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15 Publications

Neoadjuvant anti-PD-1 immunotherapy promotes a survival benefit with intratumoral and systemic immune responses in recurrent glioblastoma

Timothy F. Cloughesy, Aaron Y. Mochizuki, Joey R. Orpilla, Willy Hugo, Alexander H. Lee, Tom B. Davidson, Anthony C. Wang, Benjamin M. Ellingson, Julie A. Rytlewski, Catherine M. Sanders, Eric S. Kawaguchi, Lin Du, Gang Li, William H. Yong, Sarah C. Gaffey, Adam L. Cohen, Ingo K. Mellinghoff, Eudocia Q. Lee, David A. Reardon, Barbara J. O’Brien, Nicholas A. Butowski, Phioanh L. Nghiemphu, Jennifer L. Clarke, Isabel C. Arrillaga-Romany, Howard Colman, Thomas J. Kaley, John F. de Groot, Linda M. Liau, Patrick Y. Wen and Robert M. Prins

Nature Medicine, February 11, 2019
Summary of work

PICI scientists at UCLA found that for patients with a deadly form of brain cancer called glioblastoma, treatment with the checkpoint inhibitor pembrolizumab before surgery nearly doubled median survival time. “These results are very encouraging,” said senior author Robert Prins, Ph.D., a Parker Institute investigator at the UCLA Jonsson Comprehensive Cancer Center. “It’s one of the few times we’ve seen positive survival results using immunotherapy in this type of brain cancer.”

Why this is impactful to patients

“It’s imperative to find therapies for glioblastoma, and fast,” said Samantha Bucktrout, PhD, PICI director of research. “This groundbreaking study not only doubled survival time for this devastating disease but provided key insights into why the neoadjuvant application of anti-PD-1 therapy translated to clinical benefit when therapy following surgery didn’t.”

Multiplex single-cell tracing across time and division states enables control of T-cell differentiation

Zinaida Good, Luciene Borges, Nora Vivanco Gonzalez, Bita Sahaf, Nikolay Samusik, Robert Tibshirani, Garry P. Nolan and Sean C. Bendall

Nature Biotechnology, February 11, 2019
Summary of work

PICI scientists at Stanford used single cell mass cytometry to trace how therapeutic T-cells grow and multiply, creating a comprehensive “cellular map” of all the stages of T-cell expansion. They demonstrated that this roadmap can be used to guide cells into a more potent, active state for therapeutic purposes. The work brings a greater understanding of T-cell expansion, a key component in creating CAR-Ts and cell therapy to treat cancer. Parker Institute researchers Sean Bendall, PhD, and Garry Nolan, PhD, are senior authors. PICI Scholar Zinaida Good, PhD, also of Stanford, is first author.

Why this is impactful to patients

 To make immunotherapy more effective for more patients, researchers are hard at work to find new ways to measure all the changes that occur in the immune system following the development of a tumor. These PICI researchers at Stanford found a clever way to do this using a special dye and isotope-labeled antibody with an advanced platform called CyTOF. They can now trace back the lineage of T-cells even further using this new method, providing more insight into a T-cell’s history than was ever available before. “Together with the data from the other markers, this technical advance will allow for much more nuanced understandings of the timing and kinetics of the immune response to cancer,” said Nick Bayless, PhD, PICI research scientist.

T cells genetically engineered to overcome death signaling enhance adoptive cancer immunotherapy

Tori N. Yamamoto, Ping-Hsien Lee, Suman K. Vodnala, Devikala Gurusamy, Rigel J. Kishton, Zhiya Yu, Arash Eidizadeh, Robert Eil, Jessica Fioravanti, Luca Gattinoni, James N. Kochenderfer, Terry J. Fry, Bulent Arman Aksoy, Jeffrey E. Hammerbacher, Anthony C. Cruz, Richard M. Siegel, Nicholas P. Restifo, and Christopher A. Klebanoff

Journal of Clinical Investigation, January 29, 2019
Summary of work

One of the major challenges in adoptive cell therapy for cancer: getting engineered T-cells to multiply and live longer so that they can effectively tackle tumors over time, particularly solid tumors. PICI investigator Christopher Klebanoff, MD, of Memorial Sloan Kettering Cancer Center, shows in this paper that genetically blocking the activation of Fas – a major signaling pathway that instructs cells to self-destruct – could be a solution to this problem. The researchers engineered the T-cells to have a dominant negative receptor, which effectively turns off the Fas pathway and leads to superior longevity and cancer-killing power.

Why this is impactful to patients

This paper demonstrates a novel strategy for keeping tumor-killing CAR-T cells alive longer, preventing them from becoming “exhausted” once administered to cancer patients. The potential for applying this to treatment of solid cancers, notoriously difficult to treat with immunotherapy, is particularly exciting. “This appears to be a new and promising approach for improving T-cell persistence and therapeutic efficacy for CAR-T,” said PICI Clinical Scientist Jingying Xu, PhD. “It will be exciting to see this strategy get further explored in the clinic.”

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.”

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