Ludwig Cancer Research and the Cancer Research Institute (CRI) have launched a Phase 1/2 clinical trial of combination immunotherapy for advanced ovarian cancer. The international, multicenter trial is led by George Coukos, director of the Ludwig Institute for Cancer Research, Lausanne and Brad Monk, director of Gynecologic Oncology at St. Joseph’s Hospital and Medical Center. The study is being conducted through the CVC Trials Network, which is jointly managed by Ludwig and CRI, in collaboration with MedImmune, the global biologics research and development arm of AstraZeneca, and the biopharmaceutical company VentiRx Pharmaceuticals Inc.
“Ludwig has long supported the design and evaluation of new therapeutic strategies to improve the treatment options available to cancer patients,” said Jonathan Skipper, Ludwig’s executive vice president of Technology Development. “Employing immunotherapies in combination holds great promise in that endeavor. We are proud to be a part of this effort to bring investigational drugs being developed by different commercial partners to a single clinical trial and improve the standard of care for recurrent ovarian cancer, a disease for which patients today have few treatment options.”
The open-label trial is evaluating the combination of MedImmune’s investigational antibody cancer drug durvalumab, a PD-L1 inhibitor, and VentiRx’s investigational TLR8 agonist motolimod added to chemotherapy in locally advanced or recurrent ovarian cancers that have become resistant to platinum chemotherapy. Both of the investigational drugs have been found in other studies to have acceptable safety profiles when used alone.
The researchers expect that motolimod’s activation of TLR8 will create conditions within tumors that are optimal to enhancing the effects of durvalumab. Further, when given with chemotherapy, motolimod could boost immune responses against cancer cells that are not engaged by durvalumab by helping the immune system “see” cancer antigens. Since the two immunotherapies work in distinct ways, they could have additive effects, inducing more potent and durable anti-tumor immune responses.
“This study is a good example of what’s possible when researchers have access to new therapies and are permitted to test hypotheses supported by the most recent science,” said Ludwig Lausanne director George Coukos. “We are hopeful that the combined therapies we are testing in this trial will be of great benefit to ovarian cancer and other cancer patients.”
Patients enrolled in the trial will be treated with the chemotherapeutic drug pegylated liposomal doxorubicin (PLD), which is the current standard of care for ovarian cancer after the failure of platinum therapy. They will also receive durvalumab and motolimod, with the Phase 1 and 2 portions of the trial running successively. The primary objective of the Phase 1 cohort of the study is to evaluate the safety and optimal dosage of the combination. The Phase 2 cohort of the trial will measure the efficacy of the treatment by evaluating the number of patients whose tumors have not progressed at six months.
Durvalumab is an investigational human monoclonal antibody directed against programmed death ligand-1 (PD-L1). PD-L1 expression enables tumours to evade detection from the immune system through binding to PD-1 on cytotoxic T lymphocytes. Durvalumab blocks PD-L1 interaction with both PD-1 and CD80 on T cells, countering the tumour’s immune-evading tactics. Durvalumab is being developed, alongside other immunotherapies, to empower the patient’s immune system and attack the cancer. Durvalumab is being investigated in an extensive clinical trial program, as monotherapy or in combination with tremelimumab, in NSCLC, bladder, head and neck, gastric, pancreatic, HCC and blood cancers.
Motolimod binds and activates Toll-like receptor 8 (TLR8), which is found in a variety of immune cells and serves as a key initiator of the innate immune response. Notably, it is expressed by myeloid dendritic cells, which help direct and boost T cell responses against infectious agents and cancers. Motolimod has been shown to be safe when combined with PLD in a previous study on ovarian cancer, with evidence of clinical benefit. The motolimod-PLD combination is currently under evaluation in a large, randomized, placebo-controlled phase 2 clinical study in patients with ovarian cancer.
“This clinical trial is part of a larger clinical research program supported by Ludwig and CRI to speed the evaluation of novel cancer immunotherapies, alone or in combination with other cancer drugs,” said Adam Kolom, managing director of CRI’s Clinical Accelerator, which funds the trials. “All of the studies have, as additional objectives, the collection of genetic and immunologic data derived from clinical samples that are obtained from patients. Such information will provide clues to the impact of the evaluated therapies and suggest refined or new strategies for treating cancer.”
The National Institutes of Health has awarded an Emory-led research consortium $15 million over five years for renewal of a grant aimed at better understanding and improving human immune responses to vaccination. The grant builds on the pioneering accomplishments of the research team over the past several years in developing “systems biology” methods to accurately predict the efficacy of vaccination in humans, and providing new insights into the molecular mechanisms that drive effective immunity to vaccination.
The grant’s principal investigator is Bali Pulendran, PhD, whose laboratory is widely credited with launching the field of “systems vaccinology.” Pulendran is Charles Howard Candler Professor in the Department of Pathology and Laboratory Medicine, the Emory Vaccine Center and Yerkes National Primate Research Center
Systems vaccinology combines immunology, genomics and bioinformatics to predict the effectiveness of a vaccine without exposing individuals to infection, and offers a means to probe the molecular mechanisms underlying immunity to vaccination. Researchers already have provided proof of concept of this approach through studies of innate and adaptive human immune responses to vaccines including yellow fever, smallpox, seasonal influenza, meningococcal disease and dengue fever.
Co-principal investigator is Rafi Ahmed, PhD, director of the Emory Vaccine Center and a Georgia Research Alliance Eminent Scholar. The National Institute of Allergy and Infectious Diseases will administer the grant as part of its Human Immunology Project Consortium (HIPC) program. The research team also includes scientists at the Broad Institute; Dana Farber Cancer Institute; Georgia Institute of Technology; University of California, Berkeley; University of Chicago; University of Colorado; University of Sao Paolo, Brazil; and several pharmaceutical firms.
“Although most of our team’s studies thus far have focused on healthy young adults, the renewal grant will allow us to expand the reach of our study to include vaccine responses in populations that are particularly vulnerable to infections: infants, the elderly, and transplant patients,” says Pulendran. “This is a critical need because we know elderly individuals have weaker immune responses overall, and transplant patients have compromised immune responses due to immunosuppressive drug therapy. We want to be able to offer more effective vaccines across the lifespan as well as address myriad health-care concerns,” he continues.
The team will focus on two primary projects: (1) immune response to vaccination against varicella zoster virus (VZV), which causes chicken pox in young children and shingles in adults, and (2) immune response to pneumococcal vaccines in transplant patients.
In the first major project, researchers will study immune responses to vaccination against VZV in children and the elderly with the aim of developing new insights into the immune response at the two extremes of age. VZV vaccination is the standard of care for both infants and the elderly, but Zostavax, the licensed Merck vaccine against VZV, has limited efficacy against shingles, especially in people older than 70.
Recently, the results of a randomized phase 3 trial of Glaxo Smith-Kline’s new investigational recombinant Herpes zoster subunit (HZ/su) vaccine has shown an overall vaccine efficacy of 97.2 percent across age groups, including people over 70 years old. These results represent somewhat of a paradigm shift in vaccinology because the usual barrier of immune senescence to vaccination in the elderly (the gradual deterioration of the immune response) appears to have been overcome. However the mechanisms by which this vaccine induces protective immunity in the elderly remain unexplored, and a major focus of the program by Pulendran and colleagues will be to use systems approaches to delineate such mechanisms.
In addition, the researchers will study immune responses to vaccination against varicella infection (chickenpox) in children. Although the Varivax vaccine (identical to Zostavax but at a lower dose) is highly effective in preventing chickenpox in young children, there is little known about the nature of innate and adaptive immunity to vaccination in children. The new systems approach will include a detailed analysis of the immune response to Varivax in children.
A second major focus will evaluate immune response to pneumococcal vaccines in kidney transplant patients who are on T cell immunosuppression therapy. Pneumococcal diseases are responsible for 1.6 million deaths per year globally, and the rate of invasive pneumococcal disease is 60 times greater in kidney transplant patients than in the general population. Researchers believe their new systems analysis of vaccination against pneumococcal disease in transplant patients on immunosuppressive therapy will yield important new insights that could provide new vaccination guidelines and a broader understanding of the dynamic changes following vaccination in this special population.
“The field of immunology has made tremendous progress over the years, and through this systems biology approach we have been able to dissect responses to vaccination in a much more efficient and insightful way,” says Rafi Ahmed. “We believe that by understanding the details of the response to VZV and pneumococcal vaccines in these vulnerable populations we can have an important impact on health in the United States and globally.”
“Systems biological approaches offer a unique way of probing the molecular mechanisms driving immunity to vaccination in humans, and offer exciting new insights about the workings of our immune system,” notes Pulendran. “This approach has already resulted in new insights into the fundamental mechanisms of immunity, and we are excited about the opportunity to dissect the reasons for differing responses to vaccines in individuals and special populations at the extremes of age. This will help guide clinical trials to evaluate new vaccines and future vaccine recommendations.”
Additional investigators for the consortium include Mark Mulligan, Nadine Rouphael, Evan Anderson and Aneesh Mehta, Emory University, and Myron Levin and Adriana Weinberg, University of Colorado (clinical core); Nick Haining, Dana Farber Cancer Institute and Broad Institute, Shankar Subramaniam, UCSD, Jill Mesirov, UCSD and Broad Institute, Nir Yosef, University of California, Berkeley, and Eva Lee, Georgia Institute of Technology (computational and single cell core); Tianwei Yu, Emory University (data management and statistical core); and Helder Nakaya (University of Sao Paolo) and Shuzhao Li and Dmitri Kazmin, Emory University.
Boston Children’s Hospital physicians report the first cases of children benefiting from 3D printing of their anatomy before undergoing high-risk brain procedures. The four children had life-threatening cerebrovascular malformations (abnormalities in the brain’s blood vessels) that posed special treatment challenges.
Reporting online today in the Journal of Neurosurgery: Pediatrics, the physicians describe the use of 3D printing and synthetic resins to create custom, high-fidelity models of the children’s vessel malformations along with nearby normal blood vessels. In some cases, the surrounding brain anatomy was also printed.
“These children had unique anatomy with deep vessels that were very tricky to operate on,” says Boston Children’s neurosurgeon Edward Smith, MD, senior author of the paper and co-director of the hospital’s Cerebrovascular Surgery and Interventions Center. “The 3D-printed models allowed us to rehearse the cases beforehand and reduce operative risk as much as we could.”
The children ranged in age from 2 months to 16 years old. Three of the four children had arteriovenous malformations (AVMs), in which tangles of arteries and veins connect abnormally, and were treated surgically.
“AVMs are high-risk cases and it’s helpful to know the anatomy so we can cut the vessels in the right sequence, as quickly and efficiently as possible,” says Smith. “You can physically hold the 3D models, view them from different angles, practice the operation with real instruments and get tactile feedback.”
The 2-month-old infant had a rare vein of Galen malformation in which arteries connect directly with veins—bypassing the capillaries—and was treated with an interventional radiology technique to seal off the malformed blood vessels from the inside.
“Even for a radiologist who is comfortable working with and extrapolating from images on the computer to the patient, turning over a 3D model in your hand is transformative,” says Darren Orbach, MD, PhD, chief of Interventional and Neurointerventional Radiology at Boston Children’s and co-director of the Cerebrovascular Surgery and Interventions Center. “Our brains work in three dimensions, and treatment planning with a printed model takes on an intuitive feel that it cannot otherwise have.”
The life-sized and enlarged 3D models were created in collaboration with the Boston Children’s Hospital Simulator Program (SIMPeds) using brain magnetic resonance (MR) and MR arteriography data from each child. Measurements of the models showed 98 percent agreement with the children’s actual anatomy.
All four children’s malformations were successfully removed or eliminated with no complications. When two of the AVM patients were compared with controls who did not have 3D-printed models—matched for age, size and type of AVM, surgeon and operating room—those with 3D models had their surgical time reduced by 12 percent (30 minutes). (Actual surgical time was 254 and 257 minutes for the cases with 3D models and 285 and 288 minutes for the controls.) Even a 30-minute reduction is significant for children who are especially sensitive to anesthesia.
Smith and Orbach are continuing to use 3D models for their trickier cases. “3D printing has become a regular part of our process,” says Smith. “It’s also a tool that allows us to educate our junior colleagues and trainees in a way that’s safe, without putting a child at risk.”
SIMPeds director Peter Weinstock, MD, PhD, was first author on the paper; co-authors were Orbach, Sanjay Prabhu, MBBS, FRCR, and Katie Flynn, BS, ME, all of Boston Children’s Hospital. The study was supported by the Lucas Warner AVM Research Fund and The Kids At Heart Neurosurgery Research Fund.
New York Times
The Metropolitan Opera said on Wednesday that it would redouble its efforts to attract new audiences to the opera next season with six new productions, a star-filled roster and new initiatives, including one that will offer half-priced tickets to children during the holidays and another to court young professionals with later curtain times, discounts and social events.
“The future of opera relies upon bringing new audiences in, as we all know,” Peter Gelb, the Met’s general manager, said in an interview. “Ultimately, no matter what the economics are, how daunting they are, or how successful we are in fund-raising, at the end of the day it’s all about having an audience.”
While the initiatives are aimed at newcomers, the season should offer plenty to interest regular operagoers. Nina Stemme, the acclaimed Swedish dramatic soprano whose New York appearances have been few and far between, will return to the Met next season to sing the title roles in a new production of Strauss’s “Elektra” and a revival of Puccini’s “Turandot.”
The star tenor Jonas Kaufmann and the soprano Kristine Opolais will perform in a new production of Puccini’s “Manon Lescaut” directed by Richard Eyre. James Levine, the Met’s music director, will conduct a new production of Berg’s “Lulu,” which he described in an interview as “an inspired work, from beginning to end.” The production will be staged by the South African artist William Kentridge, who did the Met’s innovative production of “The Nose.”
And, reprising a feat that Beverly Sills was famous for, Sondra Radvanovsky will sing all three queens in Donizetti’s so-called Tudor trilogy next season. She will sing the title roles in revivals of “Anna Bolena” and “Maria Stuarda” and then, when the Met brings “Roberto Devereux” to its stage for the first time in a new David McVicar production, she will perform the role of Elizabeth I, who, unlike the other two queens, manages to keep her head.
Two more new productions will round out the season: The Met will stage its first production of Bizet’s “Les Pêcheurs de Perles” (The Pearl Fishers) since 1916. It will be directed by Penny Woolcock; conducted by Gianandrea Noseda; and star Diana Damrau, Matthew Polenzani and Mariusz Kwiecien. (Mr. Gelb noted that the last tenor to sing the role Mr. Polenzani is singing was Enrico Caruso. “Hopefully there’s been enough time in between,” he said.)
And the Met will open its season with a new production of Verdi’s “Otello” directed by Bartlett Sher; conducted by Yannick Nézet-Séguin; and starring Sonya Yoncheva, who had several star-making turns this season, as Desdemona, and Aleksandrs Antonenko in the title role.
Some of the big moments of the season will be in revivals: Anna Netrebko, who made a splash this year in Verdi’s “Macbeth,” will sing Leonora in Verdi’s “Il Trovatore” for the first time at the Met. She will make her New York recital debut with a solo concert on Feb. 28, 2016.
The Met, which has been struggling financially and at the box office in recent seasons — it ran a $22 million deficit last year — announced a series of steps to court new audiences.
Children under 18 will be able to receive half-price tickets in any section of the house between Thanksgiving and New Year’s Eve, when purchased with a full-priced ticket.
A new program called “Fridays Under Forty” will offer tickets on selected Friday nights to people under 40 for $60 and $100 and move the curtain time back to 8 p.m., from its usual 7:30 p.m., to accommodate young professionals who work long hours.
And the Met plans to build on its popular holiday presentations aimed at families by adding one for grown-ups. So in addition to reviving an abridged, English-language revival of Rossini’s “The Barber of Seville” aimed at children, starring Isabel Leonard as Rosina, the Met will add one for adults: a streamlined revival of Johann Strauss’s “Die Fledermaus,” conducted, for his first time, by Mr. Levine.
The average ticket price will increase by 1 percent to $160, the Met said. Tickets will range in price from $25 to $480, with 36 percent of the roughly 900,000 tickets available next season for under $100, and more than half available for under $150.
Mr. Levine is to conduct five operas next season. In addition to “Lulu” and “Die Fledermaus,” he will conduct Verdi’s “Simon Boccanegra” with Plácido Domingo in the title role; Mozart’s “Die Entführung aus dem Serail”; and Wagner’s “Tannhäuser” starring Johan Botha, Peter Mattei, Eva-Maria Westbroek and Michelle DeYoung.
There are no contemporary works next season, but the Met, which has made a greater priority of new works in recent years, announced that it had commissioned a new opera by Nico Muhly, the composer of “Two Boys.” Mr. Muhly will write “Marnie,” based on the 1961 Winston Graham novel that was adapted for the screen by Alfred Hitchcock, and which is scheduled to come to the Met’s stage, in a production directed by Michael Mayer, in the 2019-20 season.
“It does everything that you want an opera to do, really,” Mr. Muhly said of the book. “It’s really, really dark.”
Society and modern medicine’s approach to aging and end-of-life care needs to be more focused on extending patients’ quality of life and human connection, according to Atul Gawande, associate professor in the Department of Health Policy and Management at Harvard School of Public Health and author of a new book, Being Mortal.
Gawande, a surgeon, executive director of Ariadne Labs, and staff writer for The New Yorker, discussed the book, released October 7, 2014, in multiple media interviews, including the television shows The Daily Show with Jon Stewart and The Charlie Rose Show. He talked about how dealing with his own father’s cancer inspired him, in part, to write the book. “We don’t ask what priorities people have in their life besides just living longer. What are the tradeoffs you are willing to make or not make, what are your fears and goals, what worries you about the future? If we ask that as doctors, we have some guideposts when life is short,” Gawande told Stewart.
Gawande said the book offers a way “to remake how we in medicine and society manage mortality through the stories of patients, their family members, nursing home attendants, hospice workers, geriatricians, surgeons, oncologists, pioneers, contrarians, and many more of the more than 200 people I interviewed over the last several years.”
Watch Gawande’s appearance on The Daily Show with Jon Stewart (the interview appears at approximately 13:00)
Read an excerpt published in The New York Times: The Best Possible Day
Read an interview in The Boston Globe: Atul Gawande finds time between patients and family for writing
Listen to an interview on The Diane Rehm Show: Atul Gawande: “Being Mortal: Medicine and What Matters in the End”
Following years of futile attempts, new research from the Monell Center demonstrates that living human taste cells can be maintained in culture for at least seven months. The findings provide scientists with a valuable tool to learn about the human sense of taste and how it functions in health and disease.
This advance ultimately will assist efforts to prevent and treat taste loss or impairment due to infection, radiation, chemotherapy and chemical exposures.
“People who undergo chemotherapy or radiation therapy for oral cancer often lose their sense of taste, leading to decreased interest in food, weight loss, and malnutrition,” said lead author M. Hakan Ozdener, M.D., Ph.D., M.P.H., a cellular biologist at Monell. “The success of this technique should provide hope for these people, as it finally provides us with a way to test drugs to promote recovery.”
Washington, D.C.—A team of scientists led by Carnegie’s Jacqueline Faherty has discovered the first evidence of water ice clouds on an object outside of our own Solar System. Water ice clouds exist on our own gas giant planets–Jupiter, Saturn, Uranus, and Neptune–but have not been seen outside of the planets orbiting our Sun until now. Their findings are published by The Astrophysical Journal Letters. At the Las Campanas Observatory in Chile, Faherty, along with a team including Carnegie’s Andrew Monson, used the FourStar near infrared camera to detect the coldest brown dwarf ever characterized. Their findings are the result of 151 images taken over three nights and combined. The object, named WISE J085510.83-071442.5, or W0855, was first seen by NASA’s Wide-Field Infrared Explorer mission and published earlier this year. But it was not known if it could be detected by Earth-based facilities.
“This was a battle at the telescope to get the detection,” said Faherty.
Chris Tinney, an Astronomer at the Australian Centre for Astrobiology, UNSW Australia and co-author on the result stated: “This is a great result. This object is so faint and it’s exciting to be the first people to detect it with a telescope on the ground.”
Brown dwarfs aren’t quite very small stars, but they aren’t quite giant planets either. They are too small to sustain the hydrogen fusion process that fuels stars. Their temperatures can range from nearly as hot as a star to as cool as a planet, and their masses also range between star-like and giant planet-like. They are of particular interest to scientists because they offer clues to star-formation processes. They also overlap with the temperatures of planets, but are much easier to study since they are commonly found in isolation.W0855 is the fourth-closest system to our own Sun, practically a next-door neighbor in astronomical distances. A comparison of the team’s near-infrared images of W0855 with models for predicting the atmospheric content of brown dwarfs showed evidence of frozen clouds of sulfide and water. “Ice clouds are predicted to be very important in the atmospheres of planets beyond our Solar System, but they’ve never been observed outside of it before now,” Faherty said. The paper’s other co-author is Andrew Skemer of the University of Arizona.
The U.S. National Park Service has renewed its agreement with the American Museum of Natural History to permanently freeze biological samples collected from threatened and endangered species at the Museum’s Ambrose Monell Collection for Molecular and Microbial Research, one of the largest and most comprehensive collections of its kind.
The Monell collection now houses about 93,000 tissue samples, including more than 1,000 tissue samples submitted by the National Park Service (NPS) just in the lastyear. Some of the more noteworthy NPS additions are samples from the Channel Island fox—a once near-extinct species found only on six islands off the coast of southern
California—the bald eagle, and the Karner blue butterfly, which is drastically losing habitat in parts of the Midwest and Northeast. These frozen samples, along with the balance of the Monell collection, are available to researchers around the world for genetic and genomic research.
Under the new five-year agreement, which was signed in July 2014, NPS researchers will continue to collect tissue samples under controlled conditions using kits provided by the Museum. The documented specimens, packed in special equipment, are shipped to the Museum, where they are housed in cryogenic storage—liquid nitrogen-cooled vats at temperatures below -150 degrees Celsius. The partnership between the Museum and NPS began in 2009 and so far has resulted in the preservation of more than 2,000 tissue samples from three national parks.
With the capacity to store 1 million frozen tissue samples, the Monell collection, also known as the Ambrose Monell Cryo Collection (AMCC), is part of the Museum’s larger effort to preserve a comprehensive record of Earth’s biodiversity. Launched in 2001, this specialized collection helped develop important protocols for archiving biological specimens. For example, the facility includes an important measure of safety: in the event of an electrical failure, samples would remain super-chilled for five weeks. Major research institutions regularly reach out to the AMCC to seek advice on best practices in frozen tissue storage and data documentation. In the past year alone, staff from Denmark’s soon-to-open national tissue archive spent a week working in the Monell Collection to observe daily operations.
Carbon is the fourth-most-abundant element in the universe and takes on a wide variety of forms, called allotropes, including diamond and graphite. Scientists at Carnegie’s Geophysical Laboratory are part of a team that has discovered a new form of carbon, which is capable of withstanding extreme pressure stresses that were previously observed only in diamond. This breakthrough discovery is published by Physical Review Letters.
The team was led by Stanford’s Wendy L. Mao and her graduate student Yu Lin and includes Carnegie’s Ho-kwang (Dave) Mao, Li Zhang, Paul Chow, Yuming Xiao, Maria Baldini, and Jinfu Shu. The experiment started with a form of carbon called glassy carbon, which was first synthesized in the 1950s, and was found to combine desirable properties of glasses and ceramics with those of graphite. The team created the new carbon allotrope by compressing glassy carbon to above 400,000 times normal atmospheric pressure.
This new carbon form was capable of withstanding 1.3 million times normal atmospheric pressure in one direction while confined under a pressure of 600,000 times atmospheric levels in other directions. No substance other than diamond has been observed to withstand this type of pressure stress, indicating that the new carbon allotrope must indeed be very strong.
However, unlike diamond and other crystalline forms of carbon, the structure of this new material is not organized in repeating atomic units. It is an amorphous material, meaning that its structure lacks the long-range order of crystals. This amorphous, superhard carbon allotrope would have a potential advantage over diamond if its hardness turns out to be isotropic—that is, having hardness that is equally strong in all directions. In contrast, diamond’s hardness is highly dependent upon the direction in which the crystal is oriented.
“These findings open up possibilities for potential applications, including super hard anvils for high-pressure research and could lead to new classes of ultradense and strong materials,” said Russell Hemley, director of Carnegie’s Geophysical Laboratory.
This research was funded, in part, by the Department of Energy’s Office of Basic Energy Sciences Division of Materials Sciences and Engineering, EFree, HPCAT, where some of the experiments were performed, is funded by DOE-BES, DOE-NNSA, NSF, and the W.M. Keck Foundation. APS, where some of the experiments were performed, is supported by DOE-BES.