La Jolla Institute
La Jolla Institute
News Article | May 16, 2017
La Jolla, Calif., May 16, 2017 -- New research led by Alexey Terskikh, Ph.D., associate professor at Sanford Burnham Prebys Medical Discovery Institute (SBP), and Alex Strongin, Ph.D., professor at SBP, could be a first step toward a drug to treat Zika infections. Publishing in Antiviral Research, the scientific team discovered a compound that prevents the virus from spreading. "We identified a small molecule that inhibits the Zika virus protease, and show that it blocks viral propagation in human cells and in mice," Terskikh says. "Anti-Zika drugs are desperately needed. The fact that the compound seems to work in vivo is really promising, so we plan to use it as a starting point to make an even more potent and effective drug." The Zika virus has been declared a public health emergency of international concern by the World Health Organization, a rare designation indicating that a coordinated global response is needed. The reason Zika is considered such a threat is that it's spreading rapidly through the Americas, including parts of the U.S., and can cause severe complications. Zika has been linked to an increase in cases of microcephaly, a birth abnormality in which the head and brain are unusually small, and Guillain-Barre syndrome, a rapidly developing neurological condition that causes weakness of the arms and legs and can progress to life-threatening respiratory failure. "Microcephaly is likely just the tip of the iceberg in terms of the potential adverse effects of maternal Zika infection," comments Terskikh. "There may be other, less obvious impacts on brain development that wouldn't be apparent until later. That's something we're also investigating." The scientific team took advantage of a library of compounds that Strongin's lab had previously shown to inhibit the same component of the related West Nile virus. They also tested structurally similar molecules available at the SBP's Conrad Prebys Center for Chemical Genomics (Prebys Center) to determine whether any also blocked the protease. The screening process identified three promising compounds, which were then tested for their ability to prevent Zika infection of human brain cells. The best one of these also reduced the amount of virus circulating in the blood of Zika-infected mice. "The inhibitor's efficacy in animals is the key to the study's significance," Terskikh adds. "This, and the fact that the compound is likely to be safe make it especially promising. The compound blocks a part of the protease that's unique to viruses, so it doesn't inhibit similar human proteases. It's also much more potent than previously identified inhibitors of the Zika protease." This future drug is just one part of the fight against Zika. An experimental vaccine is set to move into phase 2 clinical trials in June. "In addition to a Zika vaccine, we still need antivirals," explains Terskikh. "Some people may be exposed who haven't been vaccinated. Having a way to treat the infection could help stop Zika from spreading and prevent its sometimes devastating effects." This research was performed in collaboration with scientists at the La Jolla Institute for Allergy & Immunology. Funding was provided by the National Institutes of Health (R21NS10047). Sanford Burnham Prebys Medical Discovery Institute (SBP) is an independent nonprofit medical research organization that conducts world-class, collaborative, biological research and translates its discoveries for the benefit of patients. SBP focuses its research on cancer, immunity, neurodegeneration, metabolic disorders and rare children's diseases. The Institute invests in talent, technology and partnerships to accelerate the translation of laboratory discoveries that will have the greatest impact on patients. Recognized for its world-class NCI-designated Cancer Center and the Conrad Prebys Center for Chemical Genomics, SBP employs about 1,100 scientists and staff in San Diego (La Jolla), Calif., and Orlando (Lake Nona), Fla. For more information, visit us at SBPdiscovery.org or on Facebook at facebook.com/SBPdiscovery and on Twitter @SBPdiscovery.
News Article | May 8, 2017
The initial study will assess immune responses of 10 healthy adults (ages 40-80) to a licensed hepatitis B vaccine. It will feature one of the most comprehensive analyses of how people respond to vaccinations to learn why some individuals are protected from a single dose, while others are not. The study will expand to include several hundred people – from neonates to the elderly in middle and low-income countries. "Developing a better understanding of why some groups of people are protected from disease is a goal that simply must be achieved," said Co-Principal Investigator Tobias Kollmann, M.D., Ph.D., professor of pediatrics at the University of British Columbia (UBC) and an investigator at the Vaccine Evaluation Center in Vancouver, Canada. "The licensed hepatitis B vaccine, which only works in about 30 percent of people on the first shot, is an ideal model vaccine to study general principles of human immunological protection because it is one of the few vaccines for which we know how it protects." The study will take place at the at the Vaccine Evaluation Center, in Vancouver, Canada, and will be augmented by extensive immunological and bioinformatic analyses at the Project's San Diego Mesa Consortium, which includes the J. Craig Venter Institute, the La Jolla Institute, The Scripps Research Institute, and UC San Diego, with clinical coordination by the Vanderbilt Institute for Clinical and Translational Research. "With technological advances in biomedical, computational and engineering sciences, we have an unprecedented opportunity to decipher the immune system's components and core principles required to generate long-lasting immunity against disease, and usher in a new era of global health," added Stanley Plotkin, M.D., Chairman of the Human Vaccines Project's Board of Directors. About the Human Vaccines Project| The Human Vaccines Project is a nonprofit public-private partnership with a mission to decode the human immune system to accelerate the development of vaccines and immunotherapies against major infectious diseases and cancers. The Project brings together leading academic research centers, industrial partners, nonprofits and governments to address the primary scientific barriers to developing new vaccines and immunotherapies. Support and funding for the Project includes the Robert Wood Johnson Foundation, John D. and Catherine T. MacArthur Foundation, GSK, Illumina, MedImmune, Sanofi Pasteur, Crucell/Janssen, Regeneron, Pfizer, Moderna, Boehringer Ingelheim, Aeras, Vanderbilt University Medical Center, UC San Diego, The Scripps Research Institute, J. Craig Venter Institute and La Jolla Institute for Allergy and Immunology. To learn more, visit www.humanvaccinesproject.org. For media inquiries, please contact Kierstin Coatney, Kierstin@globalgatewayadvisors.com or +1-716-378-1602. To view the original version on PR Newswire, visit:http://www.prnewswire.com/news-releases/new-study-aims-to-explain-the-rules-of-how-the-immune-system-works-300453028.html
News Article | June 1, 2017
EMERYVILLE, Calif.--(BUSINESS WIRE)--Gritstone Oncology, a next-generation personalized cancer immunotherapy company, today announced the expansion of its Scientific Advisory Board (SAB) with the appointment of James L. Gulley, M.D., Ph.D., chief of the Genitourinary Malignancies Branch at the Center for Cancer Research (CCR) of the National Cancer Institute (NCI), and Alessandro Sette, Dr.Biol.Sci., center head of the Division of Translational Immunology and Vaccine Discovery at the La Jolla Institute for Allergy and Immunology. Both are renowned experts in the field of immuno-oncology and will provide strategic guidance and insight to Gritstone as it advances its drug development technology platform to create personalized neoantigen therapies that harness the patient’s own immune system to attack solid tumors. “Successful neoantigen-targeted therapy demands excellence in two scientific dimensions, and we are thrilled to have global leaders in both of those domains join our team of scientific advisors,” said Andrew Allen, M.D., Ph.D., co-founder, president and chief executive officer of Gritstone Oncology. “First, we must predict which of a cancer patient’s many DNA mutations create truly neoantigenic proteins, and Alessandro has blazed the trail in understanding immune system-protein interactions. His fundamental insights have empowered companies like ours to consider tackling this problem and his counsel has already proven invaluable. Second, we must deliver tumor-specific neoantigens to patients in a highly immunogenic format. James has studied human immune responses to cancer immunotherapies for many years, deriving key observations into the link between immune response and clinical outcomes. The collective expertise of Alessandro and James will be essential as we advance our first personalized neoantigen immunotherapy into human trials and continue to assess solid tumors for their capacity to generate tumor-specific neoantigens.” “Tumor neoantigens are an exciting actionable discovery, and Gritstone Oncology has the right team of seasoned individuals in place to advance this scientific understanding to the next level in order to improve response rates and survival in cancer patients. The team has already made exceptional progress in the 20 months since the company was founded,” said Dr. Sette. “With my long-term interest in how T cells recognize antigens, I am excited to join Gritstone’s Scientific Advisory Board to help advance its novel therapeutic concept into clinical trials next year.” Dr. Gulley also serves as senior investigator and head of the Immunotherapy Section and director of the Medical Oncology Service in the Office of the Clinical Director at the CCR. He is an internationally recognized expert in cancer immunotherapy, therapeutic cancer vaccines, immune checkpoint inhibitors, and the combination of immunotherapy with other therapies. Since 1998, he has conducted investigator-initiated clinical trials at the NCI evaluating cancer vaccines and other immunostimulatory agents, as well as the combination of immunotherapy with other treatment strategies. He played a central role in the clinical development of a prostate cancer vaccine that was created at the NCI, and currently serves as principal investigator of an international, randomized Phase 3 clinical trial of that vaccine. He is also the coordinating principal investigator for an international trial of an anti-PDL1 antibody. Dr. Sette also serves as director of the Center for Infectious Disease and Head of the Initiative for Emerging Diseases and Biodefense at the La Jolla Institute for Allergy and Immunology. He has devoted more than 30 years of study to understanding basic mechanisms of antigen recognition and immune responses, measuring and predicting immune activity, and developing disease intervention strategies against cancer, infectious diseases, autoimmune diseases and allergies. His research is focused on improving the understanding of how the body successfully battles infection, and conversely, how pathogens escape the immune system, causing the individual to succumb to disease. He has developed techniques to understand the T-cell response to common allergens, which has resulted in the development of bioinformatic tools used to map the human T-cell response to a large panel of common allergens. Dr. Sette earned a Doctor in Biological Sciences at the University of Rome and completed post-doctoral work at the Laboratory of Pathology, Cassaccia, in Rome, and at the National Jewish Center for Immunology and Respiratory Medicine in Denver. He has authored more than 650 scientific publications in peer-reviewed journals and has nearly 30 issued patents. Gritstone’s SAB Comprised of Pioneers in Immuno-Oncology and Other Relevant Disciplines In addition to Drs. Gulley and Sette, other members of Gritstone Oncology’s distinguished Scientific Advisory Board include: Gritstone Oncology is a privately-held, next-generation personalized cancer immunotherapy company. Gritstone brings together distinguished scientific founders, an experienced and diverse management team, a seasoned and successful board of directors, and deep financial backing to tackle fundamental challenges at the intersection of cancer genomics, immunology and immunotherapy design. The company’s initial goal is to identify and deploy therapeutic neoantigens from individual patients’ tumor to develop novel treatments for lung cancer. Gritstone Oncology is headquartered in the San Francisco Bay Area with certain key functions located in Cambridge, Mass. The company launched in October 2015 with a Series A financing of $102 million from leading blue-chip biotechnology investors, including Versant Ventures, The Column Group and Clarus Ventures. More information can be found at www.gritstoneoncology.com.
News Article | June 20, 2017
LA JOLLA, CA -- For decades, HIV has successfully evaded all efforts to create an effective vaccine but researchers at The Scripps Research Institute (TSRI) and the La Jolla Institute for Allergy and Immunology (LJI) are steadily inching closer. Their latest study, published in the current issue of Immunity, demonstrates that optimizing the mode and timing of vaccine delivery is crucial to inducing a protective immune response in a preclinical model. More than any other factors, administering the vaccine candidate subcutaneously and increasing the time intervals between immunizations improved the efficacy of the experimental vaccine and reliably induced neutralizing antibodies. Neutralizing antibodies are a key component of an effective immune response. They latch onto and inactive invading viruses before they can gain a foothold in the body and have been notoriously difficult to generate for HIV. "This study is an important staging point on the long journey toward an HIV vaccine," says TSRI Professor Dennis R. Burton, Ph.D, who is also scientific director of the International AIDS Vaccine Initiative (IAVI) Neutralizing Antibody Center and of the National Institutes of Health's Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (CHAVI-ID) at TSRI. "The vaccine candidates we worked with here are probably the most promising prototypes out there, and one will go into people in 2018," says Burton. "There had been a lot of big question marks and this study was designed to get as many answers as possible before we go into human clinical trials," adds senior co-author Shane Crotty, Ph.D., a professor in LJI's Division of Vaccine Discovery. "We are confident that our results will be predictive going forward." HIV has faded from the headlines, mainly because the development of antiretroviral drugs has turned AIDS into a chronic, manageable disease. Yet, only about half of the roughly 36.7 million people currently infected with HIV worldwide are able to get the medicines they need to control the virus. At the same time, the rate of new infections has remained stubbornly high, emphasizing the need for a preventive vaccine. The latest findings are the culmination of years of collaborative and painstaking research by a dozen research teams centered around the development, improvement, and study of artificial protein trimers that faithfully mimic a protein spike found on the viral surface. At the core of this effort is the CHAVI-ID immunogen working group, comprised of TSRI's own William R. Schief, Ph.D., Andrew B. Ward, Ph.D., Ian A. Wilson, D.Phil. and Richard T. Wyatt, Ph.D., in addition to Crotty and Burton. This group of laboratories in collaboration with Darrell J. Irvine, Ph.D., professor at MIT, and Rogier W. Sanders, Ph.D., professor at the University of Amsterdam, provided the cutting-edge immunogens tested in the study. The recombinant trimers, or SOSIPs as they are called, were unreliable in earlier, smaller studies conducted in non-human primates. Non-human primates, and especially rhesus macaques, are considered the most appropriate pre-clinical model for HIV vaccine studies, because their immune system most closely resembles that of humans. "The animals' immune responses, although the right kind, weren't very robust and a few didn't respond at all," explains Colin Havenar-Daughton, Ph.D., a scientific associate in the Crotty lab. "That caused significant concern that the immunogen wouldn't consistently trigger an effective immune response in all individuals in a human clinical trial." In an effort to reliably induce a neutralizing antibody response, the collaborators tested multiple variations of the trimers and immunization protocols side-by-side to determine the best strategy going forward. Crotty and Burton and their colleagues teamed up with Professor Dan Barouch, M.D., Ph.D., Director of the Center for Virology and Vaccine Research at Beth Israel Deaconess Medical Center, who coordinated the immunizations. The design of the study was largely guided by what the collaborators had learned in a previous study via fine needling sampling of the lymph nodes, where the scientists observed follicular helper T cells help direct the maturation steps of antibody-producing B cells. Administering the vaccine subcutaneously versus the more conventional intramuscular route, and spacing the injection at 8 weeks instead of the more common 4-6 weeks, reliably induced a strong functional immune response in all animals. Using an osmotic pump to slowly release the vaccine over a period of two weeks resulted in the highest neutralizing antibody titers ever measured following SOSIP immunizations in non-human primates. While osmotic pumps are not a practical way to deliver vaccines, they illustrate an important point. "Depending on how we gave the vaccine, there was a bigger difference due to immunization route than we would have predicted," says Matthias Pauthner, a graduate student in Burton's lab and the study's co-lead author. "We can help translate what we know now into the clinic." "Elicitation of robust Tier 2 neutralizing antibody responses in non-human primates by HIV envelope trimer immunization using optimized approaches." Matthias Pauthner, Colin Havenar-Daughton, Devin Sok, Joseph P. Nkolola, Raiza Bastidas, Archana V. Boopathy, Diane G. Carnathan, Abishek Chandrashekar, Kimberly M. Cirelli, Christopher A. Cottrell, Alexey M. Eroshkin, Javier Guenaga, Kirti Kaushik, Daniel W. Kulp, Junyan Liu, Laura E. McCoy, Aaron L. Oom, Gabriel Ozorowski, Kai Post, Shailendra K. Sharma, Jon M. Steichen, Steven W. de Taeye, Talar Tokatlian, Alba Torrents de la Peña, Salvatore T. Butera, Celia C. LaBranche, David C. Montefiori, Guido Silvestri, Ian A. Wilson, Darrell J. Irvine, Rogier W. Sanders, William R. Schief, Andrew B. Ward, Richard T. Wyatt, Dan H. Barouch, Shane Crotty and Dennis Burton. Immunity (2017). Doi: 10.1016/j.immuni.2017.05.007 The study was supported by the National Institutes of Health (NIAID-NIH Contract Number HHSN27201100016C) and CHAVI-ID (NIAID UM1AI100663). About La Jolla Institute for Allergy and Immunology The La Jolla Institute for Allergy and Immunology is dedicated to understanding the intricacies and power of the immune system so that we may apply that knowledge to promote human health and prevent a wide range of diseases. Since its founding in 1988 as an independent, nonprofit research organization, the Institute has made numerous advances leading toward its goal: life without disease. The Scripps Research Institute (TSRI) is one of the world's largest independent, not-for-profit organizations focusing on research in the biomedical sciences. TSRI is internationally recognized for its contributions to science and health, including its role in laying the foundation for new treatments for cancer, rheumatoid arthritis, hemophilia, and other diseases. An institution that evolved from the Scripps Metabolic Clinic founded by philanthropist Ellen Browning Scripps in 1924, the institute now employs more than 2,500 people on its campuses in La Jolla, CA, and Jupiter, FL, where its renowned scientists--including two Nobel laureates and 20 members of the National Academies of Science, Engineering or Medicine--work toward their next discoveries. The institute's graduate program, which awards PhD degrees in biology and chemistry, ranks among the top ten of its kind in the nation. In October 2016, TSRI announced a strategic affiliation with the California Institute for Biomedical Research (Calibr), representing a renewed commitment to the discovery and development of new medicines to address unmet medical needs. For more information, see http://www. .
News Article | June 19, 2017
Underground Elephant, an award-winning digital marketing technology company located in downtown San Diego, announced today that it will host the IMPACT seminar with local innovators on Wednesday, June 21 at the Underground Elephant headquarters. IMPACT brings together San Diego researchers, entrepreneurs and innovation partners at the top of their field to discuss exciting scientific advances, latest trends and debate new industry research. The format will rotate between impact talks by scientists making life changing discoveries; panel discussions on trends in commercialization; and crossfire conversations with research and industry collaborators. “The IMPACT event will showcase groundbreaking research and innovations that are happening right here in our backyard,” said Jason Kulpa, CEO of Underground Elephant. “These visionaries are working on some of the most complex medical and scientific questions of our time. I’m honored to be able to help facilitate this conversation and learn from some of the most brilliant minds in the industry.” The event is sponsored by CONNECT, an organization dedicated to helping create and scale great innovation companies through access to the resources that entrepreneurs and growing companies need most – people, capital and technology. Speakers for the event include: Nicholas Cosford, Ph.D., Sanford Burnham Prebys Medical Discovery Institute; Reuben Shaw, Ph.D., Salk Institute for Biological Studies; Stephen P. Schoenberger, Ph.D., La Jolla Institute of Allergy and Immunology, San Diego Center for Cancer Immunotherapy, and Human Longevity, Inc.; and Valentino Gantz, Ph.D., UC San Diego. The event will be held from 5-7 p.m. at Underground Elephant headquarters (808 J Street San Diego, CA 92101). Tickets are $15 for CONNECT members and $30 for general admission, and can be purchased at http://www.connect.org/events/impact. Underground Elephant is also hosting a series of developer-focused seminars the week of June 19 for San Diego Startup Week. For more information about San Diego Startup Week, visit http://www.sandiegostartupweek.com. About Underground Elephant Founded by CEO Jason Kulpa in 2008, Underground Elephant is an award-winning marketing technology company that develops programmatic advertising platforms in order to bring transparency and efficiency to the buying and selling of structured lead generation. The company's robust portfolio of enterprise-grade tech solutions enhances the connection between enterprises and their prospective clients by delivering highly efficient pathways to organic sales conversations. Learn more at http://undergroundelephant.com/
News Article | June 19, 2017
Scientists have discovered a new type of immune cell that could predict which lung cancer patients will benefit most from immunotherapy treatment, according to a Cancer Research UK funded study published in Nature Immunotherapy. Researchers at the University of Southampton and La Jolla Institute for Allergy & Immunology, California, found that lung cancer patients with large amounts of a particular type of immune T-cell, called tissue-resident memory T-cells, in their tumour were 34 per cent less likely to die. The study also found that it was not just the numbers of cells that increased survival, but the cells' behaviour played a key role. The cells clustered together and 'took up residency' in a particular tissue, in this case the cancer tissue, to protect the patient. These new T-cells also produce other molecules that attack the tumour, meaning that the body's immune system could be more likely to hunt out and destroy cancer cells. Immunotherapies have shown great promise in the last decade, but identifying which patients respond to treatment and which don't has proven difficult. In future, testing for levels of these cells could help doctors identify which patients will benefit most from immunotherapies that help to ramp up the body's attack on the cancer. Scientists could take this one step further by using the T-cell as a template to develop a vaccine to boost immunotherapy even more -- helping to tackle one of the hardest to treat cancers. Professor Christian Ottensmeier, Cancer Research UK scientist at the University of Southampton, said: "These are hugely exciting results. For the first time we have a real indication of who might benefit from a particular drug before we make treatment decisions. So far when we use immunotherapy we do not know if a patient will benefit. The new findings are a big step towards making this exciting treatment much more predictable. "Our results will also make the treatment pathway more reassuring for our patients. And if we can translate our finding into clinical practice, then we will also save patients unnecessary side effects and reduce costs to the NHS." Around 35,600 people die from lung cancer each year in the UK, making it the most common cause of cancer death in the UK. Dr Justine Alford, senior science information officer at Cancer Research UK, said: "The immune system can play a powerful role in fighting lung cancer, and this research sheds more light on the interplay between cancer, our immune system, and immunotherapies. "Cancer Research UK is focusing more research on hard to treat cancers, like lung cancer, where survival has remained stubbornly low. And research like this is crucial to understanding why some people with lung cancer respond well to treatment and, in future, could guide more personalized treatments for patients."
News Article | June 21, 2017
Researchers have found the first direct evidence that autoimmunity -- in which the immune system attacks the body's own tissues -- plays a role in Parkinson's disease, the neurodegenerative movement disorder. The findings raise the possibility that the death of neurons in Parkinson's could be prevented by therapies that dampen the immune response. The study, led by scientists at Columbia University Medical Center (CUMC) and the La Jolla Institute for Allergy and Immunology, was published today in Nature. "The idea that a malfunctioning immune system contributes to Parkinson's dates back almost 100 years," said study co-leader David Sulzer, PhD, professor of neurobiology (in psychiatry, neurology and pharmacology) at CUMC. "But until now, no one has been able to connect the dots. Our findings show that two fragments of alpha-synuclein, a protein that accumulates in the brain cells of people with Parkinson's, can activate the T cells involved in autoimmune attacks. "It remains to be seen whether the immune response to alpha-synuclein is an initial cause of Parkinson's, or if it contributes to neuronal death and worsening symptoms after the onset of the disease," said study co-leader Alessandro Sette, Dr. Biol. Sci., professor in the Center for Infectious Disease at La Jolla Institute for Allergy and Immunology in La Jolla, Calif. "These findings, however, could provide a much-needed diagnostic test for Parkinson's disease, and could help us to identify individuals at risk or in the early stages of the disease." Scientists once thought that neurons were protected from autoimmune attacks. However, in a 2014 study, Dr. Sulzer's lab demonstrated that dopamine neurons (those affected by Parkinson's disease) are vulnerable because they have proteins on the cell surface that help the immune system recognize foreign substances. As a result, they concluded, T cells had the potential to mistake neurons damaged by Parkinson's disease for foreign invaders. The new study found that T cells can be tricked into thinking dopamine neurons are foreign by the buildup of damaged alpha-synuclein proteins, a key feature of Parkinson's disease. "In most cases of Parkinson's, dopamine neurons become filled with structures called Lewy bodies, which are primarily composed of a misfolded form of alpha-synuclein," said Dr. Sulzer. In the study, the researchers exposed blood samples from 67 Parkinson's disease patients and 36 age-matched healthy controls to fragments of alpha-synuclein and other proteins found in neurons. They analyzed the samples to determine which, if any, of the protein fragments triggered an immune response. Little immune cell activity was seen in blood samples from the controls. In contrast, T cells in patients' blood samples, which had been apparently primed to recognize alpha-synuclein from past exposure, showed a strong response to the protein fragments. In particular, the immune response was associated with a common form of a gene found in the immune system, which may explain why many people with Parkinson's disease carry this gene variant. Dr. Sulzer hypothesizes that autoimmunity in Parkinson's disease arises when neurons are no longer able to get rid of abnormal alpha-synuclein. "Young, healthy cells break down and recycle old or damaged proteins," he said. "But that recycling process declines with age and with certain diseases, including Parkinson's. If abnormal alpha-synuclein begins to accumulate, and the immune system hasn't seen it before, the protein could be mistaken as a pathogen that needs to be attacked." The Sulzer and Sette labs are now analyzing these responses in additional patients, and are working to identify the molecular steps that lead to the autoimmune response in animal and cellular models. "Our findings raise the possibility that an immunotherapy approach could be used to increase the immune system's tolerance for alpha-synuclein, which could help to ameliorate or prevent worsening symptoms in Parkinson's disease patients," said Dr. Sette.
News Article | June 19, 2017
LA JOLLA, CA--In recent years, immunotherapy, a new form of cancer therapy that rouses the immune system to attack tumor cells, has captivated the public's imagination. When it works, the results are breathtaking. But more often than not it doesn't, and scientists still don't know why. Publishing in the June 19, 2017, issue of Nature Immunology, researchers at La Jolla Institute for Allergy and Immunology, identify a subpopulation of T cells in tumors known as tissue-resident memory T cells (TRM) as an important distinguishing factor between cancer patients whose immune system mounts an effective anti-tumor response and those who are unable to do so. Their finding emerged from the first large-scale effort to profile the gene expression patterns of cytotoxic T cells isolated directly from patients' tumors. "Systematically studying cancer patients' immune cells reveals a lot of information," says LJI Associate Professor and William K. Bowes Jr. Distinguished Professor Pandurangan Vijayanand, M.D., Ph.D., who co-directed the study with Professor Christian Ottensmeier at the University of Southampton, England. "It could be a baseline test to predict whether a patient will respond to immunotherapy and guide the choice of immunotherapy that is most likely to be effective. It is almost like judging tumor immune fitness," adds Vijayanand. The systematic profiling of tumor-infiltrating T cells will also provide new insight into their basic biology revealing new potential immunotherapy drug targets. Scientists initially found that when T cells were swarming a patient's tumor that patient lived longer. Over time, however, they found that T-cells lose their fervor and cancer cells gain the upper hand. In the last decade they discovered why: Inhibitory molecular signals emitted from a tumor or its environment undercut the immune response, making tumor cells invisible to the immune system. One class of cancer immunotherapy drugs, known as checkpoint blockade inhibitors, disables either PD-1 or CTLA-4, two known molecules that allow cancer cells to live and multiply undetected by the immune system. "The challenge with immunotherapy based on PD-1 and CTLA-4 is that if they work, they work miraculously, but they only work in about 30 percent of patients," says the study's first author, Anusha-Preethi Ganesan, M.D., Ph.D., a physician in the Division of Pediatric Hematology and Oncology at Rady's Children's Hospital, UC San Diego. "If we are doing all these immunotherapies based on activating T cells to kill tumor cells it is really important to know what the transcriptional profiles of these T cells are, what molecules do they make?" To uncover the underlying reasons why some patients see little or no benefit and to identify those patients most likely to respond, Ganesan utilized advanced genomics tools to define the molecular features of a robust anti-tumor immune response using freshly resected tumors from patients with cancer. Comparing gene expression profiles of cytotoxic T cells (CTLs) isolated from 41 head and neck tumors and 36 untreated, early stage lung tumors with CTLs isolated from adjacent normal lung tissue, Ganesan identified a shared molecular fingerprint between different tumor types suggesting extensive reprogramming of CTLs infiltrating tumor tissue. Beyond their shared molecular signature, tumor-infiltrating CTLs differed widely in their expression of molecules associated with T cell activation and known immune checkpoints. "There is a huge deal of heterogeneity, which has a lot of implications for immunotherapy," says Ganesan. "We see the traditional immunotherapy targets but they are not expressed in every single patient, which means not every patient is a candidate for currently available immunotherapies targeted at PD-1 or CTL4-1. That's why having the full transcriptional profile is so important to understand the entire complexity of the immune network and to identify novel targets." Interestingly, gene expression patterns that signal the presence of tissue resident memory T cells (TRM) corresponded with better anti-tumor activity. The only recently identified tissue resident memory T cells act as local first responders that provide rapid onsite immune protection. A large scale analysis in an independent cohort of 689 lung cancer patients confirmed that patients with a high density of TRM cells in tumor tissue survived significantly longer, demonstrating that these cells serve a critical role in protecting against tumor recurrence. "Any time you remove a tumor, the patient is a ticking time bomb after that. In some people it will come back and it others it won't," says Vijayanand. "Our study suggests that the presence of these tissue resident memory cells is an important factor in determining whether somebody is having an effective immune response against cancer and whether they will live longer." The work was funded by the William K. Bowes Jr. Foundation, the University of Southampton, Cancer Research UK and the Wessex Clinical Research Network. Anusha-Preethi Ganesan, James Clarke, Oliver Wood, Eva M. Garrido-Martin, Serena Chee, Toby Mellows, Daniela Samaniego-Castruita, Divya Singh, Gregory Seumois, Aiman Alzetani, Edwin Woo, Peter S. Friedmann, Emma V. King, Gareth J. Thomas, Tilman Sanchez-Elsner, Pandurangan Vijayanand, Christian H. Ottensmeier. "Tissue-resident memory features are linked to the magnitude of cytotoxic T cell response in human lung cancer", Nature Immunology, 2017. Doi: 10.1038/ni.3775. The La Jolla Institute for Allergy and Immunology is dedicated to understanding the intricacies and power of the immune system so that we may apply that knowledge to promote human health and prevent a wide range of diseases. Since its founding in 1988 as an independent, nonprofit research organization, the Institute has made numerous advances leading toward its goal: life without disease.
Huang Y.,La Jolla Institute |
Huang Y.,Texas A&M University |
Rao A.,La Jolla Institute
Trends in Genetics | Year: 2014
DNA methylation has been linked to aberrant silencing of tumor suppressor genes in cancer, and an imbalance in DNA methylation-demethylation cycles is intimately implicated in the onset and progression of tumors. Ten-eleven translocation (TET) proteins are Fe(II)- and 2-oxoglutarate (2OG)-dependent dioxygenases that successively oxidize 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC), thereby mediating active DNA demethylation. In this review, we focus on the pathophysiological role of TET proteins and 5hmC in cancer. We present an overview of loss-of-function mutations and abnormal expression and regulation of TET proteins in hematological malignancies and solid tumors, and discuss the potential prognostic value of assessing TET mutations and 5hmC levels in cancer patients. We also address the crosstalk between TET and two critical enzymes involved in cell metabolism: O-linked β-. N-acetylglucosamine transferase (OGT) and isocitrate dehydrogenase (IDH). Lastly, we discuss the therapeutic potential of targeting TET proteins and aberrant DNA methylation in cancer. © 2014 Elsevier Ltd.
Gillies L.A.,La Jolla Institute |
Kuwana T.,La Jolla Institute
Journal of Cellular Biochemistry | Year: 2014
Mitochondria play a critical role in apoptosis, or programmed cell death, by releasing apoptogenic factors from the intermembrane space. This process, known as mitochondrial outer membrane permeabilization (MOMP), is tightly regulated by the Bcl-2 family proteins. Pro-apoptotic Bcl-2 family members, Bax and Bak, change their conformation when activated by BH3 domain-only proteins in the family and permeabilize the MOM, whereas pro-survival members inhibit permeabilization. The precise nature of the apoptotic pore in the MOM is unknown, but is probably lipidic. Furthermore, it has been realized that there is another layer of MOMP regulation by a protein factor termed the catalyst in the MOM in order for Bax/Bak to achieve efficient and complete membrane permeabilization. Mitochondrial dynamics do not affect MOMP directly, but seem closely coordinated with MOMP for swift protein efflux from mitochondria. This review will present current views on the molecular mechanisms and regulation of MOMP and conclude with recent developments in clinical applications based on the knowledge gleaned from the investigation. J. Cell. Biochem. 115: 632-640, 2014. © 2013 Wiley Periodicals, Inc. © 2013 Wiley Periodicals, Inc.