News Article | March 1, 2017
It's what's missing in the tumor genome, not what's mutated, that thwarts treatment of metastatic melanoma with immune checkpoint blockade drugs, researchers at The University of Texas MD Anderson Cancer Center report in Science Translational Medicine. Whole exome sequencing of tumor biopsies taken before, during and after treatment of 56 patients showed that outright loss of a variety of tumor-suppressing genes with influence on immune response leads to resistance of treatment with both CTLA4 and PD1 inhibitors. The team's research focuses on why these treatments help 20-30 percent of patients -- with some complete responses that last for years - but don't work for others. Their findings indicate that analyzing loss of blocks of the genome could provide a new predictive indicator. "Is there a trivial or simple (genomic) explanation? There doesn't seem to be one," said co-senior author Andrew Futreal, Ph.D., professor and chair of Genomic Medicine and co-leader of MD Anderson's Moon Shots Program™. "There's no obvious correlation between mutations in cancer genes or other genes and immune response in these patients." "There are, however, pretty strong genomic copy loss correlates of resistance to sequential checkpoint blockade that also pan out for single-agent treatment," Futreal said. Doctoral candidate Whijae Roh, co-lead author, Futreal, and co-senior author Jennifer Wargo, M.D., associate professor of Surgical Oncology and Genomic Medicine, and colleagues analyzed the genomic data for non-mutational effects. "We found a higher burden of copy number loss correlated to response to immune checkpoint blockade and to lower immune scores, a measure of immune activation in the tumor's microenvironment," said Roh, a graduate student in the University of Texas MD Anderson UTHealth Graduate School of Biomedical Sciences. "We also found copy loss has an effect that is independent of mutational load in the tumors." Melanoma tumors with larger volumes of genetic alterations, called mutational load, provide more targets for the immune system to detect and are more susceptible to checkpoint blockade, although that measure is not conclusive alone. "Combining mutational load and copy number loss could improve prediction of patient response," Wargo said. When the team stratified patients in another data set of patients by whether they had high or low copy loss or high or low mutational load, they found that 11 of 26 patients with high mutational load and low copy loss had a clinical benefit, while only 4 or 26 with low mutational load and high copy loss benefited from treatment. In the trial, patients were treated first with the immune checkpoint inhibitor ipilimumab, which blocks a brake called CTLA4 on T cells, the immune system's specialized warriors, freeing them to attack. Patients whose melanoma did not react then went on to anti-PD1 treatment (nivolumab), which blocks a second checkpoint on T cells. Biopsies were taken, when feasible, before, during and after treatment for molecular analysis to understand response and resistance. To better understand the mechanisms at work, the team analyzed tumor genomes for recurrent copy loss among 9 tumor biopsies from patients who did not respond to either drug and had high burden of copy number loss. They found repeated loss of blocks of chromosomes 6, 10 and 11, which harbor 13 known tumor-suppressing genes. Analysis of a second cohort of patients confirmed the findings, with no recurrent tumor-suppressor loss found among any of the patients who had a clinical benefit or long-term survival after treatment. Ipilimumab sometimes wins when it fails The researchers also found a hint that treatment with ipilimumab, even if it fails, might prime the patient's immune system for successful anti-PD1 treatment. The team analyzed the genetic variability of a region of the T cell receptors, a feature of T cells that allows them to identify, attack and remember an antigen target found on an abnormal cell or an invading microbe. They looked for evidence of T cell "clonality," an indicator of active T cell response. Among eight patients with longitudinal samples taken before treatment with both checkpoint types, all three who responded to anti-PD1 therapy had shown signs of T cell activation after anti-CTLA treatment. Only one of the five non-responders had similar indicators of T cell clonality. "That's evidence that anti-CTLA4 in some cases primes T cells for the next step, anti-PD1 immunotherapy. It's well known that if you don't have T cells in the tumor, anti-PD1 won't do anything, it doesn't bring T cells into the tumor," Futreal says. Overall, they found that T cell clonality predicts response to PD1 blockade but not to CTLA-4 blockade. "Developing an assay to predict response will take an integrated analysis, thinking about genomic signatures and pathways, to understand the patient when you start therapy and what happens as they begin to receive therapy," Wargo said. "Changes from pretreatment to on-therapy activity will be important as well." The Science Translational Medicine paper is the third set of findings either published or presented at scientific meetings by the team, which is led by Futreal and Wargo, who also is co-leader of the Melanoma Moon Shot™. Immune-monitoring analysis showed that presence of immune infiltrates in a tumor after anti-PD1 treatment begins is a strong predictor of success. They also presented evidence that the diversity and composition of a patient's gut bacteria also affects response to anti-PD1 therapy. The serial biopsy approach is a hallmark of the Adaptive Patient-Oriented Longitudinal Learning and Optimization™ (APOLLO) platform of the Moon Shots Program™, co-led by Futreal that systematically gathers samples and data to understand tumor response and resistance to treatment over time. The Moon Shots Program™ is designed to reduce cancer deaths by accelerating development of therapies, prevention and early detection from scientific discoveries. Futreal holds the The Robert A. Welch Distinguished University Chair in Chemistry at MD Anderson. Co-authors with Roh, Futreal and Wargo are co-first authors Pei-Ling Chen, M.D., of Genomic Medicine and Pathology, and Alexandre Reuben, Ph.D., of Surgical Oncology; also Christine Spencer, Feng Wang, Ph.D., Zachary Cooper, Ph.D., Curtis Gumbs, Latasha Little, Qing Chang, Wei-Shen Chen, M.D., and Jason Roszik, Ph.D., of Genomic Medicine; Michael Tetzlaff, Ph.D., M.D., and Victor Prieto, M.D., Ph.D., of Pathology; Peter Prieto, M.D., Vancheswaran Gopalakrishnan, Jacob L. Austin-Breneman, Hong Jiang, Ph.D., and Jeffrey Gershenwald, M.D., of Surgical Oncology; John Miller, Ph.D., Oncology Research for Biologics and Immunotherapy Translation (ORBIT); Sangeetha Reddy, M.D., Division of Cancer Medicine; Khalida Wani, Ph.D., Mariana Petaccia De Macedo, M.D., Ph.D., Eveline Chen, and Alexander Lazar, M.D., Ph.D., of Translational Molecular Pathology; Michael Davies, M.D., Ph.D., Hussein Tawbi, M.D., Ph.D., Patrick Hwu, M.D., Wen-Jen Hwu, M.D., Ph.D., Adi Diab, M.D., Isabella Glitza, M.D., Ph.D., Sapna Patel, M.D., Scott Woodman, M.D., Ph.D., and Rodabe Amaria, M.D., of Melanoma Medical Oncology; Jianhua Hu, Ph.D., of Biostatistics; Padmanee Sharma, M.D., Ph.D., and James Allison, Ph.D., of Immunology; Lynda Chin, M.D., University of Texas System; and Jianhua Zhang Ph.D., of the Institute for Applied Cancer Science. Wargo, Sharma and Allison are all members of the Parker Institute for Cancer Immunotherapy. The research was funded by MD Anderson's Melanoma Moon Shot™, the Melanoma Research Alliance Team Science Award, the John G. and Marie Stella Kenedy Memorial Foundation, the University of Texas System STARS program; the Cancer Prevention and Research Institute of Texas; the American Society of Clinical Oncology; Conquer Cancer Foundation; the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation; and grants from the National Cancer Institute of the National Institutes of Health (U54CA163125, 1K08CA160692-01A1, T32CA009599, NIH T32 CA009666, R01 CA187076-02) and MD Anderson's Institutional Tissue Bank (2P30CA016672) Spencer and Gopalakrishnan are graduate students in The University of Texas Health Science Center at Houston School of Public Health.
News Article | April 27, 2016
The recent launch of multiple major US cancer initiatives has infused cash into immunotherapy, one of the most promising new methods of cancer treatment. But researchers warn that the money may be wasted without concrete plans to coordinate the programmes. “There’s a lack of overt leadership, and in the absence of a logical strategy we have a tendency to throw plates of spaghetti against the wall and hope it sticks,” says Ira Mellman, vice-president of cancer immunology at the biotechnology company Genentech in South San Francisco, California. The broadest programme is the US government’s National Cancer Moonshot, which hopes to receive US$1 billion by next year for 8 areas of cancer research. Immunotherapy, which recalibrates the body’s own immune defence against cancer, is among them. It “is poised to be a critical part of our nation’s anticancer strategy”, the project’s leader, US vice-president Joe Biden, said last week at the annual meeting of the American Association for Cancer Research (AACR) in New Orleans, Louisiana. An advisory panel will release more-detailed plans for the government programme in June. Meanwhile, three privately funded immunotherapy research projects are gearing up: the $250-million Parker Institute for Cancer Immunotherapy, funded by Sean Parker, co-founder of the music-file-sharing company Napster, and announced on 13 April; a $125-million Immunotherapy Center at Johns Hopkins University in Baltimore, Maryland, unveiled in March; and the Cancer MoonShot 2020 Program, announced in January by biotechnology billionaire Patrick Soon-Shiong. This sudden proliferation of cancer initiatives is reminiscent of the spate of brain-research projects launched in the past few years — some of which have foundered through poor leadership. Europe’s Human Brain Project, for instance, almost ran aground after a series of top-down decisions alienated the neuroscience community. By contrast, the US BRAIN Initiative set priorities after consulting with neuroscientists, and awarded grants through a conventional peer-reviewed process, ensuring community acceptance. Now cancer researchers are left wondering how their moonshots will proceed. At the AACR meeting, Biden said that he had met representatives of many cancer-funding projects. “Why is all of that being done separately?” he asked scientists in the audience, noting that progress is accelerated by collaboration. The privately funded initiatives are more concerned with meeting their own goals — and satisfying their funders — than with coordinating efforts in the field. “I don’t see my role as trying to answer this larger question about how does this all fit together,” says Jeffrey Bluestone, chief executive of the Parker Institute. “I’m focused on how to make sure what we do is impactful for patients.” But Douglas Lowy, acting director of the US National Cancer Institute (NCI), which is coordinating the government moonshot, notes an overlap with the leadership of the various projects. Soon-Shiong, Bluestone and leaders of immunotherapy initiatives at Johns Hopkins and the University of Texas MD Anderson Cancer Center in Houston are on the government initiative’s advisory panel. And on 18 April, the Biden moonshot launched a website to solicit research ideas. The aim, Lowy says, is to ensure that research areas recommended by the advisory panel do not duplicate topics being covered by the private initiatives. There is wide agreement on major questions regarding immunotherapy, however. For instance, researchers don’t understand why the approach works in only 15–20% of patients. Combining immunotherapies, and studying what distinguishes patients who respond, could make treatments more effective. Pharmaceutical companies are already developing new drugs and testing therapies in combination. Philip Gotwals, executive director of oncology research at the Novartis Institutes for BioMedical Research in Cambridge, Massachusetts, estimates that industry has spent upwards of $1 billion on the field. But scientists see a lack of basic cancer immunology research, even in the new programmes. “Many of these initiatives are moving forward ideas that are already out there,” says David Raulet, faculty director of the Immunotherapeutics and Vaccine Research Initiative at the University of California, Berkeley, which began in March. Many researchers are looking to the Biden project to make a big investment in basic cancer immunology and to address broader barriers to research, such as data hoarding. Gotwals, for instance, notes that the results of industry-sponsored clinical trials now under way could help other companies to decide which approaches to test, but that results are typically not made public until 9–12 months after a trial ends. Companies are reluctant to share data before then, both to comply with regulatory requirements and to protect their intellectual property. “It’s not trivial to figure out how to make that work,” Gotwals says. Biden seems to be hearing that message. At the AACR meeting, he said that data sharing often comes up when he speaks to scientists about the moonshot. Lowy says that the NCI is already planning to open a Genomic Data Commons in June to host detailed information on cancer patients. Sharing data collected in company-sponsored clinical trials is trickier because patients must give informed consent. In the meantime, the government moonshot faces a major hurdle: its funding is at the mercy of legislators who may be loath to give US President Barack Obama a victory in his last year in office. “It will be very difficult for us to initiate all of the programmes that we’re looking forward to the blue-ribbon panel recommending if there isn’t funding,” Lowy says.
News Article | February 21, 2017
Melanoma patients' response to a major form of immunotherapy is associated with the diversity and makeup of trillions of potential allies and enemies found in the digestive tract, researchers at The University of Texas MD Anderson Cancer Center report at the ASCO-Society for Immunotherapy in Cancer meeting in Orlando. Analysis of 113 fecal samples of patients with metastatic melanoma found that those who responded to a PD1 checkpoint inhibitor had a greater diversity of gut bacteria and larger volumes of a specific type of bacteria than those who did not respond. This connection between a person's microbiome - trillions of bacteria harbored to varying degrees in the human body -- and immune system could have major implications for cancer prognosis and treatment. "Anti-PD1 immunotherapy is effective for many, but not all, melanoma patients and responses aren't always durable," said Jennifer Wargo, M.D., associate professor of Surgical Oncology. "Our findings point to two potential impacts from additional research -- analyzing the diversity and composition of the microbiome to predict response to immunotherapy and modulating the gut microbiome to enhance treatment," said Wargo, senior researcher on the project and co-leader of the Melanoma Moon Shot™, part of MD Anderson's Moon Shots Program™ to reduce cancer deaths by accelerating development of therapies from scientific discoveries. PD1 is a protein on the surface of T cells, the immune system's specialized attack cells, that shuts down immune response. Anti-PD1 drugs use an antibody to block activation of PD1 by PD-L1, a ligand found on tumors and surrounding cells. Wargo and colleagues are conducting preclinical research to better understand the mechanisms that connect bacteria and the immune system. They're also designing clinical trials to test the hypothesis that modifying the gut microbiome might improve patients' responses to checkpoint inhibitors. "Evidence from preclinical research had previously indicated a relationship between solid tumors, immune response, and the microbiome. Our study was the first of its type to look at the relationship between the microbiome and immunotherapy response in patients," said Vancheswaran Gopalakrishnan, first author and doctoral student at The University of Texas Health Science Center at Houston School of Public Health. Gopalakrishnan, Wargo and colleagues examined oral and gut microbiome samples from 228 patients with metastatic melanoma. While no differences in response were found in connection with the oral samples, the 113 fecal samples told another story. Gopalakrishnan said the team conducted 16S rRNA sequencing, an analysis of the presence of 16S ribosomal RNA used to identify bacteria. Among the 93 patients treated with anti-PD1 immune checkpoint blockade, the researchers had gut microbiome samples from 30 responders and 13 non-responders. They found: The researchers also conducted immune profiling before treatment for the presence of important immune system cells in the tumors. Responders had significantly increased immune infiltrates in their tumors, including the presence of CD8+ killer T cells, correlated to the abundance of a specific bacterium. Even as they conduct deeper research into the microbiome and the metabolites produced by bacteria to affect the immune response, the team is also studying ways to change the composition of the microbiome. "The microbiome is highly targetable in a variety of ways," Gopalakrishnan said, including by diet, probiotics to boost the presence of helpful bacteria, antibiotics or by fecal transplants. In collaboration with the Parker Institute for Cancer Immunotherapy (PICI), the first clinical trial is expected to launch later this year. Research also continues funded by MD Anderson's Melanoma Moon Shot™. The Melanoma Research Alliance and PICI also provided support for this study. Co-authors with Gopalakrishnan and Wargo are Christine Spencer, Tatiana Karpinets, Ph.D., Robert Jenq, M.D., and Andrew Futreal, Ph.D., of Genomic Medicine; Alexandre Reuben, Ph.D., Peter Prieto, M.D., and Jeffrey Gershenwald, M.D., of Surgical Oncology; Kristi Hoffman, Ph.D., of Cancer Prevention; Michael Tetzlaff, Ph.D., M.D., and Alexander Lazar, M.D., Ph.D., of Pathology; Michael Davies, M.D., Ph.D., and Patrick Hwu, M.D., of Melanoma Medical Oncology; Padmanee Sharma, M.D., Ph.D., of Genitourinary Medical Oncology and Immunology; Jim Allison, Ph.D., of Immunology; Carrie Daniel-MacDougall, Ph.D., of Epidemiology; and Diane Hutchinson, Ph.D., Nadim Ajami, Ph.D., and Joseph Petrosino, Ph.D., of Baylor College of Medicine.
News Article | December 31, 2016
Cancer in its many forms has already claimed many lives across the world. A cure for the killer disease has yet to be found but research on treatments are continuous around the globe. Whether we are a step closer to finding a cure to this killer is unknown, but what's for sure is that there is no lack of support in the battle for our lives as major investors pulled through to give the fight the big push that it needs. During his State of The Union address earlier this year, US President Barack Obama that an additional funding will be made for cancer cure research. The Cancer Moonshot Task Force was led by Vice President Joe Biden whose involvement is more personal as his own son died of Brain Cancer in 2015. The President's moonshot goal of completely eradicating cancer was accompanied by a budget goal of $1 billion. More recently, the President signed a bill that will give way to a much bigger drug treatment research fund of $6.5 billion. As the President signed together with Moonshot head and Vice President Joe Biden, the 21st Century Cures Act will move to find cures for the medical challenges that are facing many people today. Following President Obama's moonshot goals, international firm Deloitte supported the initiative by sponsoring the XPRIZE for visionaries to submit their ideas and innovations not just for a cure to cancer, but for an early detection test, much like a pregnancy test. Led by oncologist Dr. Daniel Kraft, the initiative aims to bring visionaries together to look at the treatment, detection and treatment of cancer from every possible angle in a multi-disciplinary level to ensure speedy progress. Taking on a different angle to understanding cancer, Microsoft recently announced their plans to aid the battle against cancer by introducing their AI named Hanover. Microsoft's machine's main purpose is to ingest information about a particular type of cancer and give the best and possibly most effective combination of drugs. Cancer affects different people in different ways which means treatments are also personalized. With currently over 800 different types of drugs and vaccines in the market to combat the killer disease, doctors may find it difficult to provide the most effective combination of drugs for a particular patient and that is where Hanover comes in. Hanover is just one of Microsoft's projects in developing machine-based approaches to the study and treatment of cancer. Former president of Facebook and founder of Napster and Spotify Sean Parker recently founded the Parker Institute for Cancer Immunotherapy in finding a vaccine for cancer. This project is in collaboration with six research institutes and universities such as Caltech and the Dana Farber Cancer Institute. With Parker's investment of $250 million, the goal of this collaboration aims to use algorithms to find cancer markers and take on a genetic view of not just cancer treatment, but cancer immunization. Just calling it a "moonshot" expresses how difficult the battle is, but what's hopeful about these efforts is not just the amount of money put into funding research which indicates the level of importance that is placed on this endeavor, but the fact that we are still ready to fight. © 2017 Tech Times, All rights reserved. Do not reproduce without permission.
News Article | March 1, 2017
CAMBRIDGE, Mass., March 01, 2017 (GLOBE NEWSWIRE) -- Leap Therapeutics, Inc. (Nasdaq:LPTX), a biotechnology company developing targeted and immuno-oncology therapeutics, today announced preclinical and clinical data presentations will be made during the 2017 American Association for Cancer Research (AACR) Annual Meeting, being held April 1 - 5, 2017, in Washington, D.C. Data on TRX518 will be presented as an oral presentation in a clinical trials plenary session by Roberta Zappasodi, Ph.D., Parker Institute Scholar and Research Scholar in the Ludwig Collaborative Laboratory at Memorial Sloan Kettering Cancer Center from the lab of Taha Merghoub, Ph.D., Associate Attending Lab Member of the Ludwig Collaborative Laboratory at the Memorial Sloan Kettering Cancer Center and Jedd Wolchok, M.D. Ph.D., Chief of Melanoma and Immunotherapeutics Service at Memorial Sloan Kettering Cancer Center. Abstract Number and Title: #CT018, Intratumor and peripheral Treg modulation as a pharmacodynamic biomarker of the GITR agonist antibody TRX-518 in the first in-human trial Session Title: Immuno-oncology Biomarkers in Clinical Trials Session Date and Time: Sunday Apr 2, 2017 3:28 PM - 3:43 PM Session Location: Hall D-E, Level 2, Washington Convention Center Abstract Number and Title: #369, Therapeutic targeting of the Wnt antagonist DKK1 with a humanized monoclonal antibody in oncology indications Session Title: Cell Growth Signaling Pathways 2 Session Date and Time: Sunday Apr 2, 2017 1:00 PM - 5:00 PM Session Location: Convention Center, Halls A-C, Poster Section 15 About Leap Therapeutics Leap Therapeutics’ (NASDAQ:LPTX) most advanced clinical candidate, DKN-01, is a humanized monoclonal antibody targeting the Dickkopf-1 (DKK1) protein. DKN-01 is in clinical trials in patients with gastroesophageal cancer in combination with paclitaxel and in patients with biliary tract cancers in combination with gemcitabine and cisplatin. DKN-01 has demonstrated single agent activity in non-small cell lung cancer patients. Leap’s second clinical candidate, TRX518, is a novel, humanized GITR agonist monoclonal antibody designed to enhance the immune system’s anti-tumor response. For more information about Leap Therapeutics, visit http://www.leaptx.com or our public filings with the SEC that are available via EDGAR at http://www.sec.gov or via http://www.investors.leaptx.com/. Some of the statements in this release are forward looking statements within the meaning of Section 27A of the Securities Act of 1933, Section 21E of the Securities Exchange Act of 1934 and the Private Securities Litigation Reform Act of 1995, which involve risks and uncertainties. These statements relate to future events of Leap’s development of DKN-01, TRX518, and other programs, future expectations, plans and prospects. Although Leap believes that the expectations reflected in such forward-looking statements are reasonable as of the date made, expectations may prove to have been materially different from the results expressed or implied by such forward-looking statements. Leap has attempted to identify forward looking statements by terminology including ‘‘believes,’’ ‘‘estimates,’’ ‘‘anticipates,’’ ‘‘expects,’’ ‘‘plans,’’ ‘‘projects,’’ ‘‘intends,’’ ‘‘potential,’’ ‘‘may,’’ ‘‘could,’’ ‘‘might,’’ ‘‘will,’’ ‘‘should,’’ ‘‘approximately’’ or other words that convey uncertainty of future events or outcomes to identify these forward-looking statements. These statements are only predictions and involve known and unknown risks, uncertainties, and other factors. Any forward looking statements contained in this release speak only as of its date. We undertake no obligation to update any forward-looking statements contained in this release to reflect events or circumstances occurring after its date or to reflect the occurrence of unanticipated events.
News Article | February 17, 2017
PHILADELPHIA - For most vaccines to work the body needs two cell types - B cells and T helper cells - to make antibodies. B cells are the antibody factories and the T helper cells refine the strength and accuracy of antibodies to home and attack their targets. A technique that identifies these helper immune cells could inform future vaccine design, especially for vulnerable populations. Flu vaccines work by priming the immune system with purified proteins from the outer layer of killed flu viruses. An antibody is a protein that recognizes a unique pathogen molecule called an antigen that is specific for a particular strain. Antibodies bind to their targets with precision in the best of circumstances. In doing so, the antibody blocks a harmful microbe from replicating or marks it to be killed by other immune cells. The level of antibodies in the blood tells immunologists how well a vaccine is working, specifically, how many antibodies are made and how strongly they disable microbes. The relatively scarce circulating T follicular helper cells, or cTfh for short, are key to antibody strength. Without Tfh, effective antibodies cannot be made, yet very little is known about cTfh cells in humans after vaccination. Now, a team led by researchers from the Perelman School of Medicine at the University of Pennsylvania has found a way to identify the small population of cTfh present in the blood after an annual flu vaccine to monitor their contribution to antibody strength. They published their findings in Science Immunology this week. The studies, led by Ramin Herati, MD, an instructor of Infectious Disease, used high dimensional immune-cell profiling and specific genomic tests to identify and track these rare cells over time. "The poor understanding of cTfh function is, in part, because these cells spend most of their time waiting in lymph nodes for the next infection, and not circulating in the blood," said senior author E. John Wherry, PhD, a professor of Microbiology and director of the Institute of Immunology at Penn. "To get a handle on how well these cells are doing their job following vaccination, we have needed a way to measure their responses without gaining direct access to lymph nodes. Because of the central role of circulating T follicular helper cells in antibody development, new vaccine development strategies will benefit from a better understanding of the properties of these essential cells in the immune response." Every T cell has a unique receptor on its outer surface. After receiving a vaccine, the result is one T cell with this unique bar code of sorts that replicates, making thousands of clones with identical copies of the same bar code. After vaccination this expansion of T cells dies down and a few clones remain behind. These memory cells wait it out in lymph nodes and other organs for the next time the infection or vaccine enters the body. These clones can then be called into action to protect the individual or help boost the vaccine immunity. In the current study, the team was able to track circulating helper T cells because the unique bar code they possessed is specific to the strains used in an annual flu vaccine. Wherry and colleagues traced antibody production in 12 healthy subjects, aged 20 to 45 for three years from 2013 to 2105. The circulating subset of helper follicular T cells expressed different transcription factors and cytokines -- Bcl-6, c-Maf, and IL-21 - compared to other T-cell subpopulations in the blood. The number of the cTfh cells sharply increased at seven days after a subject received a flu shot. Repeated vaccination of the study participants brought back genetically identical clones of cTfh cells in successive years, indicating robust cTfh memory to the flu vaccine. These responses are a proxy for specific antibodies to the flu vaccine each year. In addition, these results measure the dynamics of vaccine-induced cTfh memory and recall over time, allowing investigators to monitor the key human-vaccine-induced cTfh responses and gain insights into why responses to flu vaccines are suboptimal in many people. The ability to track these cTfh responses in the blood, instead of accessing lymph nodes in humans, allows for real-time monitoring of key cellular mechanisms involved in vaccination. Such knowledge should allow further optimization of vaccines for hard-to-treat diseases like the flu, but also HIV, and other infections in which inducing potent vaccines has been a challenge. "These cTfh are a missing piece of being able to truly monitor and predict their ability to induce the desired magnitude and quality of immune memory, and therefore protection by vaccines," Wherry said. The team next intends to look at elderly populations in which vaccines are not as effective and ask what role cTfh cell populations play in that part of the human population. This research was supported by the National Institutes of Health (AI114852, AG047773, AG028716, AI113047, AI108686, AI112521, AI117950, AI2010085), the Penn Center for AIDS Research (P30 AI045008), and the U.S. Broad Agency Announcement (HHSN272201100018C). E. John Wherry is a member of the Parker Institute for Cancer Immunotherapy, which supports the Penn Cancer Immunotherapy Program. Penn Medicine is one of the world's leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System, which together form a $5.3 billion enterprise. The Perelman School of Medicine has been ranked among the top five medical schools in the United States for the past 18 years, according to U.S. News & World Report's survey of research-oriented medical schools. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $373 million awarded in the 2015 fiscal year. The University of Pennsylvania Health System's patient care facilities include: The Hospital of the University of Pennsylvania and Penn Presbyterian Medical Center -- which are recognized as one of the nation's top "Honor Roll" hospitals by U.S. News & World Report -- Chester County Hospital; Lancaster General Health; Penn Wissahickon Hospice; and Pennsylvania Hospital -- the nation's first hospital, founded in 1751. Additional affiliated inpatient care facilities and services throughout the Philadelphia region include Chestnut Hill Hospital and Good Shepherd Penn Partners, a partnership between Good Shepherd Rehabilitation Network and Penn Medicine. Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2015, Penn Medicine provided $253.3 million to benefit our community.
News Article | December 1, 2016
PHILADELPHIA--An existing drug known as a JAK inhibitor may help patients who don't respond to the so-called checkpoint inhibitor immunotherapy drugs overcome that resistance, suggests a new preclinical study published online in Cell today by Penn Medicine researchers. Importantly, the results demonstrate that shutting down the interferon pathway, shown here to be critical to a tumor's resistance to immunotherapy, with a JAK inhibitor may improve checkpoint inhibitor drugs and even bypass the need for combinations of these drugs, which often come with serious side effects. Today's checkpoint inhibitor drugs target receptors such as PD1 and CTLA-4, which act as a type of "off switch" on a T cell to prevent it from attacking other cells. Inhibiting these pathways with one or a more of the drugs releases these "brakes" so the immune system can fight the disease. However, over half of patients on the drugs relapse or their cancer progresses. "The proposed approach has some elegance to it - rather than try to figure out all inhibitory pathways that the tumor has enabled, find a critical pathway that regulates many of the inhibitory signals and cripple that instead," said senior author Andy J. Minn, MD, PhD, an assistant professor of Radiation Oncology in the Perelman School of Medicine at the University of Pennsylvania. "Interferon signaling is like a critical node in a network. Disable it and a large part of that network collapses." Using breast cancer and melanoma mouse models, Minn, first-author Joseph L. Benci, a graduate student in Penn's Cell and Molecular Biology Graduate Group, and their colleagues from the departments of Radiation Oncology, Abramson Family Cancer Research Institute and Penn's Parker Institute for Cancer Immunotherapy showed that prolonged interferon signaling in tumor cells increased resistance to checkpoint inhibitors through multiple inhibitory pathways, and that blocking this response resulted in improved survival and powerful tumor responses. Authors on the paper also include Robert Vonderheide, MD, DPhil, the Hanna Wise Professor in Cancer Research, Amit Maity, MD, PhD, a professor of Radiation Oncology, and E. John Wherry, PhD, a professor of Microbiology and director of the Institute for Immunology at Penn. Studies have shown that combining checkpoint inhibitors, ipilimumab and pembrolizumab, for instance, as well as adding radiation therapy, as described in a Penn paper from the same researchers in Nature in 2015, elicits promising tumor responses in patients. But many still do not respond because of additional unidentified "brakes." Researchers modeled this unknown resistance in breast cancer and melanoma mouse models with various lab techniques, including the genetic tool CRISPR, and found that treating the mice with checkpoint inhibitors (against PD1 and/or CTLA4) with or without radiation, along with the JAK inhibitor ruxolitinib, effectively restored complete responses and long-term survival in mice with tumors that are normally highly resistant to therapy. Inhibiting this pathway could also bypass the need for multiple checkpoint inhibitors: one checkpoint inhibitor (anti-CTLA4) and the JAK inhibitor in the breast cancer mouse model resulted in a 100 percent complete response and survival. JAK inhibitors, U.S. Food and Drug Administration-approved drugs to treat myelofibrosis and psoriasis, target the well-studied interferon pathway, typically considered to be immunostimulatory. However, the authors found that over time interferon signaling changes how cells respond epigenetically to molecular signals in the tumor, switching from stimulatory to suppressive, similar to what happens in a chronic viral infection. Thus, blocking it switched off the tumor's resistance in mice. "To our surprise, blocking interferon driven resistance not only antagonizes multiple inhibitory pathways that hinders combination therapies in mice," Minn said, "but it may also provide a general strategy to the challenge of designing complex combination checkpoint blockade therapies that seek to address the well-known problem of resistance." Downgrading the number of checkpoint inhibitors for therapy has its advantages, given the severe and sometimes life-threatening toxicities that come along with combination therapies, including autoimmune complications such as colitis and fatal myocarditis. "There is a real translational implication here," Minn said. "Because the interferon signaling pathway is targetable pharmacologically, we could perhaps mimic what we did in mice using JAK inhibitors that already exist for other purposes." The team is looking to begin a new clinical study in lung cancer patients based on their findings in the upcoming months. The researchers also identified two potential biomarkers, MX1 and IFIT1, that may help identify tumors in patients under the influence of this interferon suppression. Other Penn co-authors include Bihui Xu, Yu Qiu, Tony J. Wu, Hannah Dada, Christina Twyman-Saint Victor, Lisa Cucolo, David S.M. Lee, Kristen E. Pauken, Alexander C. Huang, Tara C. Gangadhar,2 Ravi K. Amaravadi, Lynn M. Schuchter, Michael D. Feldman, and Hemant Ishwaran. The study was supported by a grant in part by the Melanoma Research Alliance, the Parker Institute for Cancer Immunotherapy, Robertson Foundation/Cancer Research Institute Irvington Fellowship, the National Institutes of Health and the National Cancer Institute (P50CA174523, P30CA016520, R01CA163739, R01CA158186, R01CA172651, U19AI082630, R01AI105343, U01AI095608, and P01AI112521), the Basser Research Center for BRCA, the Abramson Cancer Center Translational Center of Excellence in Pancreatic Cancer, the Department of Defense Era of Hope Scholar (W81XWH-09-1-0339), and Merck. Penn Medicine is one of the world's leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System, which together form a $5.3 billion enterprise. The Perelman School of Medicine has been ranked among the top five medical schools in the United States for the past 18 years, according to U.S. News & World Report's survey of research-oriented medical schools. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $373 million awarded in the 2015 fiscal year. The University of Pennsylvania Health System's patient care facilities include: The Hospital of the University of Pennsylvania and Penn Presbyterian Medical Center -- which are recognized as one of the nation's top "Honor Roll" hospitals by U.S. News & World Report -- Chester County Hospital; Lancaster General Health; Penn Wissahickon Hospice; and Pennsylvania Hospital -- the nation's first hospital, founded in 1751. Additional affiliated inpatient care facilities and services throughout the Philadelphia region include Chestnut Hill Hospital and Good Shepherd Penn Partners, a partnership between Good Shepherd Rehabilitation Network and Penn Medicine. Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2015, Penn Medicine provided $253.3 million to benefit our community.
News Article | November 12, 2016
CAMBRIDGE, Mass.--(BUSINESS WIRE)--Leap Therapeutics, Inc. today announced the presentation of data from its Phase 1 clinical trial of TRX518 in patients with advanced relapsed or refractory solid tumors. Roberta Zappasodi, Ph.D., Parker Institute Scholar and Research Scholar in the Ludwig Collaborative Laboratory at Memorial Sloan Kettering Cancer Center, a site participating in the Phase 1 study, led an oral presentation during the Presidential Session entitled “Analysis of pharmacodynamic bi
News Article | April 20, 2016
Future health spend The provision of aid for global health has stagnated since the 2008 financial crisis, following years of increases during the early 2000s, and international health-spending inequalities will persist as a result, predicts a report (J. L. Dieleman et al. Lancet http://doi.org/bfdr; 2016). In a companion report, data extrapolated from health spending between 1995 and 2013 suggest that nearly half of low- and lower-middle-income countries are likely to miss an internationally agreed goal to spend at least US$86 per person on health by 2040 (J. L. Dieleman et al. Lancet http://doi.org/bfds; 2016). By that time, the wealthiest countries will spend an average of $9,019 per person on health, compared with $164 per person by the poorest countries. Earthquakes strike Ecuador and Japan A magnitude-7.8 earthquake struck Ecuador’s coast on 16 April, collapsing buildings and killing hundreds of people. The death toll was 413 as Nature went to press. It was the country’s most powerful quake since 1979 and it devastated towns near the coast. Separately, a series of shallow earthquakes shook Japan’s Kyushu island last week, culminating in a magnitude-7 tremor on 16 April that killed at least 42 people. Buildings including a student residence, as well as turrets on a seventeenth-century castle, collapsed in Kumamoto prefecture. Zika link declared The US Centers for Disease Control and Prevention (CDC) has declared that the mosquito-borne Zika virus causes microcephaly — babies born with abnormally small heads — and other fetal brain defects. The announcement, on 13 April, is based on a review of evidence by CDC researchers (see S. A. Rasmussen et al. http://doi.org/bfc2; 2016). The mosquito season in the southern US states is looming, and the agency says that strong causal messages will reinforce advice about precautions. Some scientists caution that the proof is not yet unequivocal, but that the CDC is justified in erring on the side of caution. Antarctic cruise Swiss coordinators of the planned international Antarctic Circumpolar Expedition announced on 18 April the 22 scientific projects selected to take place on the research cruise. On 20 December, a 55-strong research crew involving scientists from 30 countries will set out from Cape Town on a three-month voyage on board the Russian research vessel Akademik Treshnikov. The scientists hope to extensively probe the Southern Ocean and map unexplored biota around Antarctica. The expedition is largely funded by the Swedish philanthropist Frederik Paulsen, founder of Ferring Pharmaceuticals. Vaccine switch Between 17 April and 1 May, 155 countries will introduce a new kind of polio vaccine as part of a global push to eradicate the disease. The switch will replace a ‘trivalent’ vaccine against the three serotypes of poliovirus with a more effective vaccine that targets the two types of virus that are still circulating. Just 10 cases of polio caused by a wild virus have been reported this year, in Pakistan and Afghanistan. Whales threat Marine-mammal experts have urged US President Barack Obama to halt permits for seismic oil and gas surveys along the mid- and southeastern US Atlantic coast. Fewer than 500 North Atlantic right whales (Eubalaena glacialis, pictured) remain in the wild, 27 right-whale experts from the United States, Canada and Britain said in a 14 April letter to Obama. Noise pollution from the airgun blasts used to return information about oil and gas deposits would affect the animals on important feeding and breeding grounds, the letter says. Glyphosate rule The European Parliament has called on the European Commission to restrict its marketing authority for the widely used herbicide glyphosate to seven years, amid controversy over whether the chemical may be harmful to health. The commission had instead proposed a 15-year renewal of the authority — which expires in June — to market glyphosate in European Union member states. Parliament’s resolution on 13 April also calls for a new independent safety review and a restriction of glyphosate use in public areas. The resolution has no legal authority, but might influence a May vote by member states on the proposal. CRISPR crops The US Department of Agriculture said on 13 April that it will not regulate a mushroom genetically modified with the CRISPR–Cas9 gene-editing tool. The mushroom can now be cultivated and sold without passing through the agency’s regulatory process; it is the first CRISPR-edited organism to receive a green light from the US government (see page 293). And on 18 April, DuPont Pioneer in Johnston, Iowa, announced plans to commercialize high-starch varieties of maize (corn) that have been genetically modified with CRISPR to boost yields. The company aims to have the maize available within five years. Untested drug Brazil’s President Dilma Rousseff has signed a law allowing patients to access an untested, unapproved compound that some claim is a miracle cure for cancer. The law, which went into effect on 14 April, allows those with a certificate verifying that they have cancer to obtain the drug; no prescription is required. The news came just weeks after Brazil’s Ministry of Science, Technology and Innovation released laboratory results showing that the compound does not kill cancer cells grown in culture. See go.nature.com/gwzswx for more. Warming review The Intergovernmental Panel on Climate Change will review the possible effects on humans and ecosystems of a rise in global temperature of 1.5 °C above pre-industrial levels. At a meeting on 11–13 April in Nairobi, the group agreed to produce three special reports: one looking at the impacts of 1.5 °C of warming, with the other two assessing the impacts of climate change on land use and terrestrial ecosystems, and on oceans, glaciers and polar ice sheets. See go.nature.com/aq3yhf for more. Green light The European Space Agency’s ambitious plans to build a space-based gravitational-wave detector are feasible and the mission could launch sooner than planned, an expert panel reported on 12 April (see Nature 531, 30; 2016). The chair of the Gravitational Observatory Advisory Team, University College Dublin physicist Michael Perryman, told the BBC that the group will suggest a launch in 2029, which would bring forward the proposed start date of the €1-billion (US$1.1‑billion) mission by 5 years. Exxon sponsorship The board of the American Geophysical Union (AGU) has decided to continue to accept sponsorship money from the oil and gas giant ExxonMobil, despite a February letter from more than 170 AGU members and others complaining about the company’s past role in spreading climate misinformation. “We concluded that it is not possible for us to determine unequivocally whether ExxonMobil is participating in misinformation about science currently,” AGU president Margaret Leinen wrote in a blog post on 14 April describing the board’s vote. Last year, the AGU accepted US$35,000 in support from ExxonMobil. Cancer institute The Parker Foundation, a charity in San Francisco, California, has committed US$250 million to harnessing the immune system to fight cancer. The money will support more than 40 laboratories at 6 centres of medical research, which together will form the Parker Institute for Cancer Immunotherapy, the foundation announced on 12 April. The institute — to be led by immunologist Jeffrey Bluestone of the University of California, San Francisco — will manage any intellectual property that emerges from the collaboration. The area planted globally with genetically modified (GM) crops declined in 2015. The 1% decline — the first in the technology’s 20-year global commercial history — was primarily due to a decrease in both GM and non-GM crops caused by low prices, says the body that tracks such crops. But the International Service for the Acquisition of Agri-Biotech Applications also said in its 13 April report that major growers of GM crops, such as the United States, are approaching saturation. 21 April The United Nations hosts a high-level debate on implementing its sustainable development goals for 2030, in New York. go.nature.com/ku8o5l 22 April Sentinel-1B, a radar observation satellite developed by the European Space Agency, will launch from Sinnamary, French Guiana. go.nature.com/9pmfp7 The Paris Agreement on climate change, adopted in December, will be signed in New York. go.nature.com/7fpxfw
News Article | October 29, 2016
Checkpoint inhibitor drugs that boost the immune system to fight cancer owe part of their existence to infectious diseases. Microbes that cause diseases like HIV, malaria, and hepatitis C exploit and often activate the same checkpoint pathways -- cell surface receptors such as CTLA4 and PD-1 -- to slow immune cells and prevent their elimination by the host. T cells that are supposed to clear an infection, instead, become "exhausted." The cell-surface receptors naturally act like brakes to tell the immune system to not react as strongly during normal situations and help the immune system avoid damaging healthy tissue or causing autoimmunity. Blocking PD-1 can reinvigorate exhausted T cells and improve control of chronic infections and cancer. However, whether blocking PD-1 can reprogram exhausted T cells into durable memory T cells is unclear. E. John Wherry, PhD, director of the Institute for Immunology at Penn and the Barbara and Richard Schiffrin President's distinguished professor of Microbiology, in the Perelman School of Medicine at the University of Pennsylvania, and colleagues found that reinvigorating exhausted T cells in mice using a PD-L1 blockade caused very few T memory cells to develop. After the blockade, re-invigorated T cells became re-exhausted if antigen from the virus remained high, and failed to become memory T cells when the virus was cleared. They published their findings in this week's issue of Science. The team found that exhausted T cells acquired an epigenetic profile distinct from effector or memory T cells. These latter two cell types can mount effective immune responses to viruses and tumors; whereas, exhausted T cells fail and memory T cells, in particular, for long-lasting durable effects. Epigenetics is the way chemical modifications to DNA and the proteins binding DNA determine which genes are expressed by a cell type. Epigenetic profiles can be highly stable and confer long-term identity to a cell. (In other words, the reason a liver cell stays a liver cell and doesn't become a lung cell is due largely to epigenetics since both liver and lung cells have the same genes.) "What these new findings on exhausted T cells tells us is that the unique epigenetic profile of exhausted T cells causes these cells to express a different overall set of genes compared to memory or effector T cells," Wherry said. However, this epigenetic pattern was only minimally changed following the PD-L1 blockade. This prevented these exhausted T cells from changing into the more protective effector or memory cell types. "We were surprised that the exhausted T cell epigenetic profile was not reprogrammed," Wherry said. "Instead, the benefit we see after PD-1 pathway blockade is caused by only transient changes in gene expression that is not durable, rather than permanent epigenetic reprogramming." These findings suggested that exhausted T cells are a distinct lineage of T cells in and of themselves instead of just being effector or memory T cells restrained by checkpoint pathways. "We predicted that exhausted T cells would not have a distinct epigenetic profile but have the molecular flexibility to obtain immune memory," Wherry said. "But we found that exhausted T cells are quite set in their ways." "We think this shows that epigenetic fate inflexibility may limit current immunotherapies based on PD-1 checkpoint inhibitors," said first author Kristen Pauken, PhD, a postdoctoral researcher in the Wherry lab. Most cancer patients respond well to PD-1 blockades at first, but the response is not sustained. This study shows how exhausted T cells do not maintain a durable switch to an effector T cell profile, although in the clinic, checkpoint inhibitors are well tolerated and their side effects such as autoimmunity are usually manageable. This lack of durability clinically is not well characterized, but these results suggest it is likely, at least partially, due to the lack of sustained or permanent reprogramming of exhausted T cells. In a companion study also published in Science, Nick Haining, MD, and colleagues from Dana-Farber Cancer Institute, also found a distinct epigenetic landscape for exhausted T cells in mice and humans, and they were able to ascribe key functions in T cell exhaustion to some of these epigenetic changes. Wherry and Pauken are co-authors on this study. Wherry, together with his colleagues in the Parker Institute for Cancer Immunotherapy at Penn, are involved in multiple checkpoint-related trials, in melanoma, lung cancer, renal cell carcinoma, and others, including combining checkpoint blockade with radiation. The ultimate goal is to precisely understand the mechanisms of checkpoint blockade effectiveness and bring next generation, sustainable immunotherapies to even more patients, perhaps using by using epigenetic drugs in combination with checkpoint blockade to allow epigenetic reprogramming of exhausted T cells into durable and functional memory T cells.