New immunotherapy targets misshapen protein in rare childhood brain cancerDecember 04, 2017
= Children with an extremely deadly form of brain cancer might benefit from a new treatment that aims to direct an immune response against an abnormally shaped protein found exclusively on cancer cells, according to a new study led by UC San Francisco researchers.
The focus of the study, published online December 4, 2017 in the Journal of Experimental Medicine, is diffuse intrinsic pontine glioma (DIPG), an aggressive pediatric brain cancer. DIPG is rare -- estimates suggest that about 300 new cases occur in the United States each year -- but almost always fatal.
Because DIPG occurs in a difficult-to-access area of the brain stem that controls vital functions such as breathing, blood pressure, and heart rate, these tumors are almost impossible to remove surgically. Radiation therapy is the current standard treatment, but is rarely effective for long, according to Hideho Okada, MD, PhD, professor of neurological surgery and director of the Brain Tumor Immunotherapy Center at UCSF, and the senior author of the study.
"It is important to develop more innovative treatment approaches for childhood brain cancers, which now are the leading cause of cancer death in children. DIPG is a very deadly type of brain cancer, and not many children survive beyond 12 months from the time of diagnosis." said Okada, also a member of the Helen Diller Family Comprehensive Cancer Center (HDFCC) at UCSF and of the Parker Institute for Cancer Immunotherapy.
Okada, along with Sabine Mueller, MD, PhD, MAS, an assistant professor of clinical neurology at UCSF and a HDFCCC member, already are leading a phase I clinical trial in children with DIPG and closely related gliomas, in order to evaluate a new anti-tumor vaccine based on the new target identified by Okada's research group.
The new study's preclinical results also support the development of an immunotherapy treatment that is potentially more powerful than a simple vaccine, one in which some of the patient's own immune cells would be genetically engineered to recognize the molecular target, which is found on tumor cells in most cases of DIPG and related gliomas, but not on normal cells.
The immune system needs a boost to fight established tumors. Normally it can distinguish a healthy cell from a cell infected by invading pathogens by inspecting bits of molecules, called antigens, which cells display on their outer surface. Very early in life the immune system learns to tolerate rather than to attack cells displaying antigens made by the body's own cells. Because tumors arise from our own cells, the immune system is likely to tolerate rather than attack the cells of an established tumor.
The target of the new DIPG treatment is a "neoantigen." A neoantigen is a fragment of a protein made by a cancer cell that has an abnormal structure -- and often an abnormal function -- due to genetic mutation, a hallmark of cancer. Researchers are developing techniques to select neoantigens that they think will be the most likely to be seen and identified as foreign by the immune system, and they aim to develop immunotherapies to boost immune responses to tumor cells displaying these neoantigens.
Tumors often have a large variety of mutated proteins, but many of these proteins are too similar to normal antigens for the immune system to recognize them as a threat. Even if the immune system can be coaxed to attack cells displaying a fragment of these mutant proteins, it might also learn to attack healthy cells displaying the protein's normal counterpart. In fact, autoimmunity is a risk for many patients given current immunotherapies, such as "checkpoint inhibitors," which release the brakes that prevent the immune system from attacking tumor cells.
The hope is that well-chosen neoantigens can be used to develop treatments that will more selectively and potently target tumors. Neoantigen-based treatments are still experimental, but many are in clinical trials.
The neoantigen Okada and colleagues worked with is a fragment of a protein called histone 3 variant 3. This protein is identically mutated in about 70 percent of cases of DIPG and results in abnormal control of gene activity in tumor cells. Earlier studies by other researchers found that when the mutation is present, it is present in all, or nearly all cells of the tumor.
"This may be an ideal case of a tumor neoantigen," Okada, said. "Most neoantigens in cancer are unique to individual patients, but this is one of very, very few examples of a shared, common neoantigen that may have the potential to be used in many patients."
The researchers used some of the latest computational techniques to predict that a specific fragment of the protein that includes the neoantigen would bind especially strongly to a protein called HLA A, which displays antigens for inspection by patrolling immune cells called T cells. The strength of this attachment ought to correspond to the likelihood that a neoantigen will be recognized as a threat by the immune system.
In laboratory experiments the researchers confirmed this prediction. They found a strong affinity between the tumor neoantigen and a type of HLA A found in about 40 percent of DIPG patients. In contrast, they found no corresponding affinity between this HLA A type and non-mutated antigens from related proteins produced by healthy cells, suggesting that treatments based on this neoantigen should be specific to tumor cells only.
The goal of the neoantigen-containing vaccine now being tested in Okada and Mueller's clinical trial is to train the immune system's T cells to recognize the neoantigen in the vaccine, which should then trigger an immune response to tumor cells in the brain that display the same neoantigen, Okada said.
The new paper also demonstrates a promising, even more powerful form of treatment based on directly engineering patients' T cells to recognize the target neoantigen. Every T cell has a particular type of T cell receptor protein that can recognize a single antigen paired with an HLA protein. The scientists used T cells from patients with the HLA A type that bound tightly to the novel DIPG neoantigen to identify naturally arising T cell receptors that recognize the combination. They selected the best T cell receptor, cloned it into other T cells, and grew large numbers of these cells in the lab. They then demonstrated that these lab-grown T cells could effectively kill human glioma tumors grown in mice.
"We saw a significant reduction in tumor progression compared to control groups," said tumor immunologist Zinal Chheda, PhD, a postdoctoral fellow with Okada's lab and the co-lead author of the study. "The T cell receptor we selected for cloning has an affinity for the neoantigen that is in the range of what we see for antigens from viruses -- orders of magnitude greater than what we generally see with neoantigens found on cancer cells."
UC San Francisco (UCSF) is a leading university dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care. It includes top-ranked graduate schools of dentistry, medicine, nursing and pharmacy; a graduate division with nationally renowned programs in basic, biomedical, translational and population sciences; and a preeminent biomedical research enterprise. It also includes UCSF Health, which comprises three top-ranked hospitals, UCSF Medical Center and UCSF Benioff Children's Hospitals in San Francisco and Oakland, and other partner and affiliated hospitals and healthcare providers throughout the Bay Area.
University of California - San Francisco
Related Cancer Articles:
East Asian female breast cancer patients receiving radiotherapy have a higher risk of developing second primary lung cancer.
Continuing PLOS Medicine's special issue on cancer genomics, Christos Hatzis of Yale University, New Haven, Conn., USA and colleagues describe a new subtype of triple negative breast cancer that may be more amenable to treatment than other cases of this difficult-to-treat disease.
Osaka University researchers revealed that the metabolite D-2-hydroxyglurate (D-2HG) promotes epithelial-mesenchymal transition of colorectal cancer cells, leading them to develop features of lower adherence to neighboring cells, increased invasiveness, and greater likelihood of metastatic spread.
University of Hawai'i Cancer Center researchers have identified an essential driver of tumor cell invasion in glioblastoma, the most aggressive form of brain cancer that can occur at any age.
University of Hawai'i Cancer Center researchers developed a computational algorithm to analyze 'Big Data' obtained from tumor samples to better understand and treat cancer.
University of Oklahoma researchers will apply a new analytical technology that could ultimately provide a powerful tool for improved treatment of cancer patients in Oklahoma and beyond.
Researchers have found that treating patients who have early stage non-small cell lung cancer with a type of radiotherapy called stereotactic body radiation therapy is associated with a small but increased risk of death from causes other than cancer.
Is investment in research to develop new treatments the best approach to controlling cancer?
The University of Illinois Cancer Center and Governors State University have received a joint four-year, $1.5 million grant from the National Cancer Institute to help both institutions conduct community-based research to reduce cancer-related health disparities in Chicago's south suburbs.
The Cancer Research Institute, the Association for Cancer Immunotherapy, the European Academy of Tumor Immunology, and the American Association for Cancer Research will join forces to sponsor the first International Cancer Immunotherapy Conference at the Sheraton New York Times Square Hotel in New York, Sept.
Related Cancer Reading:
The Cancer-Fighting Kitchen, Second Edition: Nourishing, Big-Flavor Recipes for Cancer Treatment and Recovery
by Rebecca Katz (Author), Mat Edelson (Author)
This new and revised edition of the IACP award-winning cookbook brings the healing power of delicious, nutritious foods to those whose hearts and bodies crave a revitalizing meal, through 150 new and updated recipes.
Featuring science-based, nutrient-rich recipes that are easy to prepare and designed to give patients a much-needed boost by stimulating appetite and addressing treatment side effects including fatigue, nausea, dehydration, mouth and throat soreness, tastebud changes, and weight loss. A step-by-step guide helps patients nutritionally prepare for all phases of... View Details
F*ck Cancer: A totally inappropriate self-affirming adult coloring book (Totally Inappropriate Series) (Volume 4)
by Jen Meyers (Author)
*A portion of the proceeds from this book will be donated to support research dedicated to finding a cure for cancer. Because fuck cancer.
This book is for you.
If you are fighting cancer, this is for you. If your brother, sister, mom, dad, son, daughter, relative, or friend is fighting cancer, this is for you. If you've lost someone to cancer like I have, this is for you. If cancer affects your life in any way, this is for you.
The stress of cancer can feel crushing. But perhaps this book can help you get away from it all, if only for a little... View Details
The Metabolic Approach to Cancer: Integrating Deep Nutrition, the Ketogenic Diet, and Nontoxic Bio-Individualized Therapies
by Dr. Nasha Winters ND FABNO L.Ac Dipl.OM (Author), Jess Higgins Kelley MNT (Author), Kelly Turner (Foreword)
The Optimal Terrain Ten Protocol to Reboot Cellular Health
Since the beginning of the twentieth century, cancer rates have increased exponentially―now affecting almost 50 percent of the American population. Conventional treatment continues to rely on chemotherapy, surgery, and radiation to attack cancer cells. Yet research has repeatedly shown that 95 percent of cancer cases are directly linked to diet and lifestyle. The Metabolic Approach to Cancer is the book we have been waiting for―it offers an innovative, metabolic-focused nutrition protocol that... View Details
Tripping over the Truth: How the Metabolic Theory of Cancer Is Overturning One of Medicine's Most Entrenched Paradigms
by Travis Christofferson (Author), Dominic D'Agostino (Foreword)
With a new foreword by Dr. Dominic D'Agostino, PhD and epilogue by the author
A masterful synchronization of history and cutting-edge science shines new light on humanity's darkest diagnosis.
In the wake of the Cancer Genome Atlas project's failure to provide a legible roadmap to a cure for cancer, science writer Travis Christofferson illuminates a promising blend of old and new perspectives on the disease. Tripping over the Truth follows the story of cancer’s proposed metabolic origin from the vaunted halls of the German scientific golden age to... View Details
Cancer Hates Tea: A Unique Preventive and Transformative Lifestyle Change to Help Crush Cancer
by Maria Uspenski (Author), Dr. Mary L. Hardy (Foreword)
Drink Tea to Tell Cancer ‘Hit the Road’
Become a tea lover with a purpose and help your body defend itself against cancer. Learn to embrace tea in all its varieties― green, white, black, pu-erh, herbal and more―as both a mental and physical experience to protect your health. Discover the history, growing information and health implications of each variety, as well as uniquely delicious methods to boost your intake with serving suggestions, food pairings and recipes that highlight the benefits of tea.
After her own battle with cancer, Maria Uspenski extensively... View Details
The Truth about Cancer: What You Need to Know about Cancer's History, Treatment, and Prevention
by Ty M Bollinger (Author)
Cancer touches more lives than you may think. According to the World Health Organization, one out of three women alive today, and one out of two men, will face a cancer diagnosis in their lifetime.
To Ty Bollinger, this isn’t just a statistic. It’s personal. After losing seven members of his family to cancer over the course of a decade, Ty set out on a global quest to learn as much as he possibly could about cancer treatments and the medical industry that surrounds the disease. He has written this book to share what he’s uncovered—some of which may shock you—and to give you... View Details
Cancer: 50 Essential Things to Do: 2013 Edition
by Greg Anderson (Author)
The ground-breaking classic guide to surviving cancer?now completely updated!
Revised and updated for the first time since 1999, this invaluable guide to cancer recovery offers an easily accessible plan for patients and family members. Written by a cancer survivor, the book is an inspiring, action-oriented roadmap for those who choose to adopt a stance of hope and take charge of their diagnosis.
With penetrating insights that bring together more than two decades of scientifically supported research and experience, Anderson reveals a step-by-step holistic action plan... View Details
The Cancer Revolution: A Groundbreaking Program to Reverse and Prevent Cancer
by Leigh Erin Connealy (Author)
When it comes to cancer, conventional doctors are trained to treat their patients exclusively with surgery, radiation, and chemotherapy. These methods are grueling on the whole body - and they don't treat beyond the tumor or the cancer itself. The focus is on the disease, not the whole person - and because of this, the outcomes in conventional medicine can be bleak.
But it doesn't have to be this way. Dr. Leigh Erin Connealy has developed a whole-person approach to treating cancer - and these treatments have helped thousands of patients through her Cancer Center for Healing. In... View Details
Anticancer: A New Way of Life
by David Servan-Schreiber MD PhD (Author)
The revolutionary, New York Times bestselling guide to the powerful lifestyle changes that fight and prevent cancer—an integrative approach based on the latest scientific research
“A common-sense blueprint for healthy living.” —Chicago Tribune
“Resonating with cancer support communities and recommended nationwide.” —Los Angeles Times
“Life affirming . . . filled with practical advice.” —The Seattle Times
David Servan-Schreiber was a rising... View Details
Beating Cancer with Nutrition (Fourth Edition) Rev
by Patrick Quillin (Author)
There is good news in the "war on cancer". Optimal nutrition coupled with appropriate medical treatment can dramatically improve the quality and quantity of life and chances for a complete remission for most cancer patients. A well-nourished cancer patient can better manage the disease. Cancer is the number two cause of death in America and the developed nations of the world with one out of four dying from cancer and 38% of women and 43% of men projected to develop cancer over their lifetime. While the overall death rate from cancer has not appreciably declined since... View Details