(Press-News.org) A collaborative team of leaders in the field of cancer immunology from Memorial Sloan Kettering Cancer Center has made a key discovery that advances the understanding of why some patients respond to ipilimumab, an immunotherapy drug, while others do not. MSK was at the forefront of the clinical research that brought this CTLA-4 blocking antibody to melanoma patients.
A report published online first today in the New England Journal of Medicine shows that in patients who respond to ipilimumab, their cancer cells carry a high number of gene mutations--some of which make tumors more visible to the immune system, and therefore easier to fight. The research was led by Vice Chair of Radiation Oncology and cancer genomics researcher Timothy Chan MD, PhD; oncology fellow Alexandra Snyder Charen, MD; and Chief of the Melanoma and Immunotherapeutics Service and the Lloyd J. Old Chair for Clinical Investigation Jedd Wolchok, MD, PhD.
"We are learning that there are few treatments that don't have some footprint in the cancer genome," says Dr. Chan. "For the first time, it might be feasible to develop a reliable diagnostic test to help guide treatment decisions by predicting who will respond."
Clinical trials of ipilimumab (YervoyTM) have produced practice-changing results for many types of cancer. The drug works by blocking a protein called CTLA-4, boosting the body's natural immune defense against tumors. Normally, CTLA-4 keeps the tumor-fighting activity of the immune system's T cells in check. In the presence of the drug, T cells are unleashed and their inherent ability to recognize and destroy cancer cells is enhanced.
For some patients, the drug shrinks tumors and significantly prolongs lives. Over the past decade, immunotherapy has signaled a scientific game changer. "We've spent much time and effort studying how to target the tumor. And we've only recently understood how to have the patient's immune defenses mobilized to treat the tumor. Immunotherapy is by definition how that happens," says Dr. Wolchok.
But the approach doesn't help everyone. In fact, about 80 percent of people with melanoma get little or no benefit from ipilimumab. And thus far, doctors have had no way of predicting which patients are more likely to respond to the drug.
This new study brings the team one step closer to finding an answer. "There was a correlation between having an elevated number of mutations, or more DNA changes in a tumor, and benefitting from the treatment with ipilimumab, with benefit being long-term stability or resolution of metastatic disease," explains Dr. Snyder Charen.
The team collected tumor samples from 64 melanoma patients who had been treated with ipilimumab or tremelimumab, an experimental drug that works in a similar way. The tumors were analyzed by whole-exome sequencing, a method that deciphers DNA changes across all parts of the genome that code for protein. About half of the tumors analyzed came from patients for whom the treatment had been successful and the other half from people who derived little or no benefit from it.
"We found that tumors that had responded to the drug had a higher mutational burden, or overall number of DNA changes," says Dr. Snyder Charen. "But the correlation isn't perfect. Not all patients with a high mutational burden in their tumors responded to the drug."
"This made us ask, 'What is the immune system seeing?" says Dr. Wolchok. "What is it about the mutational landscape of a tumor that helps the immune system recognize and attack it?"
Using sophisticated computational tools, the researchers were able to explore their data through the lens of immunology. They found that drug-responsive tumors share a certain type of mutation that makes cancer cells express new antigens--substances that T cells can detect and recognize as foreign to the body. The collaborative team responsible for these key findings also includes patients. "These advances would not have been made without the generosity of patients who consented to having their tumor tissue collected and analyzed," Dr. Snyder Charen concludes. "Dr. Wolchok and his lab members have spent many years banking samples, and it's an invaluable resource for research."
Eventually, these findings could translate into a diagnostic test to detect the mutations in melanoma patients. Results could help doctors and patients make more-informed treatment choices. In addition, the MSK team plans to investigate whether specific tumor mutations influence the effectiveness of other immunotherapy drugs. Dr. Chan says, "If we know a patient won't respond to ipilimumab, we may be able to identify other drugs that are more likely to be effective against this person's tumor."
INFORMATION:
About Memorial Sloan Kettering Cancer Center
We are the world's oldest and largest private cancer center, home to more than 13,000 physicians, scientists, nurses, and staff united by a relentless dedication to conquering cancer. As an independent institution, we combine 130 years of research and clinical leadership with the freedom to provide highly individualized, exceptional care to each patient. And our always-evolving educational programs continue to train new leaders in the field, here and around the world. For more information, go to http://www.mskcc.org.
This research was supported by Ludwig Cancer Research and grants from the Frederick Adler Fund, the National Institutes of Health, Swim Across America, the Ludwig Trust, the Melanoma Research Alliance, the Stand Up To Cancer-Cancer Research Institute Immunotherapy Dream Team, the Hazen-Polsky Foundation, and the STARR Cancer Consortium. Stand Up To Cancer is a program of the Entertainment Industry Foundation administered by the American Association for Cancer Research.
Barcelona, Spain: Patients with a form of advanced colorectal cancer that is driven by a mutated version of the BRAF gene have limited treatment options available. However, results from a multi-centre clinical trial suggest that the cancer may respond to a combination of three targeted drugs.
Professor Josep Tabernero, head of the medical oncology department at Vall d'Hebron University Hospital and director of the Vall d'Hebron Institute of Oncology, Barcelona, Spain, will tell the 26th EORTC-NCI-AACR [1] Symposium on Molecular Targets and Cancer Therapeutics in Barcelona ...
(PHILADELPHIA) - Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, is a neurodegenerative disease that primarily kills motor neurons, leading to paralysis and death 2 to 5 years from diagnosis. Currently ALS has no cure. Despite promising early-stage research, the majority of drugs in development for ALS have failed. Now researchers have uncovered a possible explanation. In a study published November 20th in the Annals of Clinical and Translational Neurology, researchers show that the brain's machinery for pumping out toxins is ratcheted up in ALS ...
A lot of research has shown that poor regulation of the serotonin system, caused by certain genetic variations, can increase the risk of developing psychiatric illnesses such as autism, depression, or anxiety disorders. Furthermore, genetic variations in the components of the serotonin system can interact with stress experienced during the foetal stages and/or early childhood, which can also increase the risk of developing psychiatric problems later on.
In order to better understand serotonin's influence in the developing brain, Alexandre Dayer's team in the Psychiatry ...
Working at the edge of a coal mine in India, a team of Johns Hopkins researchers and colleagues have filled in a major gap in science's understanding of the evolution of a group of animals that includes horses and rhinos. That group likely originated on the subcontinent when it was still an island headed swiftly for collision with Asia, the researchers report Nov. 20 in the online journal Nature Communications.
Modern horses, rhinos and tapirs belong to a biological group, or order, called Perissodactyla. Also known as "odd-toed ungulates," animals in the order have, ...
Bremerhaven/Germany, 20 November 2014. Scientists from the Alfred Wegener Institute, Helmholtz Centre for Polar and Marine Research (AWI) have identified a possible source of carbon dioxide (CO2) and other greenhouse gases that were abruptly released to the atmosphere in large quantities around 14,600 years ago. According to this new interpretation, the CO2 - released during the onset of the Bølling/Allerød warm period - presumably had their origin in thawing Arctic permafrost soil and amplified the initial warming through positive feedback. The study now appears ...
The residents of Longyearbyen, the largest town on the Norwegian arctic island archipelago of Svalbard, remember it as the week that the weather gods caused trouble.
Temperatures were ridiculously warm - and reached a maximum of nearly +8 degrees C in one location at a time when mean temperatures are normally -15 degrees C. It rained in record amounts.
Snow packs became so saturated that slushy snow avalanches from the mountains surrounding Longyearbyen covered roads and took out a major pedestrian bridge.
Snowy streets and the tundra were transformed into icy, ...
MEDFORD/SOMERVILLE, Mass-- Tufts University School of Engineering researchers and collaborators from Texas A&M University have published the first research to use computational modeling to predict and identify the metabolic products of gastrointestinal (GI) tract microorganisms. Understanding these metabolic products, or metabolites, could influence how clinicians diagnose and treat GI diseases, as well as many other metabolic and neurological diseases increasingly associated with compromised GI function. The research appears in the November 20 edition of Nature Communications ...
AMHERST, Mass. -- Predicting the beginning of influenza outbreaks is notoriously difficult, and can affect prevention and control efforts. Now, just in time for flu season, biostatistician Nicholas Reich of the University of Massachusetts Amherst and colleagues at Johns Hopkins have devised a simple yet accurate method for hospitals and public health departments to determine the onset of elevated influenza activity at the community level.
Hospital epidemiologists and others responsible for public health decisions do not declare the start of flu season lightly, Reich ...
A team of scientists hope to trace the origins of gamma-ray bursts with the aid of giant space 'microphones'.
Researchers at Cardiff University are trying to work out the possible sounds scientists might expect to hear when the ultra-sensitive LIGO and Virgo detectors are switched on in 2015.
It's hoped the kilometre-scale microphones will detect gravitational waves created by black holes, and shed light on the origins of the Universe.
Researchers Dr Francesco Pannarale and Dr Frank Ohme, in Cardiff University's School of Physics and Astronomy, are exploring the potential ...
(PHILADELPHIA) - Pulmonary fibrosis has no cure. It's caused by scarring that seems to feed on itself, with the tougher, less elastic tissue replacing the ever moving and stretching lung, making it increasingly difficult for patients to breathe. Researchers debate whether the lung tissue is directly damaged, or whether immune cells initiate the scarring process - an important distinction when trying to find new ways to battle the disease. Now research shows that both processes may be important, and suggest a new direction for developing novel therapies. The work will publish ...
