UPMC Physician Resources

UPCI-Tested Immunotherapy Prolongs Life, Reduces Side Effects and Improves Quality of Life

The immunotherapy nivolumab significantly increases survival and causes fewer adverse side-effects in patients with recurrent head and neck cancer, according to a randomized trial co-led by investigators at the University of Pittsburgh Cancer Institute (UPCI), partners with UPMC CancerCenter.

The results of the international CheckMate-141 phase III clinical trial were reported Sunday in the New England Journal of Medicine, following preliminary presentations at the annual American Society of Clinical Oncology and American Association for Cancer Research meetings earlier this year. Patients on nivolumab were doing so much better than those receiving standard therapy that the trial was stopped early to allow all patients to receive it.

“Due to our clinical trial, anti-PD-1 therapies like nivolumab are now the recommended treatment for patients with this very difficult, devastating cancer,” said lead author and trial co-chair Robert Ferris, MD, PhD, UPMC Endowed Professor, and chief of the Division of Head and Neck Surgery and co-leader of the Cancer Immunology Program at UPCI.

Worldwide, more than 600,000 cases of squamous-cell carcinoma of the head and neck are diagnosed annually, and the cancer recurs in more than half the patients within three years. The cancer typically returns because it has evaded the immune system and become resistant to chemotherapy.

Alcohol and tobacco use are the two main risk factors for head and neck cancers. Infection with the human papillomavirus (HPV) also is a risk factor, and rates of head and neck cancer attributable to HPV infection have increased 250 percent over the past several decades.

Nivolumab, which belongs to a class of drugs known as immunotherapeutics, enables the body’s immune system to destroy cancer cells. It currently is approved to treat certain types of cancers, including melanoma and lung cancer.

The CheckMate-141 trial enrolled 361 patients receiving care at 64 locations worldwide for recurrent head and neck cancer that had progressed within six months of chemotherapy. From June 2014 through August 2015, the researchers randomly assigned 240 patients to receive nivolumab and 121 to receive standard therapy, which consisted of one of three chemotherapy drugs.

On average, the patients on nivolumab survived 7.5 months, versus 5.1 months for the patients on standard therapy. At one year, 36 percent of the nivolumab patients were still living, compared with 16.6 percent of the standard-care patients.

Additionally, only 13.1 percent of the patients receiving nivolumab suffered serious, quality-of-life-disrupting side effects of the treatment, compared with 35.1 percent of those receiving standard therapy.

“It is wonderful news that we have a new, better option for patients with recurrent head and neck cancer,” said Dr. Ferris. “But for the vast majority of patients, nivolumab isn’t a cure and more research is needed to find one. Perhaps even more important, we need to prevent this cancer from ever occurring. We have to help people to stop smoking or chewing tobacco, and encourage them to never start. We also need to continue to encourage children to be vaccinated against HPV.”

The trial’s other co-chair is Maura Gillison, MD, PhD, from Ohio State University. Additional US institutions that participated in the trial include University of Texas MD Anderson Cancer Center, Stanford Cancer Institute, University of Chicago, University of Michigan, Emory University, Dana-Farber Cancer Institute and Bristol-Myers Squibb.

International collaborators are located at Centre Leon Berard, Centre Antoine Lacassagne, and Institut Gustave Roussy, all in France; Fondazione IRCCS Istituto Nazionale Tumori, in Italy; The Institute of Cancer Research, in the United Kingdom; University Hospital Essen, in Germany; Hospital Universitario 12 de Octubre, in Spain; University Hospital Zurich, in Switzerland; and National Cancer Center Hospital East and Kobe University Hospital, both in Japan.

The trial was funded by Bristol-Myers Squibb, which is now seeking US Food and Drug Administration approval for the use of nivolumab in head and neck carcinoma.

UPMC’s Dr. Stanley Marks Honored with Endowed Chair in His Name to Recruit Cancer Leaders

Stanley Marks, MD, a leading UPMC oncologist and advocate for cancer patients throughout the western Pennsylvania region, was honored by UPMC and his medical partners at Oncology Hematology Association (OHA) through the establishment of the Stanley M. Marks – OHA Endowed Chair in Hematology/Oncology Leadership.

Every one of his 48 partners at OHA, a UPMC-owned practice, financially committed to create this chair, which also was supported by UPMC, for a total of $2.2 million.

The permanent endowment will support the recruitment and retention of outstanding leaders in the University of Pittsburgh Division of Hematology/Oncology. It also will help to train professionals devoted to research and improved treatments for patients.

Dr. Marks has directed and overseen the continued growth and success of the UPMC CancerCenter, a partner with the University of Pittsburgh Cancer Institute and now one of the largest cancer care networks in the nation.

“None of this would have been possible without the support of my colleagues and UPMC,” said Dr. Marks. “This endowment will enable us to recruit a medical and scientific star, ultimately leading to better care for our patients.”

Added Barry Lembersky, MD, “Through his decades-long leadership of OHA and the UPMC CancerCenter, Stan has made a significant impact on cancer care and research in our region and beyond. All of the physicians in OHA wish to honor his outstanding contributions and provide a legacy to benefit patients for generations to come.”

Dr. Marks serves as chairman of UPMC CancerCenter, chief of the Division of Hematology and Oncology at UPMC Shadyside, and as a clinical professor of medicine at the University of Pittsburgh School Of Medicine. He also has been named consistently as one of the “Top Physicians in Pittsburgh” and “Best Doctors of America” in hematology and medical oncology by Best Doctors®.

Quest to Cure Blindness: Pitt, UPMC Recruit World-Renowned Expert in Research and Therapies for Blindness and Vision Impairment

PITTSBURGH, Oct. 5, 2016 – One of the world’s top experts in retinal diseases, who is developing an artificial retina as well as other regenerative therapies to treat blindness and vision impairments, has been named as the chair of the Department of Ophthalmology at the University of Pittsburgh School of Medicine, director of the UPMC Eye Center, and the Eye and Ear Foundation Chair of Ophthalmology.

José-Alain Sahel, M.D., founder and director of the Vision Institute in Paris and currently a professor at the Sorbonne’s medical school Université Pierre-et-Marie-Curie, has joined UPMC and Pitt’s faculty.

Dr. Sahel is known worldwide for his expertise in vision restoration techniques. He has developed several interventions— including stem cell implantation, gene therapy, innovative pharmacologic approaches and the artificial retina—for retinitis pigmentosa, age-related macular degeneration, vascular eye disease and other vision impairments that currently are untreatable.  Over the past decade he has led pioneering efforts in optogenetic vision restoration, a technique in which cells in the retina are genetically modified to express light sensitive proteins. This therapeutic technique has the potential to help patients who are blind or visually impaired as a result of a genetic defect.

He also brings a strong neuroscience perspective to ophthalmology research, such as exploring the application of brain-computer interface technology, for which Pitt and UPMC are well known.

“We are delighted that Dr. Sahel has chosen to bring his remarkable talent to UPMC where he will, with immediacy, translate laboratory advances into treatment for patients with visual impairment,” said Steve Shapiro, M.D., chief medical and scientific officer at UPMC. “His creativity and commitment to bringing everything from rigorous basic science to eyesight-saving surgery to patient care are unparalleled. With his leadership, we expect to build on the amazing accomplishments he already has achieved in Paris as well as break new ground in vision research and care.”

“Dr. Sahel is a gifted physician-scientist with a heartfelt dedication to his patients and a broad intellectual reach. His work will soon have great impact on the ophthalmology department, on bench-to-bedside treatments for patients, and also on Pitt as a whole,” said Arthur S. Levine, M.D., Pitt’s senior vice chancellor for the health sciences and John and Gertrude Petersen Dean of Medicine.

Dr. Sahel will sustain his engagement with the Vision Institute, one of the world’s largest centers of integrated research on eye diseases, through a partnership formed between the Institute, the Sorbonne, Pitt School of Medicine and UPMC.

“I am very impressed with the strong support and energy at UPMC and Pitt, and share their objectives of developing creative new treatments and diagnostic tools to better serve patients,” Dr. Sahel said. “It was clear to me during my visits that the community is warm and welcoming, and rightfully proud of its city. I look forward to contributing to these impressive academic and health care legacies.”

As director of UPMC Eye Center, which is rated among the top ophthalmology programs in the United States in the delivery of care, Dr. Sahel will see patients, particularly those with complex diseases, and will lead UPMC clinicians in the diagnosis and treatment of both common and unusual eye disorders. The UPMC Eye Center is home to an outstanding ophthalmology teaching program that trains residents and clinical fellows in their pursuit of clinical, research and clinician-scientist careers.

Dr. Sahel is a co-inventor on more than 40 patents, several of which have led to start-up companies including Fovéa Inc., which Dr. Sahel founded and later became the Ophthalmologic Division of Sanofi Aventis. He also is a scientific co-founder of GenSight Biologics Inc. and Pixium Vision Inc. He is a member of 11 editorial boards, including the Journal of Clinical Investigation and Science Translational Medicine.

He also holds the positions of Cumberlege Professor of Biomedical Sciences at the Institute of Ophthalmology, University College London, and chairman of the Departments of Ophthalmology at the Quinze-Vingts National Eye Hospital and at the Rothschild Ophthalmology Foundation, both in Paris.  At the Paris-based Ophthalmology Clinical Investigation Center, he oversees more than 50 clinical trials, many of which are focused on retinal implants, gene therapy and other advanced biomedical technologies. He also heads the French National Reference Center for Retinal Dystrophies and chairs a network of more than 90 European clinical trial centers focused on retinal diseases.

He has been the recipient of numerous honors and awards, which include membership in the Legion of Honour (2008); the National Order of Merit (2002) and induction into the Collège de France, the highest honor awarded to a French scientist. He is an elected member of the Académie des sciences-Institut de France, the Académie des technologies, the Academia Ophthalmologia Internationalis and the German National Academy of Sciences. He has also received the Grand Prix for Neurosciences of the Foundation NRJ, Institut de France; the CNRS Medal of Innovation; the Foundation for Fighting Blindness Trustee Award and the Liura Liggett-Gund Award, among others. Dr. Sahel holds an honorary degree from the University of Geneva.

Dr. Sahel, who was born in Algeria, studied medicine at Strasbourg University and in Lariboisière, Saint-Louis. He received his medical degree with a Medal of the Faculty of Paris and obtained his specialty certification in ophthalmology. He completed a residency in neurology and neurosurgery at the Louis Pasteur University Hospital in Strasbourg. He also was a research fellow at the Massachusetts Eye and Ear Infirmary and a visiting scholar in the Department of Molecular and Cellular Biology at Harvard University.

Altoona Native Tapped as New Director of Cardiac Surgery at UPMC Altoona

The UPMC Heart and Vascular Institute has named Louis Russo, MD, clinical assistant professor of cardiothoracic surgery at the University of Pittsburgh School of Medicine, as its new director of cardiac surgery at UPMC Altoona. The new role is a homecoming for Dr. Russo, who was raised in Altoona.

“Altoona has always been the place I consider home,” said Dr. Russo, who has enjoyed spending time in Altoona on a regular basis since leaving as a young man. “My parents and many friends still live here, and now I’m back. As a homegrown surgeon from Pennsylvania, I am looking forward to providing excellent care for patients in my hometown.”

A graduate of Penn State University and board certified in general and cardiothoracic surgery, Dr. Russo earned his medical degree from Thomas Jefferson University Medical College in Philadelphia before completing his residency at Allegheny General Hospital in Pittsburgh. He previously served as director of the Ventricular Assist Device Program at Maine Medical Center, and has served as the principal investigator and co-investigator on several clinical trials. His clinical practice includes all aspects of adult cardiac surgery.

Dr. Russo joined the UPMC family in 2013 and has been caring for patients at UPMC Hamot in Erie, Pennsylvania. There, he served as vice-chairman of the Department of Cardiovascular Medicine and Surgery.

“Dr. Russo has been part of UPMC’s world-class cardiac surgery program for more than three years and has headed up UPMC Hamot’s quality efforts during that time,” said Jerry Murray, president of UPMC Altoona. “He is a seasoned surgeon who will provide a clinical connection between Pittsburgh and Altoona, and we’re confident he’ll build on the successes he had at UPMC Hamot.”

UPMC Altoona offers a wide spectrum of state-of-the-art cardiac surgery, including the latest techniques in surgical treatment of coronary artery disease and valvular heart disease.  This includes coronary artery bypass grafting; aortic, mitral and tricuspid valve replacement; and repairs of mitral and tricuspid valves. In collaboration with the cardiologists from the UPMC Heart and Vascular Institute, Dr. Russo will also offer advanced anti-arrhythmic surgery.

The UPMC Heart and Vascular Institute is one of the world’s premier centers for comprehensive care, developing revolutionary devices and new models of treatment that improve the lives of those facing the most complex heart and vascular conditions.

Correcting Metabolic Deficiencies May Improve Depression Symptoms

Identifying and treating metabolic deficiencies in patients with treatment-resistant depression can improve symptoms and in some cases even lead to remission, according to new research from the University of Pittsburgh School of Medicine published online today in the American Journal of Psychiatry.

This research is funded through a 2014 Pitt Innovation Challenge Award from Pitt’s Clinical and Translational Science Institute.

“What’s really promising about these new findings is that they indicate that there may be physiological mechanisms underlying depression that we can use to improve the quality of life in patients with this disabling illness,” said David Lewis, MD, Thomas Detre Professor and Chair of Pitt’s Department of Psychiatry.

Major depressive disorder, also referred to simply as depression, affects nearly 15 million American adults and is one of the most common mental disorders. Unfortunately, at least 15 percent of patients don’t find relief from conventional treatments such as antidepressant medications and psychotherapy, explained lead study investigator Lisa Pan, MD, professor of psychiatry, and clinical and translational science, Pitt School of Medicine. Depression also is the cause of more than two-thirds of suicides that occur annually.

The groundwork for the current study was laid five years ago when Dr. Pan and David Brent, MD, Endowed Chair in suicide studies at Pitt, treated a teen with a history of suicide attempts and long-standing depression. “Over a period of years, we tried every treatment available to help this patient, and yet he still found no relief from his depression symptoms,” she explained.

Searching for answers, Dr. Pan contacted Jerry Vockley, MD, PhD, chair of genetics, Children’s Hospital of Pittsburgh of UPMC, and David Finegold, MD, professor of human genetics at Pitt’s Graduate School of Public Health, and through a series of biochemical tests, the three discovered that the patient had a cerebrospinal fluid deficiency in biopterin, a protein involved in the synthesis of several brain signaling chemicals called neurotransmitters.

After receiving an analogue of biopterin to correct the deficiency, the patient’s depression symptoms largely disappeared and today he is a thriving college student.

The success prompted the researchers to examine other young adults with depression who were not responding to treatment, explained Dr. Pan.

In the published trial, the researchers looked for metabolic abnormalities in 33 adolescents and young adults with treatment-resistant depression and 16 controls. Although the specific metabolites affected differed among patients, the researchers found that 64 percent of the patients had a deficiency in neurotransmitter metabolism, compared with none of the controls.

In almost all of these patients, treating the underlying deficiency improved their depression symptoms, and some patients even experienced complete remission. In addition, the further along the patients progress in the treatment, the better they are getting, Dr. Pan added.

“It’s really exciting that we now have another avenue to pursue for patients for whom our currently available treatments have failed. This is a potentially transformative finding for certain groups of people with depression,” said Dr. Pan.

Additional collaborators on the study are Jerry Vockley, MD, PhD,  David Brent, MD, David Finegold, MD, David Peters, PhD, Petra Martin, BS, Thomas Zimmer, BS, Anna Maria Segreti, BS, Sivan Kassiff, BS, Brian McKain, RN, MSN, Cynthia Baca, RN, MSN, Manivel Rengasamy, MD, Nicolette Walano, MS, Marion Hughes, MD, Steven Dobrowolski, PhD, Michele Pasquino, BS, Rasim Diler, MD, and James Perel, PhD, all of Pitt School of Medicine; Robert Naviaux, MD, PhD, of University of California, San Diego; Keith Hyland, PhD, of MNG Laboratories in Atlanta, Georgia; and Robert Steinfeld, MD, of University Medical Center Gottingen in Germany.

This research also was supported by funding from the American Foundation for Suicide Prevention and a Brain and Behavior Research Foundation NARSAD Young Investigator Award. Additional funding from the Beck and Lohman families through the Children’s Hospital of Pittsburgh Foundation is supporting the testing and follow up of additional patients with treatment-resistant depression and suicidal behavior, and allowing the researchers to begin to understand the underlying biological changes.

Pitt Receives $5.5M CDC Grant to Continue Flu Vaccine Effectiveness Evaluation

The high productivity of the University of Pittsburgh’s Vaccination Research Group (PittVax) earned the program a $5.5 million, five-year renewal from the US Centers for Disease Control and Prevention (CDC) to continue evaluation of the annual influenza vaccine and, once licensed, the respiratory syncytial virus (RSV) vaccine. The PittVax team collaborates with investigators in Pitt’s schools of Medicine and Public Health and across UPMC, including Children’s Hospital of Pittsburgh.

Starting in 2011, PittVax became one of five US Influenza Vaccine Effectiveness Network sites that provide data and analysis needed for public health officials to make or adjust recommendations for vaccination, antiviral and other treatments. PittVax is directed by Richard K. Zimmerman, MD, MPH, professor, and Tricia Nowalk, PhD, RD, associate professor, both in Pitt School of Medicine’s Department of Family Medicine.

“The information we collect and share is one of the primary data sources that the CDC uses in setting its vaccination policies and recommendations for clinicians treating patients in any given flu season,” said Dr. Zimmerman, also professor in the Pitt Graduate School of Public Health’s Department of Behavioral and Community Health Sciences. “In past years, we’ve given the evidence needed to prompt earlier and more widespread use of flu antiviral drugs. This season, our work has led to the recommendation to discontinue nasal spray flu vaccine because it has not been effective at preventing type A flu.”

The Pittsburgh site collects data from hundreds of patients seen at UPMC outpatient facilities with symptoms of an acute respiratory infection who consent to participate. They are tested to determine if they have flu or another illness, such as RSV, or simply a cold. The researchers also confirm whether or not the participants were immunized against flu earlier in the season and conduct a follow-up survey on participants’ recovery.

In the past five years, PittVax participants had the highest follow-up survey completion rate of any of the other sites and higher enrollment rates than required, with well over the 1,100 necessary participants annually. The program is supported by ongoing outbreak surveillance at six UPMC sites, with more than 14,000 respiratory virus tests performed each flu season.

These data allow PittVax and the other sites to determine if the flu vaccine—which is designed to work against the three or four strains of flu that the World Health Organization predicts most likely to be circulating when the flu vaccine is manufactured, months before flu season actually starts—is effective against whatever strains of flu ultimately circulate.

Last season, the flu vaccine was nearly 60 percent effective, which means that the chances someone vaccinated against flu would get sick with the virus were less than half the chances of illness in someone who didn’t get the flu vaccine. In the 2014-2015 season, the vaccine was only 23 percent effective, the lowest in nearly a decade, but still offered considerably more protection against flu than not being vaccinated. On average, the vaccine is about 50 to 60 percent effective.

Based on data collected from 2015 to 2016 by PittVax and other sites, the nasal spray flu vaccine often offered to children was found to be only 3 percent effective, and the CDC’s Advisory Committee on Immunization Practices recommended it not be offered this season, instead recommending the traditional influenza vaccination with a needle for everyone six months and older.

In the event of a flu pandemic—when a new strain of flu to which people have little existing immunity emerges and spreads globally—PittVax will be prepared to collect respiratory samples and conduct studies estimating how many people are affected and how well antivirals or existing flu vaccines work against it.

New with this grant, PittVax also will be prepared to collect and provide data and analysis on the effectiveness of the RSV vaccine, which is expected to be offered to older adults within the next five years, if clinical trials go well.

In his decades as a physician and family medicine and public health scientist, Dr. Zimmerman unequivocally recommends the flu vaccine for everyone included in the CDC policy.

“I’m vaccinated, my wife’s vaccinated, the kids at home are vaccinated, and I tell all my patients who should be vaccinated to get it,” said Dr. Zimmerman. “It is the single best way to avoid getting and spreading the flu, which is a deadly illness.”

PittVax is funded by CDC grant 1U01IP001035.

UPCI Secures Federal Contract For Up To $10M in Preclinical Cancer Drug Development Work

The University of Pittsburgh Cancer Institute (UPCI), partner with UPMC CancerCenter, secured a highly prestigious contract from the National Cancer Institute (NCI) to perform preclinical research crucial to the development of new cancer drugs. This commitment could bring up to $10 million in research projects to UPCI over the next five years.

The contract cements UPCI’s role in all five stages of NCI’s drug development process, with UPCI researchers now holding funding mechanisms in drug screening, preclinical research, and Phase I, II and III clinical trials.

“It is exceedingly rare for an academic cancer institute to have funding in every one of these NCI drug development stages,” said Nancy E. Davidson, MD, director of UPCI. “By being involved in every stage of NCI drug development, UPCI is able to truly consider and understand each part, bringing extra knowledge and value to every cancer drug research project we perform. Contracts like this are a crucial part of how we get the best therapies to our patients.”

Julie Eiseman, PhD, DABT, professor of pharmacology and chemical biology, and Jan Beumer, PharmD, PhD, DABT, associate professor of pharmaceutical sciences and medicine, both of UPCI, are co-principal investigators on the new NCI preclinical research contract. They also hold a previous NCI preclinical contract, which will conclude next year.

Under the new preclinical contract, UPCI will perform the research necessary to collect drug pharmacology data and determine the most efficacious routes and doses of proposed cancer drugs so that they can be used in human clinical trials.

“What sets UPCI apart is that we provide an added value by being able to think outside the box,” said Dr. Beumer, who also is co-principal investigator on the NCI phase I clinical trial grant at UPCI. “We can connect these preclinical studies with the clinical trials that will follow and make suggestions to help both phases be as efficient and effective as possible.”

The researchers do not yet know specifically what potential drugs they’ll be investigating or which cancers they’ll ultimately be intended to tackle.

“That’s what we help to determine,” said. Dr. Eiseman. “In the past we’ve evaluated potential drugs for use in cancers of the colon, breast, pancreas, and head and neck, among others. It’s a team effort. No one person could develop these therapies alone.”

The Contract Number is HHSN2612016000221; the NCI Control Number is N02CM-2016-00022.

UPMC Makes U.S. News & World Report’s Honor Roll of America’s ‘Best Hospitals’ for 17th Time

 UPMC is recognized on the national stage once again for its clinical expertise, earning 12th position on the annual US News & World Report Honor Roll of America’s “Best Hospitals,” moving up from 13th place in last year’s rankings.

“We are extremely pleased to be on the Honor Roll for the 17th year,” said Leslie C. Davis, senior vice president of UPMC, and executive vice president and chief operating officer of the Health Services Division. “What a fine testament year after year for our physicians, nurses and other clinical specialists and support teams who dedicate their work every day to providing this level of care for our patients and their families.”

US News & World Report analyzed approximately 5,000 hospitals nationwide based on a variety of factors, including hospital volume, patient safety, outcomes, and reputation for delivering high-quality care. The 2016-17 Honor Roll recognizes the 20 hospitals that earned the most points across 16 specialty areas included in the analysis. The Honor Roll is ranked from No. 1 to No. 20, based on earned points.

Nationally, UPMC is ranked for excellence in 15 of the 16 specialty areas, and is among the top 10 hospitals in four specialties: ear, nose and throat; gastroenterology and GI surgery; pulmonology; and rheumatology.

“In addition to our clinical excellence and patient care expertise across the board, we have a close affiliation with one of the best medical schools in the country, the University of Pittsburgh School of Medicine, to advance our scientific research that leads to clinical innovation in many specialties,” said Steven Shapiro, MD, executive vice president and chief medical and scientific officer at UPMC and president of the Health Services Division. “We are proud of that collaborative work.”

UPMC’s inclusion on the Honor Roll comes weeks after US News & World Report named its 2016 Honor
Roll of America’s Best Children’s Hospitals, recognizing Children’s Hospital of Pittsburgh of UPMC as No. 7 in the country, up from No. 8 last year. This is the 7th year that Children’s made the Honor Roll, ranking in 9 of 10 pediatrics specialty areas covered.

‘Starving’ Immune Cell Discovery Points to Cancer Immunotherapy-Boosting Strategies

The microenvironment that supports a cancerous tumor also starves the immune cells that the body sends in to destroy the cancer, University of Pittsburgh Cancer Institute (UPCI) scientists revealed in a discovery that holds the potential to significantly boost the performance of breakthrough immunotherapy drugs.

The UPCI team showed that when immune T cells enter the tumor microenvironment, their mitochondria—which act as mini-factories inside cells, making energy and crucial reagents a cell needs to survive—begin to shrink and disappear, indicating that the T cell is out of fuel and can’t do its tumor-destroying job. The finding, reported online today and scheduled for next week’s issue of the journal Immunity, opens the door to several potential clinical approaches that could help keep T cells functioning and boost the body’s ability to fight cancer.

“Immunotherapy to stimulate the body’s immune system has increasingly become the way we treat people with aggressive cancers. It’s effective for a subset of patients, but the truth is that only about 20 to 40 percent of patients will respond to the treatment, and it is still unclear why,” said senior author Greg M. Delgoffe, PhD, assistant professor of immunology and member of the Tumor Microenvironment Center at UPCI, partner with UPMC CancerCenter. “It’s a huge question in the cancer immunotherapy field, and we think we’ve found a big part of the answer.”

As tumors grow, they build a microenvironment, which develops its own blood supply and keeps the tumor thriving, protected and voraciously consuming all available nutrients.

When T cells enter the microenvironment, it’s as if they’re “automobiles that suddenly had the emergency brake applied; they can’t keep driving,” explained Dr. Delgoffe. Immunotherapies, like those that target negative regulators on the T cell surface, take these brakes off. “However, what we’re discovering in many cases is that even though the brakes have been taken off, there isn’t any fuel in the tank,” Dr. Delgoffe said. Or—in scientific terms—the lack of mitochondria in the tumor-infiltrating T cells keeps them from functioning.

“This is an exciting discovery because we already have various strategies to ‘fill the fuel tank’ and support T cell function in the tumor microenvironment,” said Dr. Delgoffe.

In laboratory experiments and tests with mice, Dr. Delgoffe and his team found that when they boosted the mitochondria in the T cells, they were better able to clear the tumor.

Dr. Delgoffe is partnering with other scientists to test various mitochondria-boosting strategies, including using drugs that already have proven safe in humans, such as those for type 2 diabetes, to stimulate T cell metabolism. He’s also working with existing immunotherapy studies to further modify the T cells so that their metabolism functions better in the tumor microenvironment.

Additional authors on this research are Nicole E. Scharping, BSc, Ashley V. Menk, BSc, Rebecca S. Moreci, BA, Ryan D. Whetstone, MS, PhD, Rebekah E. Dadey, BS, Simon C. Watkins, PhD, and Robert L. Ferris, MD, PhD, all of Pitt.

This work was supported in part by Sidney Kimmel Foundation for Cancer Research grant SKF-015-039 and National Institutes of Health grants 1S10OD016236-01, P50 CA097190 (UPCI Head and Neck Specialized Program of Research Excellence (SPORE)) and P50CA121973 (UPCI Skin Cancer SPORE).

Genetic Variant Newly Linked to Crohn’s Disease Also Associated with Altered Gut Microbiome Composition

An international team led by researchers at the University of Pittsburgh, Cedars-Sinai Medical Center and the University of California Los Angeles discovered that a genetic variation previously linked to obesity, cholesterol levels, blood pressure and schizophrenia also is associated with Crohn’s disease, a chronic inflammatory condition of the gastrointestinal tract that is estimated to cost the US $6 billion annually.
In addition, the genetic variant is associated with changes in the composition of the gut microbiome—which is made up of potentially billions of microbes that help people digest food, synthesize nutrients and perform myriad other essential functions—in healthy people, overweight people and people with Crohn’s disease. The findings are reported online and scheduled for the October issue of the journal Gastroenterology, and the research was funded by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and Helmsley Charitable Trust, among others.
“We knew from previous studies that there is reduced diversity of the gut microbiome in patients with Crohn’s disease,” said co-senior and corresponding author Richard Duerr, MD, a professor in Pitt’s School of Medicine, and co-director and scientific director of the UPMC Inflammatory Bowel Disease Center. “But that left us with a question: Does Crohn’s disease alter the composition of the gut microbiota, or do pre-existing changes in the gut microbiota confer risk for Crohn’s disease? Our study found that there is a reduction in the abundance of hundreds of minor species of gut bacteria in healthy, overweight and Crohn’s disease-affected people who carry this genetic variant, suggesting that the genetic variant may increase risk for disease by altering the gut habitat. This is an important step toward understanding how the disease works so we can develop therapies or a cure in the future.”
Under the leadership of Dr. Duerr and co-senior author Dermot McGovern, MD, PhD, FRCP (Lon), director of Translational Medicine in the Cedars-Sinai F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, the team focused their analysis on 10,523 blood samples from people with inflammatory bowel disease (half had been diagnosed with Crohn’s disease) and 5,726 samples from healthy people.  They discovered that a variation in the SLC39A8 gene is associated with Crohn’s disease.“This finding is another important example of how a particular genetic variant can have a role in the development and course of many diseases. Our study of this variant suggests that therapies effective in treating one disease also may benefit the treatment of some patients with other illnesses,” said Dr. McGovern, who also is director of Precision Medicine at Cedars-Sinai.

Taking it a step further, the team identified healthy people, overweight people and Crohn’s disease-affected people with the genetic variant and analyzed their gut microbiomes under the leadership of co-senior author Jonathan Braun, MD, PhD, chair and professor of pathology and laboratory medicine in the David Geffen School of Medicine at UCLA. That is how they discovered that the genetic variant is not just linked to Crohn’s and other conditions, but also to a reduction in hundreds of species of gut bacteria.
“Many of these species are believed to play roles in protecting the intestine against Crohn’s disease, and also in preserving a lean body physiology,” said Dr. Braun. “So, this may be an example where the gene increases risk for disease via its effect on types of bacteria we need to preserve our health.”

The findings have sparked additional questions and potential research avenues, but therapies are still quite a ways off, said Dr. Duerr, also a professor in the Pitt Graduate School of Public Health Department of Human Genetics. However, the recent establishment of the University of Pittsburgh Center for Medicine and the Microbiome will help accelerate this research and bring potential therapies—which may involve the center’s clinical fecal transplantation program—to patients.

“This study illustrates the remarkable interaction between our proper genome and our symbiome—the organisms and environment inside and outside of us that influence our well-being—in the setting of inflammatory bowel disease,” said Mark T. Gladwin, MD, chair of medicine and Dr. Jack D. Myers Professor of Internal Medicine at Pitt. “Insights from this study are likely to guide the development of microbiome modulating therapies that hold the promise to alleviate patient suffering.”

Additional institutions with researchers who participated in this study are Cleveland Clinic; Yale University; Karolinska Institutet and Örebro University, both in Sweden; Biocruces Health Research Institute in Spain; University Hospital Munich-Grosshadern, University of Ulm, Krankenhaus Waldfriede and Ludwig-Maximilians-University, all in Germany; QIMR Berghofer Medical Research Institute, Royal Brisbane and Women’s Hospital and University of Queensland, all in Australia; Inselspital Bern and University Hospital Basel, both in Switzerland; Emory University; University of Chicago; Harvard University; Université de Montréal, Hôpital Maisonneuve-Rosemont, University of Toronto and Montreal Heart Institute, all in Canada; Icahn School of Medicine at Mount Sinai; University of California Riverside; The Children’s Hospital of Philadelphia; Massachusetts Institute of Technology; and Johns Hopkins University.

Additional support for this research was provided by numerous grants to the individual researchers, as listed in the Gastroenterology research publication.

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