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A Structured Tumor-Immune Microenvironment in Triple Negative Breast Cancer Revealed by Multiplexed Ion Beam Imaging

Leeat Keren, Marc Bosse, Diana Marquez, Roshan Angoshtari, Samir Jain, Sushama Varma, Soo-Ryum Yang, Allison Kurian, David Van Valen, Robert West, Sean C. Bendall and Michael Angelo

Cell, September 6, 2018
Summary of work

Parker Institute investigator Sean Bendall, PhD, working with Michael Angelo and other colleagues at Stanford, used an emerging imaging technology called Multiplex Ion Beam Imaging by Time-of-Flight (MIBI-ToF) to gain deeper insights about triple negative breast cancer and its relationship with the local immune system. This cutting-edge imaging allowed the researchers to examine 36 proteins on immune cells and cancer cells in the tumor and surrounding tissue. Among the 41 patients, they found large differences in both the composition and total number of immune cells, with important findings on spatial relationships between immune cells and tumor cells that were predictive of survival. When immune cells and tumor cells were intermingled like grains of sand, researchers found that was associated with a more negative patient outcome with chemotherapy. When the tumor cells were separate – like clumps of tumor cells floating in an ocean of immune cells – that was associated with positive results for overall survival.

Why this is impactful to patients

“We’ve never been able to study triple negative breast cancer with this amount of resolution before, and in a way that preserves the spatial relationships between tumor and immune cells. It provides a much deeper understanding of the immunobiology of this tumor type and how that relates to patient survival,” said Samantha Bucktrout, PhD, director of research at the Parker Institute. “We have a significant amount to learn about this type of cancer, and this new data helped define it more and will open up additional paths to explore.”

Impact of Baseline Steroids on Efficacy of Programmed Cell Death-1 and Programmed Death-Ligand 1 Blockade in Patients With Non–Small-Cell Lung Cancer

Kathryn C. Arbour, Laura Mezquita, Niamh Long, Hira Rizvi, Edouard Auclin, Andy Ni, Gala Martínez-Bernal, Roberto Ferrara, W. Victoria Lai, Lizza E.L. Hendriks, Joshua K. Sabari, Caroline Caramella, Andrew J. Plodkowski, Darragh Halpenny, Jamie E. Chaft, David Planchard, Gregory J. Riely, Benjamin Besse and Matthew D. Hellmann

Journal of Clinical Oncology, August 20, 2018
Summary of work

Corticosteroids are commonly used in late-stage non-small-cell lung cancer patients (NSCLC) who receive checkpoint inhibitors to control a variety of immune-related side effects such as shortness of breath or fatigue. However, there is evidence to indicate that corticosteroids could dampen the effectiveness of immunotherapy. To investigate further, Parker Institute researcher Matthew Hellmann, MD, reviewed records of 640 NSCLC patients treated with a single PD-1 or PD-L1 checkpoint inhibitor immunotherapy and found that corticosteroid use (of ≥ 10 mg of prednisone or a drug equivalent) was strongly associated with a poorer outcome in patients. The work was done in cross-collaboration between colleagues at Memorial Sloan Kettering Cancer Center and the Gustave Roussy Cancer Center.

Why this is impactful to patients

PICI research scientist Christine Spencer, PhD, explains, “this is the first paper to show that steroid use is indeed associated with poorer patient outcomes in the context of checkpoint immunotherapy.” The paper suggests that clinicians should be cautious and conservative with using steroids before and at the start of PD-1/PD-L1 treatment. In addition, more research needs to be done to study the effect of steroids on other common NSCLC treatments that combine chemotherapy and immunotherapy.

Reprogramming human T cell function and specificity with non-viral genome targeting

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

Nature, July 11, 2018
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

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

Immunity, May 15, 2018
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

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

Nature Medicine, April 23, 2018
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, PICI co-director Mark Davis, PhD, of Stanford University 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

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

New England Journal of Medicine, April 16, 2018
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.

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