Five-Year Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma October 17, 2019 | New England Journal of Medicine James Larkin, Vanna Chiarion-Sileni, Rene Gonzalez, Jean-Jacques Grob, Piotr Rutkowski, Christopher D. Lao, C. Lance Cowey, Dirk Schadendorf, John Wagstaff, Reinhard Dummer, Pier F. Ferrucci, Michael Smylie, David Hogg, Andrew Hill, Ivan Márquez-Rodas, John Haanen, Massimo Guidoboni, Michele Maio, Patrick Schöffski, Matteo S. Carlino, Céleste Lebbé, Grant McArthur, Paolo A. Ascierto, Gregory A. Daniels, Georgina V. Long, Lars Bastholt, Jasmine I. Rizzo, Agnes Balogh, Andriy Moshyk, F. Stephen Hodi, and Jedd D. Wolchok PubMed Article More Summary of work In a 5-year follow-up with patients with advanced melanoma, patients who received nivolumab plus ipilimumab or nivolumab alone tended to live longer and their tumors progressed more slowly than those who received ipilimumab alone. Overall survival at 5 years was 52% in the nivolumab-plus-ipilimumab group and 44% in the nivolumab group, as compared with 26% in the ipilimumab group. Five-year progression-free survival was 36%, 29%, and 8% in the nivolumab-plus-ipilimumab, nivolumab, and ipilimumab groups, respectively. There was no sustained decline of health-related quality of life during or after treatment with the immunotherapy regimen. No new late toxic effects were observed in this study. Co-senior authors on the paper include PICI researchers F. Stephen Hodi, MD and co-director Jedd Wolchok, MD, PhD. Why this is impactful to patients “10 years ago, only one in twenty patients with advanced melanoma survived beyond five years. This impressive research demonstrates that this immunotherapy combination increases the chances of a patient surviving advanced melanoma significantly.” says Leo Nissola, MD, a senior clinical scientist at PICI. The study has great impact for the field as well. “This was the first trial to use two immunotherapies in tandem to treat a disease. And, this five year milestone is the longest phase 3 follow-up of a combination therapy.” The jury is still out on whether the combination therapy or nivolumab alone is a better option for patients. However, the research affirms that two good options now exist outside of chemotherapy. “It is exciting progress,” said Dr. Nissola.
Neoadjuvant anti-PD-1 immunotherapy promotes a survival benefit with intratumoral and systemic immune responses in recurrent glioblastoma February 11, 2019 | Nature Medicine 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 PubMed Article More 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, PhD, 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 February 11, 2019 | Nature Biotechnology Zinaida Good, Luciene Borges, Nora Vivanco Gonzalez, Bita Sahaf, Nikolay Samusik, Robert Tibshirani, Garry P. Nolan and Sean C. Bendall PubMed Article More 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 January 29, 2019 | Journal of Clinical Investigation 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 PubMed Article More 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 November 14, 2018 | Cell 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 PubMed Article More 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 November 1, 2018 | Cell 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 PubMed Article More 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 October 18, 2018 | Cell 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 PubMed Article More 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 October 8, 2018 | Nature Medicine 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 PubMed Article More 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 September 6, 2018 | Cell 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 PubMed Article More 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 August 20, 2018 | Journal of Clinical Oncology 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 PubMed Article More 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.