancer March 6, 2018 | Cancer Discovery Catherine S. Grasso, Marios Giannakis, Daniel K. Wells, Tsuyoshi Hamada, Xinmeng Jasmine Mu, Michael Quist, Jonathan A. Nowak, Reiko Nishihara, Zhi Rong Qian, Kentaro Inamura, Teppei Morikawa, Katsuhiko Nosho, Gabriel Abril-Rodriguez, Charles Connolly, Helena Escuin-Ordinas, Milan S. Geybels, William M. Grady, Li Hsu, Siwen Hu-Lieskovan, Jeroen R. Huyghe, Yeon Joo Kim, Paige E. Krystofinski, Mark DM Leiserson, Dennis J. Montoya, Brian B. Nadel, Matteo Pellegrini, Colin C. Pritchard, Cristina Puig-Saus, Elleanor H. Quist, Benjamin J. Raphael, Stephen J. Salipante, Daniel Sanghoon Shin, Eve Shinbrot, Brian Shirts, Sachet Shukla, Janet L. Stanford, Wei Sun, Jennifer Tsoi, Alexander Upfill-Brown, David A. Wheeler, Catherine J. Wu, Ming Yu, Syed H. Zaidi, Jesse M. Zaretsky, Stacey B. Gabriel, Eric S Lander, Levi A. Garraway, Thomas J. Hudson, Charles S. Fuchs, Antoni Ribas, Shuji Ogino and Ulrike Peters PubMed Article More Summary of work Parker Institute researchers at the UCLA Jonsson Comprehensive Cancer Center, led by Catherine Grasso, PhD, have discovered genetic mutations that may explain how some colorectal cancers hide from the immune system, making them resistant to immunotherapy treatment. Working with investigators at the Broad Institute, Dana-Farber Cancer Institute and Fred Hutchinson Cancer Research Center, the team analyzed more than 1,200 colon cancer samples, focusing on a subset of highly mutated tumors known as microsatellite instability-high or MSI-high tumors. Significant findings were three-fold: 1. Certain mutations in genes B2M, HLA, Tap2, NLRC5 help the cancer avoid immune detection; 2. Some cancers are innately resistant before treatment; 3. A therapeutic target called the WNT pathway could enhance immunotherapy response. Other Parker Institute researchers involved in the study include Antoni Ribas, MD, PhD, Danny Wells, PhD and Jesse Zaretsky, PhD. Why this is impactful to patients “What was significant is that they identified new genetic clues that explain how certain colorectal cancers are able to avoid being recognized and attacked by the immune system, limiting the effectiveness of immunotherapy,” says Fred Ramsdell, PhD, vice president of research at the Parker Institute. “The findings also suggest there might be new approaches for tackling colorectal cancer, which remains difficult to treat.” Colorectal cancer is the third most diagnosed cancer in the United States, according to the American Cancer Society.
Selective Targeting of Engineered T cells using Orthogonal IL-2 Cytokine-Receptor Complexes March 2, 2018 | Science Jonathan T. Sockolosky, Eleonora Trotta, Giulia Parisi, Lora Picton, Leon L. Su, Alan C. Le, Akanksha Chhabra, Stephanie L. Silveria, Benson M. George, Indigo C. King, Matthew R. Tiffany, Kevin Jude, Leah V. Sibener, David Baker, Judith A. Shizuru, Antoni Ribas, Jeffrey A. Bluestone and K. Christopher Garcia PubMed Article More Summary of work The T-cell growth factor IL-2 plays an important role in helping activated T-cells persist and expand so that they can fight diseases such as cancer. This makes IL-2 a potentially powerful ally when paired with anti-tumor T-cell therapies, such as CAR-T. However, IL-2 can also cause serious side effects, limiting its use in the clinic. In this paper, researchers engineered a synthetic IL-2 receptor system that in mice effectively boosted T-cell growth in vivo and in vitro, while limiting off-target effects and toxicity. Parker Institute project member K. Christopher Garcia, PhD, of Stanford University, is senior author. He collaborated with co-authors Jeffrey Bluestone, PhD, Parker Institute president and CEO, and Antoni Ribas, MD, PhD, Parker Institute director at UCLA. Why this is impactful to patients “T-cell expansion and persistence remains a significant challenge in the field of T-cell therapy,” said Samantha Bucktrout, PhD, director of research at the Parker Institute. “To solve that problem, the investigators developed a novel approach using IL-2 that boosts T-cell growth and activity but should minimize side effects.”