First-In-Human Clinical Trial Aims to Extend Remission for Children and Young Adults With Leukemia Treated With T-Cell Immunotherapy

Phase 1 pilot study utilizes T-cell antigen presenting cells to prolong the persistence of cancer-fighting chimeric antigen receptor (CAR) T cells, reduce the relapse rate

After phase 1 results of Seattle Children’s Pediatric Leukemia Adoptive Therapy (PLAT-02) trial have shown T-cell immunotherapy to be effective in getting  93 percent of patients with relapsed or refractory acute lymphoblastic leukemia (ALL) into complete initial remission, researchers have now opened a first-in-human clinical trial aimed at reducing the rate of relapse after the therapy, which is about 50 percent. The new phase 1 pilot study, PLAT-03, will examine the feasibility and safety of administering a second T-cell product intended to increase the long-term persistence of the patient’s chimeric antigen receptor (CAR) T cells that were reprogrammed to detect and destroy cancer.

The research team, led by Dr. Mike Jensen at the Ben Towne Center for Childhood Cancer Research at Seattle Children’s Research Institute, is exploring this strategy after discovering that of the patients who relapse in the PLAT-02 trial, about half of them have lost their CAR T cells. Lasting persistence of the CAR T cells is critical in combating a recurrence of cancer cells.

“While it’s promising that we’re able to get these patients who are very sick back into remission, we’re also seeing that the loss of the CAR T cells in some patients may be opening the door for the cancer to return,” said Dr. Colleen Annesley, an oncologist at Seattle Children’s and the lead investigator of the PLAT-03 trial. “We’re pleased to now be able to offer patients who have lost or are at risk of losing their cancer-fighting T cells an option that will hopefully lead to them achieving long-term remission.”

In the PLAT-03 trial, patients will receive “booster” infusions of a second T-cell product, called T antigen-presenting cells (T-APCs). The T-APCs have been genetically modified to express the CD19 target for the cancer-fighting CAR T cells to recognize. Patients will receive a full dose of T-APCs every 28 days for at least one and up to six doses. By stimulating the CAR T cells with a steady stream of target cells to attack, researchers hope the CAR T cells will re-activate, helping to ensure their persistence long enough to put patients into long-term remission.

PLAT-03 is now open to patients who first enroll in phase 2 of Seattle Children’s PLAT-02 trial and who are also identified as being at risk for early loss of their reprogrammed CAR T cells, or those who lose their reprogrammed CAR T cells within six months of receiving them.

The PLAT-03 trial is one of several trials that Seattle Children’s researchers are planning to open within the next year aimed at further improving the long-term efficacy of T-cell immunotherapy. In addition to the current T-cell immunotherapy trial that is open for children with neuroblastoma, researchers also hope to expand this promising therapy to other solid tumor cancers.

“We are pleased to be at a pivotal point where we are now looking at several new strategies to further improve CAR T-cell immunotherapy so it remains a long-term defense for all of our patients,” said Dr. Rebecca Gardner, Seattle Children’s oncologist and the lead investigator of the PLAT-02 trial. “We’re also excited to be working to apply this therapy to several other forms of pediatric cancer beyond ALL, with the hope that T-cell immunotherapy becomes a first line of defense, reducing the need for toxic therapies and minimizing the length of treatment to only weeks.”

To read about the experience of one of the patients in the PLAT-02 trial, please visit Seattle Children’s On the Pulse blog.

The T-cell immunotherapy trials at Seattle Children’s are funded in part by Strong Against Cancer, a national philanthropic initiative with worldwide implications for potentially curing childhood cancers. If you are interested in supporting the advancement of immunotherapy and cancer research, please visit Strong Against Cancer’s donation page.

For more information on immunotherapy research trials at Seattle Children’s, please call (206) 987-2106 or email immunotherapy@seattlechildrens.org.

Cord Blood Test Might Help Predict Fatal Lung Disease in Preemies

Interventions for babies at risk could be started at birth to prevent disease

Findings published in the Journal of Pediatrics describe growth factors in cord blood that may identify premature infants at risk for bronchopulmonary dysplasia-associated pulmonary hypertension (BPD-PH) – an often fatal lung disease in which the vessels carrying blood from the heart to the lungs become narrowed and dysfunctional. Identifying these babies at birth would allow earlier interventions to prevent the disease that manifests in some preemies two to three months after birth.

“We have many promising interventions and it would be exciting to start them at birth in babies at risk, before they become extremely sick,” said lead author Karen Mestan, MD, a neonatologist at Ann & Robert H. Lurie Children’s Hospital of Chicago and Associate Professor at Northwestern University Feinberg School of Medicine. “Currently we do not use cord blood for prediction of disease, but our study shows that it has tremendous potential to save lives.”

Using a large repository of cord blood and placental tissues from a wide gestational age range, Mestan and colleagues examined 15 biomarkers in cord blood, looking for correlations with lesions in the placenta that cause insufficient blood flow between the mother and fetus. They found that two growth factors – granulocyte colony-stimulating factor (G-CSF) and placental growth factor (PlGF) – were decreased with these placental lesions. They also found that these two growth factors were almost undetectable in extremely premature babies who later developed BPD-PH, as opposed to others who escaped the disease. The team validated these findings in a large sample of babies born at less than 28 weeks of gestation.

“Our findings also have implications for what we do during pregnancy,” said Mestan. “The growth factors we identified potentially could be measured in the mom’s blood, and if they are low, that would signal lesions in the placenta that place the baby at risk for severe lung disease. Better understanding about fetal origins of disease, which is still a mystery, would help us find new ways to improve outcomes even before the child is born.”

While the findings do not establish that deficiency in the two growth factors causes BPD-PH, they suggest a possible mechanism behind the disease. “There are many undifferentiated stem cells in cord blood and these growth factors might help mobilize them to get assigned to specific immune functions involved in the healing process,” said Mestan. “Preemies who are deficient in G-CSF and PlGF might not be able to fight off the development of lung damage. But what if we could replenish these babies with healthier stem cells or even replenish the growth factors? We could then regenerate lung tissue. This is a thrilling area of research that could have huge impact.”

Larger, multicenter studies are needed to validate findings before the growth factors can be used clinically to identify premature infants at risk for BPD-PH in order to initiate earlier interventions.

AACR: Phase II Trial Shows Rice Bran Promotes Microbiome Diversity, Slows Growth of Colorectal Cancer Cells

Today at the American Association for Cancer Research (AACR) Annual Meeting 2017, University of Colorado Cancer Center researchers at Colorado State University present results of a phase II clinical trial of 29 people exploring the effects of adding rice bran or navy beans to the diets of colorectal cancer survivors. After the 4-week randomized-controlled trial during which people added rice bran, navy bean powder or neither, both the rice bran and navy bean groups showed increased dietary fiber, iron, zinc, thiamin, niacin, vitamin B6, folate, and alpha-tocopherol. The rice bran group also showed increased microbiome richness and diversity. When researchers treated colorectal cancer cells with stool extracts from these groups, they saw reduced cell growth from the groups that had increased rice bran and navy bean consumption.

Previous work shows the ability of these diets to decrease colorectal cancer risk in animal models. The current trial confirms that people can eat enough bean- and rice bran-enhanced foods to promote gut health at levels shown to prevent colorectal cancer in animals.

Guidelines from the American Institute for Cancer Research recommend reducing the risk of cancer by eating more vegetables, fruits, whole grains and legumes, such as beans. Ryan has established from these studies that eating a half-cup of beans and 30 grams of rice bran per day is enough to see changes in small molecules that can confer protection against colorectal cancer.

“The simple message is, ‘Food is medicine,’ and we are looking at how to simplify that and make it apply to our everyday lives,” says study co-author Regina Brown, MD, assistant professor at the CU School of Medicine and oncologist for CUHealth.

Brown is long-time collaborator of CU Cancer Center investigator and CSU assistant professor, Elizabeth Ryan, PhD. The Ryan Lab in the CSU College of Veterinary Medicine and Biomedical Sciences studies the potential power of navy beans and rice bran to promote digestive health and to prevent metabolic alterations in obesity, heart disease and certain cancers.

“The evidence is there in animals and we can now study this in people. The question is, what are we doing to achieve adequate levels of intake of these foods?” Ryan said. “It’s not enough to say ‘I eat them once in a while.’ That’s not going to work, particularly if you are at higher risk. You have to meet a dose, just like you need a dose of a certain drug, you need to reach intake levels and consume increased amounts of these foods, and that’s where people, including me, are challenged. Not everyone wants to open up a can of beans and eat them every day.”

The two met about 10 years ago, when Ryan was a researcher in CSU professor Henry Thompson’s Cancer Prevention Lab, and Brown was practicing medicine in Fort Collins and caring for her mother, who had uterine cancer.

“It was kind of a novel partnership and had we not dug in our heels it could have died, but I told Elizabeth, ‘Your work is so interesting and so valuable. We have to take this translational research from the benchtop to the clinic.’ I guarantee, nine out of 10 of my patients, the first thing they ask is about their diet,” Brown said.

The study’s lead author is Erica Borresen, Ryan’s research associate and study coordinator, who worked with colorectal cancer survivors to make sure they ate their beans and rice bran provided in meals and snacks, and that they filled out their food logs and gastrointestinal health questionnaires. It was sometimes intimate and awkward, but so is getting a colonoscopy and being treated for colorectal cancer.

“Our participants donated their time and effort, and I want to make sure they understand they are appreciated,” said Borresen, who earned her Master of Public Health at the Colorado School of Public Health, and plans to become a physician’s assistant. “I came to realize I love the patient interaction – that’s one of my favorite parts about coordinating our studies.”

The next phase of Ryan’s research examines effects of the cooked navy bean powder and rice bran on the colon tissue of people who have already had colorectal cancer and are at high risk for recurrence.

“I really feel that there’s hope in this being a practical solution to improve gut health and specifically colorectal cancer prevention,” says Ryan.

First in Human’ Trial Defines Safe Dosage for Small Molecule Drug ONC201 for Solid Cancer Tumors

Research from Rutgers Cancer Institute of New Jersey examines oral drug that targets cancer cells and spares healthy tissue

A ‘first in human’ clinical trial examining the small molecule drug ONC201 in cancer patients with advanced solid tumors shows that this investigational drug is well tolerated at the recommended phase II dose. That’s according to Rutgers Cancer Institute of New Jersey investigators and colleagues whose research also showed early signs of clinical benefit in patients with advanced prostate and endometrial cancers. The work appears in the ‘OnlineFirst’ section of Clinical Cancer Research (DOI: 10.1158/1078-0432.CCR-16-2658).

At focus is the investigational drug ONC201 that targets a dopamine receptor, a member of the G protein-coupled receptor superfamily residing on the surface of cancer cells, to cause their destruction. ONC201 is the first of a new family of therapeutic compounds called imipridones. Previous research on the study drug conducted by Rutgers Cancer Institute and Oncoceutics, Inc. – which is also supporting this trial – suggests that ONC201 may be capable of turning off proteins that maintain tumor growth and and may help kill cancer cells while sparing normal ones. Pre-clinical study demonstrated ONC201 was effective in laboratory models against a number of solid tumors including colon cancer, brain cancer, triple-negative breast cancer and non-small cell lung cancer.

In this phase I dose-escalation study, 10 patients over age 18 with advanced solid tumors that were resistant to standard therapies were enrolled through Rutgers Cancer Institute between January and July 2015. Participants received a starting dose of 125mg of the study drug, which was taken orally via capsule every 21 days (one cycle). The dosage for this cohort was increased incrementally up to a maximum dose of 625mg, which is five-fold above the dose that was effective in laboratory models. An additional 18 patients were enrolled in an expansion phase between August 2015 and February 2016 and treated at the recommended phase II dose of 625mg in order to collect additional safety, pharmacokinetic and pharmacodynamic information.

There were no drug-related adverse events over Grade 1 in either the dose escalation phase or the expansion phase. The few low grade events that were recorded (nausea, fever) were resolved quickly, note the authors. While the study achieved the aim of identifying the recommended phase II dose of the drug, findings also showed tumor regression in patients with metastatic disease. Results also demonstrated prolonged stable disease following more than nine cycles (27 weeks) of treatment – particularly in prostate and endometrial cancer patients that had lymph node, bone and lung lesion involvement. Out of the 28 participants, 10 completed at least four cycles of treatment with two patients receiving at least nine cycles. The authors note while a 90-year old prostate cancer patient saw his primary tumor and metastatic bone lesion shrink by about 25 percent after taking two 625mg doses of ONC201, a 72-year old patient with advanced clear cell endometrial cancer had a mixed response after two doses, with multiple nodes decreasing by more than 30 percent but experiencing the development of new nodes.

“By exploring a novel agent that targets the cancer but leaves non-cancerous tissue untouched, we have an opportunity to not only provide a new treatment option for patients who have exhausted standard forms of therapy without the typical toxicities associated with anticancer treatment, but to also offer them a therapeutic that may result in a better quality of life since healthy cells are not impacted,” notes Rutgers Cancer Institute medical oncologist Mark Stein, MD, who is an associate professor of medicine at Rutgers Robert Wood Johnson Medical School and lead investigator of the work. “While meaningful to confirm the safety profile of this dosage for ONC201, it is noteworthy that our findings also showed some evidence of clinical benefit to some patients.”

Pivotal Trial Begins for Breast Fibroadenoma Using Focused Ultrasound

Patients with benign breast tumors may be eligible for a new focused ultrasound–based investigational treatment as part of a pivotal, multi-center clinical study. The trial began last month at the University of Virginia (UVA) Medical Center.

David Brenin, MD, Associate Professor of Surgery and Chief of Breast Surgery at UVA, is the Principal Investigator for the trial. He recently completed a 20-patient pilot study to test the safety and efficacy of the device, Theraclion’s EchoPulse system. Now, in this single arm prospective study, the procedure will be performed in 100 patients at several sites worldwide, including UVA, Montefiore Medical Center, Columbia Presbyterian, Bellevue Hospital Center in New York, and others. As these new sites begin treating, the list of locations will be updated on our website and on clinicaltrials.gov.

“The patient selection criteria have been updated since the pilot study,” says Dr. Brenin. “The new parameters for the size of the fibroadenoma and the range of symptoms should allow us to include more patients. Furthermore, our experience and improvements to the device have allowed us to decrease the overall treatment time.”

EchoPulse is designed to non-invasively ablate benign breast tumors using ultrasound-guided focused ultrasound treatment. Although it is not yet approved by the US Food and Drug Administration, the system received the CE Mark in Europe five years ago, where it is also used to treat breast fibroadenomas and treat thyroid nodules and is also under investigation for other conditions.

“If this multi-center trial is successful, we will seek regulatory approval in the US,” says Theraclion’s Chief Medical Officer, Michel Nuta, MD. “Approval by the FDA would allow many more women to receive precise treatment of breast fibroadenomas non-invasively and on an outpatient basis, enabling them to return to their daily lives almost immediately.”

Patients who are interested in this study at the University of Virginia (IRB# 19437) should contact Research Coordinator Katie Rea via phone (434) 243-0315 or email uvastac@virginia.edu. More information for patients and referring physicians can also be found on the UVA website.

Dr. Brenin plans to present the initial data from the pilot study at the 18th Annual Meeting of the American Society of Breast Surgeons in Las Vegas in April 2017.

Prostate Cancer Clinical Trial Shows Treating with Precision Radiotherapy Reduces Course of Treatment by 50%

An Ontario-led international clinical trial with 1,206 men with localized prostate cancer shows that compressing radiation treatments into four weeks from eight delivers similar outcomes.

The findings, published online today in the Journal of Clinical Oncology, provide a new standard of care worldwide, which the participating centres have already adopted, says co-principal investigator Charles Catton, radiation oncologist, Princess Margaret Cancer Centre, University Health Network. Dr. Catton is also a Professor, Department of Radiation Oncology, University of Toronto.

“We conducted a randomized clinical trial looking at a way of improving radiation therapy for men with intermediate-risk prostate cancer. Using modern radiation therapy techniques that are very precise, we determined there was no noticeable difference between eight- and four-week treatment regimens in terms of cancer control or side effects of treatment,” says Dr. Catton. The trial participants were followed for six years.

“In fact, for some men, the shorter regimen meant slightly fewer side effects (particularly regarding bowel function) and therefore improved quality of life. The compressed course of treatment is of great benefit to patients and also to the system in terms of being able to treat more patients in less time,” he says. In Canada, 20,000 men are diagnosed with prostate cancer every year; many of whom have intermediate-risk disease that has not spread.

The trial was conducted with co-principal investigator Himu Lukka, radiation oncologist, Juravinski Cancer Centre, and Professor, Department of Oncology, McMaster University, and coordinated by the Ontario Clinical Oncology Group, Hamilton, Ontario. Twenty-seven cancer centres in Canada, Australia and France participated in the study, which began in 2005.

Dr. Catton says the trial further improved patient care by standardizing quality delivery of precision radiation techniques among participating institutions.

The research was funded by the Canadian Institutes for Health Research and The Princess Margaret Cancer Foundation.

Monoclonal Antibody Drug Superior to Chemotherapy for Advanced Acute Lymphoblastic Leukemia

More than 100 centers participate in Phase III randomized trial revealing longer overall survival

A Phase III clinical trial involving 101 centers in 21 countries revealed the monoclonal antibody blinatumomab to be more effective than standard chemotherapy for treatment of advanced acute lymphoblastic leukemia (ALL). Study findings were published in the March 1 online issue of the New England Journal of Medicine.

The study, led by The University of Texas MD Anderson Cancer Center, randomly assigned 405 patients 18 years or older to groups receiving either blinatumomab or chemotherapy. Overall survival was significantly longer in the blinatumomab group with median survival of 7.7 months versus four months for those on chemotherapy. Remission rates within 12 weeks after treatment began were higher in the blinatumomab group with complete remission rates of 34 percent reported in this group versus 16 percent for those on chemotherapy. The study also showed that patients treated with blinatumomab had a lower rate of adverse effects.

While the prognosis for newly diagnosed ALL has improved over the last three decades with intensive chemotherapy regimens resulting in complete remission rates of 85 to 90 percent and long-term survival rates of 30 to 50 percent, most adult patients with the B-cell precursor ALL, the most common form, ultimately relapse and die from disease complications. The accepted standard of care is to help the patient maintain remission long enough to receive allogeneic or donor stem-cell transplantation, considered the most effective therapy.

“Among adults with relapsed ALL, remission rates are18 to 44 percent with standard chemotherapy but the duration of remission is typically short. A major goal for these patients is to induce remission with sufficient duration to prepare for stem-cell transplantation,” said Hagop Kantarjian, M.D., chair of the Department of Leukemia, and lead author for the New England Journal of Medicine paper. “In this study, 24 percent of patients in each treatment group underwent allogeneic stem cell transplantation.”

Blinatumomab, developed by Amgen, works by binding simultaneously to specific cytotoxic T-cells and B-cells, which allows the patient’s healthy T-cells to recognize and eliminate cancer stem cells called blasts.

“The activity of an immune-based therapy such as blinatumomab, which depends on functioning T-cells for its activity, provides encouragement that responses may be further enhanced and made durable with additional immune activation strategies,” said Kantarjian.

The study, designed and funded by Amgen, did not include patients who had other active cancers, relevant central nervous system conditions, autoimmune disease, acute or chronic graft-versus-host disease, chemotherapy or radiotherapy within two weeks before the study, donor stem cell transplantation within 12 weeks before the trial or autologous stem cell transplantation within six week preceding the study. Patients who received immunotherapy in the month before the trial or who were undertaking other investigational treatments were also excluded.

Georgetown Announces Phase II Clinical Trial of Nilotinib for Parkinson’s Disease

Georgetown University Medical Center (GUMC) today announces the launch of a phase II clinical trial to study the safety of the cancer drug nilotinib and its effects on clinical outcomes and biomarkers in people with Parkinson’s disease.

GUMC is recruiting volunteers for the study in collaboration with its clinical partner, MedStar Georgetown University Hospital.

The clinical trial is a phase II, randomized, double-blind, placebo-controlled study designed to evaluate the safety and tolerability of low doses of nilotinib, the efficacy on disease biomarkers, and clinical outcomes in people with mid-stage Parkinson’s disease. Fernando Pagan, MD, medical director of the GUMC Translational Neurotherapeutics Program and director of the Movement Disorders Clinic at MedStar Georgetown University Hospital will serve as principal investigator on this study.

As part of the year-long random ascending dose trial, a third of the participants will receive 150mg of nilotinib, another third will receive 300mg of nilotinib and the final third will receive a placebo (inactive drug). Clinical outcomes will be assessed at six and 12 months and compared to assessments at the start of the trial. A one-year open-label extension trial, in which all participants will be randomized to 150mg or 300mg nilotinib, is also planned upon completion of the placebo-controlled trial to evaluate nilotinib’s long-term effects.

The clinical trial follows a proof of concept study conducted at Georgetown (published July 11, 2016 in the Journal of Parkinson’s Disease) providing molecular evidence that nilotinib significantly increased brain dopamine (the chemical lost as a result of neuronal destruction) and reduced toxic proteins linked to disease progression in Parkinson’s disease or dementia with Lewy bodies. Twelve participants were enrolled in the initial study; one patient withdrew due to an adverse event. Researchers say the drug appeared to be safe and well tolerated in the remaining 11 participants who completed the study.

“The early proof of concept study conducted in 2015 and published in 2016 provided encouraging results, but we won’t know the exact effects of nilotinib on Parkinson’s disease until larger trials like this new one are complete,” says Pagan.

“I am pleased to offer this study to my patients, which demonstrates the importance of teaming Parkinson’s care with academic research. Only through clinical trials will we be able to move the field forward so that we can offer better treatments to our patients in the future,” he adds.

Nilotinib is approved by the U.S. Food and Drug Administration at much higher doses for the treatment of chronic myeloid leukemia (CML). In 2016, the U.S. Food and Drug Administration reviewed Georgetown’s investigational new drug application (IND) for the nilotinib study in Parkinson’s disease and informed GUMC investigators that the trial could proceed.

The Parkinson’s study and the recently announced Alzheimer’s clinical trial with nilotinib build on research from the GUMC Translational Neurotherapeutics Program led by Charbel Moussa, MB, PhD. He and his colleagues are examining tyrosine kinase inhibitors, like nilotinib, in the treatment of neurodegenerative diseases. Tyrosine kinases appear to play a role in neurodegeneration, protein clearance and inflammation. (Moussa is an inventor on a US patent owned by Georgetown University and on other pending US and foreign patent applications for use of nilotinib and other tyrosine kinase inhibitors for the treatment of neurodegenerative diseases).

The Parkinson’s study is funded by the generous support of donors. Novartis, the maker of nilotinib, is providing nilotinib and matching placebo free of cost to Georgetown University for all participants while on the study.

More information can be found at ClinicalTrials.gov. Patients and families can sign up to receive more information about the Parkinson’s study and other Georgetown neurodegenerative clinical trials.

University Hospitals Seidman Cancer Center Enrolls First Patient in New National Head and Neck Cancer Study

Study tests safety of immunotherapy drug added to regimen of surgery, chemotherapy and radiation therapy; same drug used on President Jimmy Carter’s brain cancer

University Hospitals (UH) Seidman Cancer Center patient Richard Bartlett, 62, of Magnolia, Ohio, has become the first in the nation to enroll in a new study for very high risk head and neck cancer.

“The study is one of the first ever to use ‘quadra-modality’ therapy, or in other words, four different types of therapy for this cancer,” said Min Yao, MD, PhD, the UH principal investigator, a radiation oncologist at UH and a professor of radiation oncology at the Case Western Reserve University School of Medicine.

Standard treatment for this cancer is surgery, followed by radiation and chemotherapy. This study will add an immunotherapy drug called pembrolizumab to activate the body’s immune system in the fight against the cancer. The drug, originally developed to treat melanoma, made the news in 2015 when President Jimmy Carter was treated with it for his brain metastases from melanoma.

Mr. Bartlett volunteered for the study for several reasons. “I want to have the best outcome possible,” he said, “and I have a responsibility to my family. I also know that people in the past have made sacrifices for research and I know cancer research is in its infancy in many ways and I’d like to do what I can to help.”

Pembrolizumab is one of the first immunotherapy drugs. Instead of directly killing cancer cells, these drugs boost the immune system to do the job.

This phase I trial will study the side effects and best dose and schedule of pembrolizumab when given together with the chemotherapy drug called cisplatin and radiation therapy.

Despite advances in cancer detection and treatment, the five-year overall survival rate for high risk head and neck squamous cell cancer is only 40 to 60 percent.

“This is a four-pronged attack on the cancer,” said Dr. Yao. “With surgery, we remove as much of the tumor as we can. Chemotherapy works to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Radiation therapy uses high-energy X-rays to kill tumor cells. And now with pembrolizumab, we trigger the immune system in the fight.”

This phase 1 study is for safety and will lay the groundwork for a future phase 3 study.

The study will enroll 56 patients nationally in seven study sites. Data collection is estimated to be completed by May 2018. UH Seidman Cancer Center and CWRU School of Medicine comprise the only Ohio site. The Cleveland site for the study is funded by a National Cancer Institute grant to the CWRU School of Medicine.

Mr. Bartlett’s head and neck cancer was discovered after he went to a dentist for a wisdom tooth extraction and a sore on the inside of his right cheek. He thought the sore was caused by the problem tooth rubbing against the cheek. The dentist recommended a biopsy on the sore.

It turned out to be cancerous and he was referred to Pierre Lavertu, MD, Director of Head and Neck Surgery and Oncology at UH Cleveland Medical Center. Dr. Lavertu and Chad Zender, MD, of the UH Department of Otolaryngology, did the surgery.

Mr. Bartlett had surgery on Dec. 22, 2016 and his cancer was more aggressive than originally thought. He has begun his chemo, radiation, and immunotherapy under the care of Michael Gibson, MD, PhD, Medical Director of the Head and Neck Oncology Team at UH Seidman Cancer Center, and Dr. Yao of the Radiation Oncology Team. All of his physicians are members of the faculty at the CWRU School of Medicine.

Mr. Bartlett and his wife Nancy have been together for 25 years and have been married the past 10 years. They met when she worked as a cashier in a store where he was shopping. He found a plastic flower on the floor and gave it to her. “There was no turning back after that,” laughed Mr. Bartlett.

Nancy said they are both pleased with the care that Richard has received at UH Seidman Cancer Center. “The doctors and the staff have been very nice. We came here because they have the latest in cancer care,” she said.

Penn Team Tracks Rare T Cells in Blood to Better Understand Annual Flu Vaccine

For most vaccines to work the body needs two cell types – B cells and T helper cells – to make antibodies. B cells are the antibody factories and the T helper cells refine the strength and accuracy of antibodies to home and attack their targets. A technique that identifies these helper immune cells could inform future vaccine design, especially for vulnerable populations.

Flu vaccines work by priming the immune system with purified proteins from the outer layer of killed flu viruses. An antibody is a protein that recognizes a unique pathogen molecule called an antigen that is specific for a particular strain. Antibodies bind to their targets with precision in the best of circumstances. In doing so, the antibody blocks a harmful microbe from replicating or marks it to be killed by other immune cells.

The level of antibodies in the blood tells immunologists how well a vaccine is working, specifically, how many antibodies are made and how strongly they disable microbes. The relatively scarce circulating T follicular helper cells, or cTfh for short, are key to antibody strength. Without Tfh, effective antibodies cannot be made, yet very little is known about cTfh cells in humans after vaccination.

Now, a team led by researchers from the Perelman School of Medicine at the University of Pennsylvania has found a way to identify the small population of cTfh present in the blood after an annual flu vaccine to monitor their contribution to antibody strength. They published their findings in Science Immunology this week. The studies, led by Ramin Herati, MD, an instructor of Infectious Disease, used high dimensional immune-cell profiling and specific genomic tests to identify and track these rare cells over time.

“The poor understanding of cTfh function is, in part, because these cells spend most of their time waiting in lymph nodes for the next infection, and not circulating in the blood,” said senior author E. John Wherry, PhD, a professor of Microbiology and director of the Institute of Immunology at Penn. “To get a handle on how well these cells are doing their job following vaccination, we have needed a way to measure their responses without gaining direct access to lymph nodes. Because of the central role of circulating T follicular helper cells in antibody development, new vaccine development strategies will benefit from a better understanding of the properties of these essential cells in the immune response.”

Molecular Bar Codes
Every T cell has a unique receptor on its outer surface. After receiving a vaccine, the result is one T cell with this unique bar code of sorts that replicates, making thousands of clones with identical copies of the same bar code. After vaccination this expansion of T cells dies down and a few clones remain behind. These memory cells wait it out in lymph nodes and other organs for the next time the infection or vaccine enters the body. These clones can then be called into action to protect the individual or help boost the vaccine immunity.

In the current study, the team was able to track circulating helper T cells because the unique bar code they possessed is specific to the strains used in an annual flu vaccine. Wherry and colleagues traced antibody production in 12 healthy subjects, aged 20 to 45 for three years from 2013 to 2105. The circulating subset of helper follicular T cells expressed different transcription factors and cytokines — Bcl-6, c-Maf, and IL-21 – compared to other T-cell subpopulations in the blood. The number of the cTfh cells sharply increased at seven days after a subject received a flu shot.

Repeated vaccination of the study participants brought back genetically identical clones of cTfh cells in successive years, indicating robust cTfh memory to the flu vaccine. These responses are a proxy for specific antibodies to the flu vaccine each year. In addition, these results measure the dynamics of vaccine-induced cTfh memory and recall over time, allowing investigators to monitor the key human-vaccine-induced cTfh responses and gain insights into why responses to flu vaccines are suboptimal in many people.

The ability to track these cTfh responses in the blood, instead of accessing lymph nodes in humans, allows for real-time monitoring of key cellular mechanisms involved in vaccination. Such knowledge should allow further optimization of vaccines for hard-to-treat diseases like the flu, but also HIV, and other infections in which inducing potent vaccines has been a challenge.

“These cTfh are a missing piece of being able to truly monitor and predict their ability to induce the desired magnitude and quality of immune memory, and therefore protection by vaccines,” Wherry said. The team next intends to look at elderly populations in which vaccines are not as effective and ask what role cTfh cell populations play in that part of the human population.

Co-authors are Alexander Muselman, Laura Vella, Bertram Bengsch, Kaela Parkhouse, Daniel Del Alcazar, Jonathan Kotzin, Susan A. Doyle, Pablo Tebas, Scott E. Hensley, Laura F. Su, and Kenneth E. Schmader.

 

16 Aplastic Anemia Patients Free Of Disease After Bone Marrow Transplant and Chemo

Physicians at the Johns Hopkins Kimmel Cancer Center report they have successfully treated 16 patients with a rare and lethal form of bone marrow failure called severe aplastic anemia using partially matched bone marrow transplants followed by two high doses of a common chemotherapy drug. In a report on the new transplant-chemo regimen, published online Dec. 22, 2016, in Biology of Blood and Marrow Transplantation, the Johns Hopkins team says that more than a year after their transplants, all of the patients have stopped taking immunosuppressive drugs commonly used to treat the disorder and have no evidence of the disease.

“Our findings have the potential to greatly widen treatment options for the vast majority of severe aplastic anemia patients,” according to Robert Brodsky, M.D., professor of medicine and oncology at the Johns Hopkins Kimmel Cancer Center and an author of the report.

Results of the small clinical trial have already prompted the organization of a larger national trial being led by Amy DeZern, M.D., an assistant professor of oncology and medicine at the Johns Hopkins Kimmel Cancer Center, with plans to involve patients at 25 medical centers across the country.

Diagnosed in about one in 250,000 people each year, aplastic anemia occurs when one’s own immune system damages blood-making bone marrow cells, which gradually stop producing red and white blood cells and platelets.

Patients must receive frequent blood transfusions, take multiple medicines to suppress the autoimmune response that damages the marrow, take other drugs to prevent infections, and limit contact with the outside world to avoid infection and even minor injury. Over the long term, most patients eventually die of infections.

When immunosuppressive therapy fails to keep the disease in check — in as many as 30 to 40 percent of patients — doctors usually prescribe a drug called eltrombopag, which is used in a variety of blood disorders to increase platelets. The drug, according to the Johns Hopkins experts, works only in about 30 percent of patients and usually leads to a partial, not complete, response.

Brodsky and DeZern say that the only curative treatment is a bone marrow transplant, but few patients have donors who are “fully matched” — sharing the same collection of immune-stimulating proteins that decorate every cell in the body.

In an effort to overcome the donor shortage and offer transplant to more patients, DeZern, Brodsky and their colleagues enrolled 16 patients between 11 and 69 years of age in this study from July 2011 through August 2016.

Each of the patients had failed to respond to immunosuppressive therapy or other drug treatments. None had access to a related fully matched bone marrow donor but did have an available and willing donor who was a half match. Three patients used unrelated donors.

After administering a cocktail of drugs designed to suppress their immune system and prevent rejection of the donor marrow, the patients received half-matched bone marrow transplants, some from siblings or parents, and others from unrelated donors.

Three and four days after their transplants, the patients received high doses of the chemotherapy drug cyclophosphamide. For the next year, or slightly longer, they remained on immunosuppressive medications, including tacrolimus, then stopped taking them.

Within weeks of their transplants, tests showed that each of the patients’ red and white blood cell and platelet counts had returned to normal levels without the need for blood transfusions. Once immunosuppressive therapy was stopped, none of the patients required further treatment related to their disease, the Johns Hopkins team reported.

Although 13 patients were able to discontinue immunosuppressive drugs a year after their transplant, three developed mild graft-versus-host disease (GVHD), a common complication of bone marrow transplants that occurs when immune cells in the transplant attack the newly transplanted cells. Two patients had mild GVHD that appeared on their skin, and one patient’s GVHD occurred in the mouth and skin. After a few extra months of immunosuppressive therapy, their GVHD subsided, and they also were able to stop taking these medications.

Ending all therapy related to their disease has been life-changing for the patients, says DeZern. “It’s like night and day,” she says. “They go from not knowing if they have a future to hoping for what they’d hoped for before they got sick. It’s that transformative.”

Successful transplants using partial match donors, Brodsky says, open up the transplant option to nearly all patients with this condition, especially minority patients. Seven of the 16 patients treated at Johns Hopkins self-identified as nonwhite.

A full sibling only has a 25 percent chance of being a full match. However, 100 percent of parents and 50 percent of siblings or half-siblings are half matches, regardless of ethnicity. The average person in the United States has about four half matches or better. “Now, a therapy that used to be available to 25 to 30 percent of patients with severe aplastic anemia is potentially available to more than 95 percent,” says Brodsky.

The idea of using cyclophosphamide after a partial-match transplant was first pioneered decades ago by Johns Hopkins Kimmel Cancer Center experts. Brodsky says the drug destroys patient’s diseased immune system cells but does not harm the donor’s blood stem cells, which create new disease-free blood cells in the patient.

Bone marrow transplants are costly — sometimes exceeding more than $300,000. However, Brodsky and DeZern say that full and half-matched transplants are life-saving for many, and there is cost-saving potential when aplastic anemia patients can avoid a lifetime of immunosuppressive therapy, hospitalizations, medications and blood transfusions.

Two New Trials for Pediatric Brain Cancer Open at UTHealth/Children’s Memorial Hermann

Two new clinical trials for pediatric brain cancer have begun at The University of Texas Health Science Center at Houston (UTHealth) and Children’s Memorial Hermann Hospital.

The pilot trials, approved by the U.S. Food and Drug Administration, both focus on the administration of chemotherapy agents directly into the fourth ventricle of the brain, the most common site for pediatric brain tumors and one that is difficult to access surgically.

“Administering chemotherapy directly to the site of the tumor can enable very high drug levels at the site of active disease while decreasing the likelihood of systemic toxicity,” said David Sandberg, M.D., the Dr. Marnie Rose Professor in Pediatric Neurosurgery at McGovern Medical School at UTHealth, who pioneered the procedure. “Current treatment options can have serious side effects, and we need to do better. Radiation therapy can be harmful to the developing brain and chemotherapy in the high levels needed to cross the blood-brain barrier can cause many side effects as well as damage to organs throughout a child’s body.”

Both trials are designed to target brain tumors that develop in the posterior fossa portion of the brain that includes the cerebellum, brain stem and fourth ventricle.

One trial builds on Sandberg’s previous research that investigated the infusion of methotrexate for pediatric brain tumors. Results of the research, published in October 2015 in the Journal of Neuro-Oncology, showed that some patients with recurrent medulloblastoma experienced a beneficial anti-tumor effect. The new study will look at combining methotrexate with another chemotherapy agent, etoposide, for infusion into the fourth ventricle for medulloblastoma, the most common malignant brain tumor in children. Children with other tumors such as atypical teratoid rhabdoid tumor (ATRT) are also eligible.

The second trial focuses on a different chemotherapy agent for a type of brain tumor called recurrent posterior fossa ependymoma. Ependymomas form from ependymal cells that line the ventricles and passageways in the brain and spinal cord, according to the National Cancer Institute.

The chemotherapy agent, 5-azacytidine (5-AZA), is infused directly into the fourth ventricle. The agent has never been injected into a human brain before but has been shown to be promising in treating ependymomas in the laboratory. No systemic chemotherapy will be given to clinical trial participants.

Both studies are open to patients age 1 to 21.

The procedures will be done at Children’s Memorial Hermann Hospital, where Sandberg is director of Pediatric Neurosurgery. He is also director of Pediatric Neurosurgery at Memorial Hermann Mischer Neuroscience Institute at the Texas Medical Center. Sandberg is a professor in both the Department of Pediatric Surgery and the Vivian L. Smith Department of Neurosurgery at McGovern Medical School.

University Hospitals Rainbow Babies & Children’s Hospital Opens First Stem Cell Study in Patients with Cystic Fibrosis

Study is first step toward goal of developing therapy to quell CF’s lung inflammation

A 39-year-old man with cystic fibrosis (CF) made history by becoming the first person to receive human adult stem cells in a new research study that researchers hope will someday lead to the development of a therapy to reduce the inflammation and infection caused by CF.

The pioneering subject in the study is Bob Held from Alliance, Ohio, who on Jan. 26 received an infusion of cells called allogeneic human mesenchymal stem cells (hMSC), adult stem cells collected from the bone marrow of healthy volunteers. Mr. Held was diagnosed with CF when he was 16 months old.

Currently, there is no cure for CF, and life expectancy for patients who survive into adulthood is approximately 41 years of age.

“It was a very exciting day for us with the very first participant in the first stem cell trial for cystic fibrosis,” said James Chmiel, MD, the principal investigator of the study at University Hospitals Rainbow Babies & Children’s Hospital.

The Phase 1 trial will assess the safety and tolerability of hMSCs in adult patients with CF.

“This is an early phase trial, and the most important thing is to ensure safety,” said Dr. Chmiel. “This study consists of a single infusion of stem cells. We will follow the study participants for a year to make sure it’s safe. Before applying any therapy on a broad basis, we want to make sure that it’s safe.”

While the goal of the study is safety, Dr. Chmiel hopes this is a first step towards the ultimate goal of developing a therapy to reduce lung inflammation and infection, resulting in longer and healthier lives for people with CF.

“While there’s been a tremendous increase in survival for people with CF from when I entered the field in the 1990s, that’s still not good enough,” said Dr. Chmiel, Director of the Cystic Fibrosis Therapeutics Development Center at UH Rainbow Babies & Children’s Hospital and Professor of Pediatrics at Case Western Reserve University School of Medicine. “While we’ve made great progress, we still have a long way to go.”
The stem cells that Mr. Held received were collected from the bone marrow of a healthy adult volunteer. UH is a national leader in the use of stem cell therapy with hMSCs. Researchers from UH, along with the CWRU School of Medicine, discovered hMSCs. The hMSCs possess many properties that are ideal for the treatment of inflammatory and degenerative diseases, and they possess natural abilities to detect changes in their environment, such as inflammation. The hope is that hMSCs can reduce the inflammation in the lungs caused by CF.

CF’s main effect is on the lungs. They fill with a sticky mucus as a reaction – really an over-reaction – by the body’s immune system to bacteria. The lungs are the source for much of the illness and shortened lifespan seen in CF.

“One of the issues in CF is that people with the disease get bacterial infections in their lungs, and these bacteria incite a vigorous and excessive inflammatory response,” explained Dr. Chmiel. “It’s actually the body’s inflammatory response that damages the lungs. The inflammatory response tries to eliminate the bacteria, but it’s not successful. Instead, the inflammatory system releases molecules that damage the individual’s own airways. The lung disease causes much of the illness and is responsible for the majority of the mortality of the disease.”

The stem cells are donated by healthy adult volunteers who go through a rigorous screening process. The stem cells are cultured in the UH stem cell facility. Volunteers with CF who are in the study receive an infusion through an IV.
“Once in the patient’s body, the stem cell tracks to the area where there’s a significant amount of inflammation, and they take up residence there. The stem cells then respond to the environment, and hopefully reverse some of the abnormalities,” said Dr. Chmiel. “We hope in future studies to demonstrate that the stem cells reduce the infection and inflammation and return the lungs to a more normal state.”

“This therapy aims to turn down the inflammatory response, not eliminate it because we still have to keep the bacteria in check. We want to reduce inflammation and the subsequent lung damage caused by inflammation without allowing the bacteria to proliferate,” said Dr. Chmiel.

A total of 15 clinically stable adults with CF will be enrolled in the study. Support for the study is from the Cystic Fibrosis Foundation.

The patient, Mr. Held, considers himself fortunate to be close to 40 with CF. When he was growing up, he said he’d miss 50 days of school each year because of the disease. Every day, he needs to breathe in aerosols for about two hours in the morning and 1-1/2 hours before bed to keep his lungs functioning. While he hasn’t been sick from the illness since his late teens, he does check himself into the hospital a couple of times a year for precautionary measures and to prevent himself from “getting into a valley” with CF.

His late wife, Michelle, died of CF seven years ago. They had met when they were kids, but didn’t get married until 2012. She died from the disease suddenly 28 days after they married.

“My only regret is that I didn’t ask her out sooner,” said Mr. Held.
He is participating in the study to carry on Michelle’s legacy, and “I am hoping the future generations of CF patients can get better treatments and that eventually a cure will be found for them,” he said.

Patients with Severe Chronic Rhinosinusitis Show Improvement with Verapamil Treatment

A small clinical trial at Massachusetts Eye and Ear found that patients with chronic rhinosinusitis (CRS) with nasal polyps improved with Verapamil therapy

A clinical trial studying the use of Verapamil (a drug currently in use for cardiovascular disease and cluster headache) in alleviating chronic rhinosinusitis (CRS) with nasal polyps revealed significant improvement in the symptoms of this subset of patients. It is the first study of its kind to explore treatment for CRS by inhibiting P-glycoprotein, a protein pump within the nasal lining that Mass. Eye and Ear researchers previously identified as a mechanism for these severe cases of CRS marked by the presence of nasal polyps. The clinical trial results, published online today in the Journal of Allergy and Clinical Immunology: In Practice, suggest that Verapamil represents a promising novel therapy for the treatment of CRS with nasal polyps.

“Recently, we became aware that some of the inflammation in CRS with nasal polyps is generated by the nasal lining itself, when a particular protein pump (P-glycoprotein) is overexpressed and leads to the hyper-secretion of inflammatory cytokines,” said senior author Benjamin S. Bleier, M.D., a sinus surgeon at Mass. Eye and Ear and an assistant professor of otolaryngology at Harvard Medical School. “Verapamil is a first-generation inhibitor that is well-established in blocking P-glycoprotein. In some patients with CRS with nasal polyps, we saw dramatic improvement in their symptom scores.”

One of the more prevalent chronic illnesses in the United States, CRS has been known to cause significant quality of life detriments to affected patients, who often cannot breathe or sleep easily due to obstructed nasal and sinus passages. The presence of nasal polyps represents a particularly severe presentation of the disease. Current treatment strategies (most often long-term steroid use) are plagued by difficult side effects and fail to target an underlying source of the disease.

Motivated by their previous finding of the presence of P-glycoprotein overexpression in the nasal lining of patients with CRS with nasal polyps, the study authors conducted a randomized, double-blind, placebo-controlled clinical trial studying the use of low-dose Verapamil in 18 patients with CRS with nasal polyps. An analysis of these patients demonstrated improved outcomes for those in the Verapamil group in relation to those in the placebo group. However, the researchers also observed that the treatment effect was significantly limited among patients with higher body mass indices. Future studies are being planned to determine if a higher dose of Verapamil may be needed to be therapeutic for some patients.

“Chronic rhinosinusitis with nasal polyps is among our most challenging diagnoses to treat, because these patients essentially have chronic, lifelong inflammation that needs chronic, lifelong treatment,” said Dr. Bleier. “We observed no significant side effects at the doses we used, and we are very encouraged by the results of this first step toward a more targeted therapy for our patients.”

Innovative Imaging and Surgery Used to Treat Lymphatic Condition in Adults

CHOP Researchers Report Successes in Plastic Bronchitis, Removing Branching Casts in Lungs.

Researchers who developed a safe and effective procedure to remove thick clogs in children’s airways are now reporting similar success in adult patients. In this rare condition, called plastic bronchitis, patients develop thick, caulk-like casts that form in the branching paths of their airways.

The researchers developed new imaging tools and a minimally invasive catheterization technique to treat a form of plastic bronchitis caused when abnormally circulating lymphatic fluid dries into solid casts. “In some cases, the cause of this condition is unknown, but this new study suggests that most adult patients with plastic bronchitis have abnormal pulmonary flow of lymphatic fluid that we can safely treat,” said study leader Maxim G. Itkin, MD, a radiologist at Children’s Hospital of Philadelphia (CHOP) and the Perelman School of Medicine at the University of Pennsylvania.

Itkin and his co-author Yoav Dori, MD, a pediatric cardiologist at CHOP and Penn Medicine, co-lead a specialized team at the Center for Lymphatic Imaging and Interventions jointly operated by CHOP and Penn. They collaborated on the current study with pulmonologist Francis X. McCormack, MD, of the University of Cincinnati, in a paper in the October 2016 issue of the Annals of the American Thoracic Society.

The study reports on seven adults with a mean age of 50 years old who presented with branching bronchial casts, associated with chronic cough and/or asthma. Using a customized type of magnetic resonance imaging called dynamic contrast-enhanced MR lymphangiography (DCMRL), the team found that six of the seven patients had abnormal lymphatic flow, which they now propose designating as pulmonary perfusion syndrome, as distinct from idiopathic plastic bronchitis, in which the cause is unknown.

The team treated the six patients with lymphatic embolization, which involves inserting a combination of glue and coils through catheters to halt the flow of lymphatic fluid. Five patients reported immediate and complete resolution of symptoms, and the sixth patient reported significant partial improvement. Four patients had minor abdominal pain, which resolved after treatment with painkillers. The average follow-up was 11 months after initial treatment.

Earlier this year, Itkin and Dori reported a retrospective case study of 18 children who had plastic bronchitis as a complication of palliative surgery for single-ventricle heart disease. While rare, plastic bronchitis can cause life-threatening respiratory distress in children. In adults, the condition may go undiagnosed for years in patients who may initially be diagnosed with asthma or chronic cough. Plastic bronchitis has a long medical pedigree—the Greek physician Galen described a form of it in the second century.

“This was a small study, and a first report of this treatment in adults with lymphatic plastic bronchitis,” said Dori. “Longer follow-up will be needed to confirm the long-term risks and benefits of this procedure.”

The Center for Lymphatic Imaging and Intervention is one of CHOP’s inaugural Frontier Programs. Frontier Programs embody the connection between research breakthroughs and extraordinary clinical care, and are a novel way to bring research more quickly to the bedside.

Moffitt Cancer Center Researchers Report Promising Clinical Activity and Minimal Toxicities for HER2-Targeted Dendritic Cell Vaccines in Early-Stage Breast Cancer Patients

HER2-Targeted Dendritic Cell Vaccines Stimulate Immune Responses and Regression of HER2-Expressing Early-Stage Breast Tumors

Deregulation and inhibition of the immune system contributes to cancer development. Many therapeutic strategies aim to restimulate the immune system to recognize cancer cells and target them for destruction. Researchers from Moffitt Cancer Center report that a dendritic cell vaccine that targets the HER2 protein on breast cancer cells is safe and effectively stimulates the immune system leading to regression of early-stage breast cancer.

The HER2 protein is overexpressed in 20-25% of all breast cancer tumors and is associated with aggressive disease and poor prognosis. Moffitt researchers have previously shown that immune cells are less able to recognize and target cancer cells that express HER2 as breast cancer progresses into a more advanced and invasive stage. This suggests that strategies that can restimulate the immune system to recognize and target HER2 early during cancer development may be effective treatment options.

The Moffitt researchers previously developed a vaccine that helps the immune system recognize the HER2 protein on breast cancer cells. Their approach involves creating the vaccine from immune cells called dendritic cells that are harvested from each individual patient to create a personalized vaccine.

In order to determine if the HER2-dendritic cell vaccine is safe and effective, the Moffitt researchers performed a clinical trial in 54 women who have HER2-expressing early-stage breast cancer. The dendritic cell vaccines were prepared by isolating dendritic cells from each patients’ blood and exposing them to fragments of the HER2 protein. Patients were injected with a dose of their personal dendritic cell vaccine once a week for 6 weeks into either a lymph node, the breast tumor, or into both sites.

The researchers report that the dendritic cell vaccines were well-tolerated and patients only experienced low-grade toxicities. The most common adverse events were fatigue, injection site reactions, and chills. They also show that the vaccine was able to stimulate an immune response in the majority of the patients. Approximately 80% of evaluable patients had a detectable immune response in their peripheral blood and/or in their sentinel lymph node wherein their cancer is most likely to spread to first. Importantly, the immune responses among the patients were similar, regardless of the route of vaccine administration.

The Moffitt researchers assessed the effectiveness of the vaccine by determining the percentage of patients who had detectable disease within surgical specimens after resection. The absence of disease is termed a pathological complete response (pCR). They report that 13 patients achieved a pCR and patients who had early non-invasive disease called ductal carcinoma in situ (DCIS) achieved a higher rate of pCR than patients who had early-stage invasive disease. Interestingly, patients who achieved a pCR had a higher immune response within their local sentinel lymph nodes.

“These results suggest that vaccines are more effective in DCIS, thereby warranting further evaluation in DCIS or other minimal disease settings, and the local regional sentinel lymph node may serve as a more meaningful immunologic endpoint,” said Brian J. Czerniecki, MD, PhD, Chair of the Department of Breast Oncology at Moffitt Cancer Center.

New Trial Hopes to Increase Survival for Kids With Cancer, Reduce Risk of Long Term Cardiac Damage

Imagine conquering childhood cancer, only to find out that years down the road your heart may fail. Unfortunately, many children who have battled cancer face this reality. While often lifesaving, the effects of chemotherapy treatment (drugs that kill cancer cells) can take a toll on the developing body of a child, potentially resulting in life-threatening late side effects like cardiac damage.

“You go through terrible chemotherapy, achieve remission, have a new lease on life and then your heart fails,” said Dr. Todd Cooper, director of the Pediatric Leukemia/Lymphoma Program and Evans Family Endowed Chair in Pediatric Cancer at Seattle Children’s. “It’s not fair, and we’re determined to change this reality.”

Cooper is leading a new nationwide clinical trial, conducted within the Children’s Oncology Group (COG), for children and adolescents with relapsed acute myelogenous leukemia (AML) to test a drug, CPX-351, which has been designed to kill leukemia cells while minimizing damage to the heart. According to Cooper, up to 30% of patients who undergo chemotherapy for AML will have late term side effects that affect the heart. For Cooper, that’s 30% too many.

AML is an aggressive type of cancer that affects the bone marrow and blood. AML can be difficult to treat and requires intensive chemotherapy and often bone marrow transplantation.

Cooper says previous trials testing the effectiveness and efficacy of CPX-351 have shown tremendous promise in adults, and so he’s hoping to bring that same success to pediatric patients.

Bringing hope to children with acute myelogenous leukemia
Because AML is difficult to treat, standard treatment commonly involves multiple chemotherapy medicines that are given at a higher dose in order to kill the cancer cells.

“The chemotherapy tends to be very intensive,” said Cooper. “Some of the most effective medicines work really well against leukemia, but the side effects, including damage to the heart, can be severe.”

CPX-351 delivers chemotherapy in a different way than standard chemotherapy. The medicines are contained in a liposomal formulation which is thought to be safer for the heart. The liposome is used as a vehicle to transport the drugs into the body and into leukemia cells in the bone marrow. We hope that by being housed inside the liposome, that less of the chemotherapy will be deposited into the heart.

In phase 3 trials for adults with high-risk, secondary AML, there was a statistically significant improvement in overall survival compared to patients who received a regimen using chemotherapy drugs delivered in the standard way. The use of CPX-351 reduced the risk of death by 31% compared to the use of the chemotherapy drugs cytarabine and daunorubicin.

“This trial not only offers hope for more children to be cured, but for more children to live longer, leading more productive lives without late term cardiac damage,” said Cooper. “I am thrilled to bring this therapy to children through the trial because I want kids to have access as soon as possible to these potentially lifesaving drugs.”

Although results from the trial will not be completed for a couple of years, Cooper is optimistic CPX-351 will improve outcomes for children with relapsed AML and may one day become a frontline treatment.

New heart imaging test identifies improved outcomes in patients with amyloidosis

Researchers at Boston Medical Center (BMC) have reported that a new heart imaging test can determine whether cardiac amyloidosis patients are expected to survive after a stem cell transplant. They accomplished this by analyzing the results of an echocardiogram–a standard ultrasound test that assesses the heart’s functionality. The findings, published in the European Heart Journal – Cardiovascular Imaging, may change the way doctors predict who will benefit from stem cell transplants in this disease.

Light-chain or AL amyloidosis is a rare disease that occurs when an abnormal protein called amyloid builds up in an organ, including the heart. There is no definitive cure for AL amyloidosis, however treatment can help limit further production of the amyloid protein and prolong survival significantly. The most effective treatment combines a potent chemotherapy drug called melphalan with autologous stem cell transplantation (ASCT). With this treatment, a patient’s blood stem cells are collected, the bone marrow cells that produce the toxic amyloid precursor protein are destroyed, and then the stem cells are reintroduced. Once a patient undergoes a stem cell transplant, patients are closely monitored using blood biomarkers and echocardiograms to assess improvements in their heart.

The Amyloidosis Center at Boston University School of Medicine (BUSM) and BMC is recognized internationally as a leader in basic and clinical research on amyloidosis–treating over 400 patients each year.

“We’ve known for some time that a disconnect exists between the symptomatic and clinical improvement we see in patients after their stem cell transplant with echocardiographic measurements of heart function,” said Frederick L. Ruberg, MD, director of advanced cardiac imaging at BMC and associate professor of medicine and radiology at BUSM, who serves as the study’s corresponding author. “These measurements seem to take much longer to show improvement.”

Ruberg and his team, including Francesco Salinaro, MD, the paper’s first author and a visiting scientist from Italy, evaluated the echocardiograms of over 60 cardiac AL amyloidosis patients to determine if a new measure, called a longitudinal strain, would be predictive of survival at one year after stem cell transplantation. They found that strain not only predicted survival, but outperformed other conventionally measured biomarkers found in the blood.

Additionally, researchers discovered that the strain pattern abnormalities characteristic of cardiac amyloidosis improved following treatment. These strain improvements were seen before changes were detected in any of the more conventional echocardiographic measures, such as wall thickness or ejection fraction.

“While these findings are consistent with other studies looking at cardiac function in patients with AL amyloidosis, this report was the first to study exclusively patients with cardiac involvement.” said Ruberg. “Having these additional data will allow us to make more informed decisions about which treatments would be most beneficial for our patients.”

Leukemia Drug Combo Is Encouraging in Early Phase I Clinical Trial

In a small study, 67 percent of leukemia patients treated with combination of thioguanine and decitabine responded to treatment

Researchers from Columbia University Medical Center and NewYork-Presbyterian reported that 8 out of 12 patients with relapsed and/or chemotherapy refractory acute myeloid leukemia (AML) or other blood cancers responded to a regimen including the chemotherapy drugs thioguanine and decitabine. Results from this small phase I study were reported at the American Society of Hematology’s annual conference.

“Outcomes are typically poor for older patients with advanced blood cancers, and new therapies are desperately needed to help patients with these cancers achieve remission,” said Mark Frattini, MD, PhD, associate professor of medicine at Columbia University Medical Center (CUMC) and blood cancer specialist at NewYork-Presbyterian. “While our study was small, the response we saw in this phase I, dose-escalating trial was encouraging.”

Previously, Frattini and colleagues had used a proprietary chemosensitivity screening assay to demonstrate that combining thioguanine and decitabine—chemotherapy drugs that are commonly used as single agents to treat patients with AML—restored therapeutic efficacy in leukemia cells from patients with relapsed and/or refractory disease.

In this study, the researchers tested the efficacy of the combination therapy in 12 older patients (median age of 67 years) with relapsed or chemotherapy refractory AML or chronic myelomonocytic leukemia, including 6 patients whose disease progressed after being treated previously with decitabine as a single agent. Of these, 11 patients completed the first treatment cycle, and 6 completed a second cycle, with a median of 3 rounds of treatment. Eight of the 11 evaluable patients responded to the combination therapy, including 6 who achieved a complete remission (5 in complete remission with incomplete count recovery). In addition, all of the patients who had progressed after prior treatment with decitabine alone responded to the combination therapy, demonstrating that the combination could overcome disease resistance to decitabine. Chemosensitivity assay results, obtained before treatment, accurately predicted each patient’s response to the combination therapy.

After treatment with the combination therapy, 4 of the responders went on to have a stem cell transplant.

“The goal of chemotherapy for patients with relapsed and/or refractory AML and other blood cancers is to achieve a remission that enables them to undergo a potentially curative stem cell transplant,” said Dr. Frattini. “With our phase I results, we have shown that this combination therapy can get some patients—including those who failed to respond to or progressed after previous chemotherapy treatment with a single agent such as decitabine—to that point. The next challenge for hematologic oncologists is to reduce morbidity and mortality associated with stem cell transplantation.”

After the study, 2 of the patients who had a stem cell transplant died from transplant-related toxicity, and another relapsed. One patient has remained in remission for more than 2 years.