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Genome-wide CRISPR Screens in Primary Human T Cells Reveal Key Regulators of Immune Function

Eric Shifrut, Julia Carnevale, Victoria Tobin, Theodore L. Roth, Jonathan M. Woo, Christina T. Bui, P. Jonathan Li, Morgan E. Diolaiti, Alan Ashworth, Alexander Marson

Cell, November 14, 2018
Summary of work

Using the gene-editing tool CRISPR, a research team led by PICI researcher Alexander Marson, MD, PhD, of UCSF designed a new way to evaluate thousands of genetic mutations in human T-cells at one time. This technique is called SLICE, for “single guide RNA lentiviral infection with Cas9 protein electroporation” and can quickly determine which genes may impact cellular growth, development and stimulation. In the paper, the researchers showed many possible applications for cancer immunotherapy and immunology. For example, the team found genes associated with T-cell proliferation and immunosuppression. In an experiment targeting these newly found immunosuppression-related genes, T-cells exposed to tumor cells exhibited heightened cancer-killing ability.

Why this is impactful to patients

This new CRISPR screening method provides scientists with a powerful tool to find new cancer targets and build the next generation of tumor-fighting immunotherapies. “Essentially, what SLICE does is create a faster, more reliable way to probe many different pathways that may impact T-cells, which play a central role in immunotherapy’s power to fight cancer,” said Samantha Bucktrout, PhD, director of research at PICI. “Ideally, this could lead to new and more effective immuno-oncology drugs as well as a better understanding of immune system regulation.”

Defining T Cell States Associated with Response to Checkpoint Immunotherapy in Melanoma

Moshe Sade-Feldman, Keren Yizhak, Stacey L. Bjorgaard, John P. Ray, Carl G. de Boer, Russell W. Jenkins, David J. Lieb, Jonathan H. Chen, Dennie T. Frederick, Michal Barzily-Rokni, Samuel S. Freeman, Alexandre Reuben, Paul J. Hoover, Alexandra-Chloé Villani, Elena Ivanova, Andrew Portell, Patrick H. Lizotte, Amir R. Aref, Jean-Pierre Eliane, Marc R. Hammond, Hans Vitzthum, Shauna M. Blackmon, Bo Li, Vancheswaran Gopalakrishnan, Sangeetha M. Reddy, Zachary A. Cooper, Cloud P. Paweletz, David A. Barbie, Anat Stemmer-Rachamimov, Keith T. Flaherty, Jennifer A. Wargo, Genevieve M. Boland, Ryan J. Sullivan, Gad Getz, Nir Hacohen

Cell, November 1, 2018
Summary of work

A team led by PICI Scientific Steering Committee member Nir Hacohen, PhD, at Massachusetts General Hospital, found a new potential biomarker for response to immunotherapy treatment. Using single cell sequencing, researchers identified clusters of T-cells associated with response or lack of response to checkpoint inhibitors, the most commonly used form of immunotherapy. Among the cluster of T-cells linked to cancer regression after treatment, they found the expression of the transcription factor TCF7 was higher and linked to positive outcomes in patients. The team demonstrated how an immunofluorescence assay could be used to measure TCF7 in a clinical setting with patient samples, showing an association with effective therapy. Jennifer Wargo, MD, a PICI investigator at MD Anderson Cancer Center, is a co-author.

Why this is impactful to patients

To make checkpoint inhibitors work for more patients and more types of cancer, scientists have been searching for biomarkers that will help predict which people will respond successfully to these drugs. This paper provides the first evidence that TCF7, a master regulator of T-cell development that is important for generating an immune response against cancer, could be an important new immunotherapy biomarker worthy of additional investigation, said Daniel Wells, PhD, PICI senior data scientist. “They not only discovered what appears to be an important new biomarker, but also that it could be useful in the clinic sooner rather than later using a common assay, which would be of great benefit to patients,” Wells said.

High-dimensional analysis delineates myeloid and lymphoid compartment remodeling during successful immune-checkpoint cancer therapy

Matthew M. Gubin, Ekaterina Esaulova, Jeffrey P. Ward, Olga N. Malkov, Daniele Runci, Pamela Wong, Takuro Noguchi, Cora D. Arthur, Wei Meng, Elise Alspach, Ruan F.V. Medrano, Catrina Fronick, Michael Fehlings, Evan W. Newell, Robert S. Fulton, Kathleen C.F. Sheehan, Stephen T. Oh, Robert D. Schreiber, Maxim N. Artyomov

Cell, October 18, 2018
Summary of work

Not all patients respond to checkpoint inhibitor therapy, and researchers seek to understand why. Senior authors Robert Schreiber, PhD, a Parker Institute researcher, and Maxim Artyomov, both of Washington University in St. Louis used single cell analysis to compare the tumor microenvironment in patients who responded and didn’t respond to treatment with anti PD-1, anti CTLA-4 or the combination. What they discovered were dynamic changes in essential, but different components of the immune system – not only in the lymphoid compartment, which is the target of the checkpoint inhibitor treatment and provides long lasting immune protection, but also in the myeloid compartment, which is a complex system that can either stimulate or inhibit immune responses against cancer. These results indicate that targeting specific components in each compartment could improve the efficacy of checkpoint therapy in more cancer patients.

Why this is impactful to patients

“This study gives insight to improving checkpoint inhibitor therapy by targeting myeloid and lymphoid cells,” says Samantha Bucktrout, PhD, director of research at PICI. “Work remains to bridge these findings in mice to patients, but deep characterization of dynamic immune responses during successful immunotherapy provides an important framework for advancing cancer immunotherapy.”

Neoadjuvant immune checkpoint blockade in high-risk resectable melanoma

Rodabe N. Amaria, Sangeetha M. Reddy, Hussein A. Tawbi, Michael A. Davies, Merrick I. Ross, Isabella C. Glitza, Janice N. Cormier, Carol Lewis, Wen-Jen Hwu, Ehab Hanna, Adi Diab, Michael K. Wong, Richard Royal, Neil Gross, Randal Weber, Stephen Y. Lai, Richard Ehlers, Jorge Blando, Denái R. Milton, Scott Woodman, Robin Kageyama, Daniel K. Wells, Patrick Hwu, Sapna P. Patel, Anthony Lucci, Amy Hessel, Jeffrey E. Lee, Jeffrey Gershenwald, Lauren Simpson, Elizabeth M. Burton, Liberty Posada, Lauren Haydu, Linghua Wang, Shaojun Zhang, Alexander J. Lazar, Courtney W. Hudgens, Vancheswaran Gopalakrishnan, Alexandre Reuben, Miles C. Andrews, Christine N. Spencer, Victor Prieto, Padmanee Sharma, James Allison, Michael T. Tetzlaff, Jennifer A. Wargo

Nature Medicine, October 8, 2018
Summary of work

Early studies in mice suggest that treatment with checkpoint inhibitors before surgery in melanoma patients could be beneficial. This study, led by PICI investigator Jennifer Wargo, MD, of MD Anderson Cancer Center, was one of the first of its kind in patients to test this hypothesis. The study demonstrated that combining anti-PD-1 and CTLA-4 checkpoint blockade before surgery produced a better response than anti-PD-1 alone, but at the expense of significant toxicity to the patient. Due to the side effects, investigators re-designed the study to explore the safety and efficacy of anti-PD-1 plus an inhibitor of the LAG3 immune checkpoint, which they believe may be more effective than the single agent and less toxic than the original combination. Other co-authors include PICI co-director Padmanee Sharma, MD, PhD, and PICI director James Allison, PhD, at MD Anderson Cancer Center. PICI informatics scientists Christine Spencer, PhD, Danny Wells, PhD, and Robin Kageyama, PhD, are also co-authors of the paper.

Why this is impactful to patients

“With a patient population as high-risk as this one, it is critical to thoroughly test new interventions and gather high-quality data so that the field can move towards helping these patients who, with current standard of care options, are very likely to have their cancer recur,” PICI scientist Christine Spencer, PhD, and a co-author of the study explains. “This trial demonstrates potential limitations and opportunities to pre-surgery treatment with checkpoint blockades and was also helpful in exposing novel biomarkers that may be involved in responders.”

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.

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