Tag Archive for: chemotherapy

model of the brain

A new way to treat pediatric gliomas with BRAF V600 mutations

model of the brain

Gliomas account for 45% of all pediatric tumors of the central nervous system.

Gliomas, which can be classified according to histologic grade as high or low grade, account for 45% of all pediatric tumors of the central nervous system. Detection of the BRAF V600E mutation in pediatric low-grade glioma has been associated with a lower response to standard chemotherapy. In previous trials, dabrafenib (both as monotherapy and in combination with trametinib) has shown efficacy in recurrent pediatric low-grade glioma with BRAF V600 mutations, findings that researchers found warrant further evaluation of this combination as first-line therapy.

The big picture

In a recent study published in the New England Journal of Medicine, experts found that among a randomized cohort of 110 children with low-grade glioma with BRAF V600 mutations, dabrafenib plus trametinib resulted in significantly more responses, longer progression-free survival and a better safety profile than standard chemotherapy as first-line therapy.

“For the past 20 to 30 years, the only effective safe therapy was chemotherapy. In older children, radiation can also be effective, but there’s reluctance on using radiation on a developing brain,” said Roger Packer, M.D., director of the Brain Tumor Institute at Children’s National Hospital and co-author of the study. “As we learned the specific molecular genetic makeups of these tumors, either high- or low-grade gliomas, we found it to be effective to use molecular therapies. These are safer and more effective than chemotherapy alone.”

Dr. Packer also added that there’s approval from the FDA, proving that the industry sees value in investing in pediatrics.

Why it matters

This randomized trial shows the superiority of dabrafenib plus trametinib as a first systemic therapy for pediatric patients with low-grade glioma with BRAF V600 mutations as compared with carboplatin plus vincristine, the standard chemotherapy approach. This benefit was evident in the higher independently determined response, longer progression-free survival and better side-effect profile as reflected in the lower frequency of treatment discontinuation because of toxicity.

“Children treated with a molecular targeted therapy could safely tolerate the therapy and had better outcomes than children who were treated with chemotherapy,” Dr. Packer added.

Overall, these findings show the value of early molecular testing in children with low-grade glioma to determine the presence or absence of BRAF V600 mutations.

You can read the full study “Dabrafenib plus Trametinib in Pediatric Glioma with BRAF V600 Mutations” here.

marro replaced with aute lymphoblastic lukemia

New approach to maintenance chemotherapy may improve children’s quality of life

marro replaced with aute lymphoblastic lukemia

Marrow replaced with acute lymphoblastic leukemia.

According to a study that accrued over 9,000 patients, a new approach to maintenance therapy lessens the burden of treatment and potential toxicity in children experiencing the most common cancer — B-acute lymphoblastic leukemia (B-ALL). The average-risk (AR) B-ALL subset of patients demonstrated an overall five-year survival rate of 98% despite less frequent chemotherapy pulses. Researchers from Children’s National Hospital led the 10-year study published on Jan. 7, 2021, in the Journal of Clinical Oncology.

This phase III clinical trial, which opened at over 200 centers, helped inform an alternative maintenance therapy with less frequent administration of vincristine and dexamethasone. These standard drugs are part of a multiagent treatment approach used to treat acute lymphoblastic leukemia (ALL).

“For decades, the common maintenance therapy approach [within the Children’s Oncology Group] was administering vincristine or steroid pulses every four weeks. The steroids can trigger disruptive behaviors like moodiness, sleep disturbance, food cravings, poor school attendance or physical aggression and vincristine can cause declines in fine motor and sensory-perceptual performance,” said Anne Angiolillo, M.D., lead author of the study and director of the Leukemia and Lymphoma Program at Children’s National. “We can now lessen the burden of this therapy while still maintaining excellent outcomes, which is a huge benefit to our patients and their families.”

The findings suggest that the decreased frequency of both vincristine and dexamethasone pulses every four weeks to every 12 weeks alleviates the therapy burden and reduces toxicity, potentially improving children’s quality of life.

Simultaneously, the researchers tried increasing the starting dose of oral methotrexate, a standard chemotherapy drug, given once weekly in the maintenance phase to see if it would improve the five-year disease-free survival rate, but, according to the data, it did not improve outcomes.

The world’s largest organization devoted exclusively to pediatric cancer research, the Children’s Oncology Group (COG), adopted the approach of less frequent pulses into the frontlines of their new B-ALL trials, given the study’s findings, to help decrease the therapy burden for patients and their families.

“I am very excited that the results of AALL0932 [the clinical trial] will have a major effect on the schedule of maintenance therapy for children with standard and high-risk B acute lymphoblastic leukemia in all future COG therapeutic trials,” said Dr. Angiolillo.

Dr. Angiolillo, and co-author Reuven Schore, M.D., pediatric oncologist at Children’s National were the chair and vice-chair of the clinical trial, respectively. Dr. Schore is also a member of the Leukemia and Lymphoma Program at Children’s National.

ALL can progress quickly, affect the bone marrow and the blood, including B cells and T cells. Among the children with ALL, approximately 55% comprise of the newly diagnosed National Cancer Institute (NCI) standard-risk (SR) B-ALL.

The study enrolled 9,229 patients with B-ALL between August 2010 and March 2018. Only 2,364 patients classified as average-risk received a random assignment to one of the four maintenance arms at the start of maintenance therapy. The researchers administered either vincristine/dexamethasone pulses every 12 weeks or every four weeks and a starting dose of once-weekly oral methotrexate of 20 mg/m2 or 40 mg/m2 during the maintenance phase.

“This trial establishes that with improved risk stratification utilizing blast cytogenetics and rate of response, a relatively low-intensity premaintenance backbone with a three-drug induction, and lower exposure to chemotherapy in maintenance, results in outstanding outcomes,” said Angiolillo et al.

Jeffrey Dome

Treating Wilms Tumor with vincristine and irinotecan

Jeffrey Dome

“The study was impactful because it established the activity of vincristine/irinotecan against Wilms tumor. Based on these findings, this chemotherapy combination will be applied more broadly in the treatment of Wilms tumor,” says study leader Jeffrey S. Dome, M.D, Ph.D.

Wilms tumor, the most common kidney cancer of childhood, may be classified into different subtypes based on its appearance under the microscope. The “favorable histology” subtype is associated with an excellent survival rate of approximately 90%, whereas the “diffuse anaplastic” subtype is associated with survival rates of only 55% for patients with stage II-IV disease.

The Children’s Oncology Group AREN0321 study, led by Jeffrey S. Dome, M.D, Ph.D., vice president of the Center for Cancer and Blood Disorders at Children’s National Hospital, tested the anti-tumor activity of the chemotherapy combination vincristine and irinotecan in patients with metastatic diffuse anaplastic Wilms tumor.

The study also evaluated whether a new treatment regimen containing carboplatin in addition to the currently used agents (vincristine, doxorubicin, cyclophosphamide and etoposide) would improve patient outcomes. The results, published in the March 5th issue of the Journal of Clinical Oncology, showed that the vincristine/irinotecan combination is highly active. Out of the group, 78% of patients who received this combination had an objective tumor response.

The study also demonstrated that additional chemotherapy drugs can reduce the rate of relapse, but it is likely that we have reached the limit of what children can tolerate. “Future gains will likely be made by using agents with novel mechanisms of action, such as immunotherapy and new drugs that target the molecular abnormalities of Wilms tumor cells,” says Dr. Dome.

Moreover, the additional chemotherapy agents improved cancer-free survival rates to levels unprecedented for diffuse anaplastic Wilms tumor. However, the decrease in relapse rate came at the cost of increased toxicity.

“The study was impactful because it established the activity of vincristine/irinotecan against Wilms tumor. Based on these findings, this chemotherapy combination will be applied more broadly in the treatment of Wilms tumor,” Dr. Dome added.

Vote for STAT Madness

It’s a three-peat! Children’s National again competes in STAT Madness

Vote for STAT Madness

Children’s National Hospital collects patients’ blood, extracts T-cells and replicates them in the presence of specific proteins found on cancer cells which, in essence, teaches the T-cells to target specific tumor markers. Training the T-cells, growing them to sufficient quantities and ensuring they are safe for administration takes weeks. But when patients return to the outpatient clinic, their T-cell infusion lasts just a few minutes.

For the third consecutive year, Children’s National was selected to compete in STAT Madness, an annual bracket-style competition that chooses the year’s most impactful biomedical innovation by popular vote. Children’s entry, “Immunotherapy of relapsed and refractory solid tumors with ex vivo expanded multi-tumor associated antigen specific cytotoxic T lymphocytes,” uses the body’s own immune system to attack and eliminate cancer cells in pediatric and adult patients with solid tumor malignancies.

In 2018, Children’s first-ever STAT Madness entry advanced through five brackets in the national competition and, in the championship round, finished second. That innovation, which enables more timely diagnoses of rare diseases and common genetic disorders, helping to improve kids’ health outcomes around the world, also was among four “Editor’s Pick” finalists, entries that spanned a diverse range of scientific disciplines.

An estimated 11,000 new cases of pediatric cancer were diagnosed in children 14 and younger in the U.S. in 2019. And, when it comes to disease, cancer remains the leading cause of death among children, according to the National Institutes of Health. An enterprising research team led by Children’s National faculty leveraged T-cells – essential players in the body’s immune system – to treat pediatric and adult patients with relapsed or refractory solid tumors who had exhausted all other therapeutic options.

“We’re using the patient’s own immune system to fight their cancer, rather than more traditional chemotherapy drugs,” says Catherine M. Bollard, M.D., director of the Center for Cancer & Immunology Research at Children’s National and co-senior author of the study. “It’s more targeted and less toxic to the patient. These T-cells home in on any cancer cells that might be in the body, allowing healthy cells to continue to grow,” Dr. Bollard adds.

That means patients treated in the Phase I, first-in-human trial didn’t lose their hair and weren’t hospitalized for the treatment. After a quick clinical visit for their treatment, they returned to normal activities, like school, with good energy levels.

“With our specially trained T-cell therapy, many patients who previously had rapidly progressing disease experienced prolonged disease stabilization,” says Holly J. Meany, M.D., a Children’s National oncologist and the study’s co-senior author. “Patients treated at the highest dose level showed the best clinical outcomes, with a six-month, progression-free survival of 73% after tumor-associated antigen cytotoxic T-cell (TAA-T) infusion, compared with 38% with their immediate prior therapy.”

The multi-institutional team published their findings from the study online July 29, 2019, in the Journal of Clinical Oncology.

“Our research team and our parents are delighted that some patients treated in our study continue to do well following T-cell therapy without additional treatment. In some cases, two years after treatment, patients do not appear to have active disease and are maintaining an excellent quality of life,” says Amy B. Hont, M.D., the study’s lead author. “One of these was a patient whose parents were told his only other option was palliative care. Our innovation gives these families new hope,” Dr. Hont adds.

The 2020 STAT Madness #Core64 bracket opened March 2, and the champion will be announced April 6.

In addition to Drs. Hont, Meany and Bollard, Children’s National co-authors include C. Russell Cruz, M.D., Ph.D., Robert Ulrey, MS, Barbara O’Brien, BS, Maja Stanojevic, M.D., Anushree Datar, MS, Shuroug Albihani, MS, Devin Saunders, BA, Ryo Hanajiri, M.D., Ph.D., Karuna Panchapakesan, MS, Payal Banerjee, MS, Maria Fernanda Fortiz, BS, Fahmida Hoq, MBBS, MS, Haili Lang, M.D., Yunfei Wang, DrPH, Patrick J. Hanley, Ph.D., and Jeffrey S. Dome, M.D., Ph.D.; and Sam Darko, MS, National Institute of Allergy and Infectious Diseases.

Financial support for the research described in this post was provided by the Children’s National Hospital Heroes Gala, Alex’s Army Foundation, the Children’s National Board of Visitors and Hyundai Hope on Wheels Young Investigator Grant to Support Pediatric Cancer Research, the Children’s National Research Institute Bioinformatics Unit, the Clinical and Translational Science Institute and the National Institutes of Health under award No. UL1-TR001876.

Chromosomes

Precision medicine for Wilms tumor patients

Chromosomes

Previously, researchers discovered that loss of heterozygosity (LOH) on chromosomes 1 and 16 is associated with a significantly increased risk of relapse of Wilms tumor.

About 650 children are diagnosed each year in the U.S. with Wilms tumor, the most common pediatric kidney cancer. The vast majority of patients respond well to the current standard of care involving a combination of surgery, chemotherapy and radiation. However, approximately 20% of patients with “favorable histology” Wilms tumor experience recurrence.

Previously, researchers discovered that loss of heterozygosity (LOH) on chromosomes 1 and 16 is associated with a significantly increased risk of relapse. A research team in the Children’s Oncology Group (COG), led by Jeffrey Dome, M.D., Ph.D., vice president of the Center for Cancer and Blood Disorders at Children’s National Hospital, sought to determine whether an augmented chemotherapy regimen can overcome the negative effect of LOH.

More than 2,500 patients with Wilms tumor were enrolled in the biology and classification study over a 7–year period. Tumor tissue was tested for LOH and patients with LOH at both chromosomes 1 and 16 received more intensive chemotherapy regimens compared to the standard approach. The results showed that the increased treatment provided a statistically significant benefit in the 4-year event-free survival, with trends toward improved overall survival. For low-stage disease (stage I-II), the four-year event-free survival was 87.3%, compared to a historical rate of 68.8%. Similarly, for advanced stage disease (stage III/IV) four-year event-free survival was 90.2%, compared with 61.3% historically.

Although the new regimens involved additional chemotherapy agents compared to the standard regimens, the short-term toxicities were expected and manageable. There is an increased risk of long-term toxicity including infertility and second malignancies, which requires careful discussion with families. Future studies will seek to mitigate these risks with newer chemotherapy agents.

By better understanding which patients might benefit from more intensive treatment regimens through precision medicine, doctors can tailor therapy according to the risk of relapse, Dr. Dome says.

“This study represents a significant milestone in the treatment of Wilms tumor because it is the first to demonstrate that patient outcome can be improved using a molecular biomarker to guide treatment,” he explains. “We have entered the age of precision medicine for Wilms tumor.”

Epstein Barr virus

Fighting lymphoma with targeted T-cells

Epstein-Barr virus

The Epstein-Barr virus (EBV) is best known as the cause of mononucleosis, the ubiquitous “kissing disease” that most people contract at some point in their life. But in rare instances, this virus plays a more sinister role as the impetus of lymphomas, cancers that affect the white blood cells known as lymphocytes.

The Epstein-Barr virus (EBV) is best known as the cause of mononucleosis, the ubiquitous “kissing disease” that most people contract at some point in their life. But in rare instances, this virus plays a more sinister role as the impetus of lymphomas, cancers that affect the white blood cells known as lymphocytes. EBV-associated lymphomas account for about 40% of Hodgkin lymphomas, 20% of diffuse large B-cell lymphomas, and more than 90% of natural killer/T-cell lymphomas. This latter type of lymphoma typically has a very poor prognosis even with the “standard of care” lymphoma treatments such as chemotherapy and/or radiation.

When these interventions fail, the only curative approach is an allogeneic  hematopoietic stem cell transplant from a healthy donor, a treatment that’s tough on patients’ bodies and carries significant risks, says Lauren P. McLaughlin, M.D., a pediatrician specializing in hematology and oncology at Children’s National in Washington, D.C. Patients who receive these allogenic transplants are immune-compromised until the donor cells engraft; the grafts can attack patients’ healthy cells in a phenomenon called graft versus host disease; and if patients relapse or don’t respond to this treatment, few options remain.

To help improve outcomes, Dr. McLaughlin and colleagues tested an addition to the allogeneic hematopoietic stem cell transplant procedure for patients with EBV-associated lymphomas: infusion of a type of immune cell called T cells specifically trained to fight cells infected with EBV.

Dr. McLaughlin, along with Senior Author Catherine M. Bollard, M.D., M.B.Ch.B., director of the Center for Cancer and Immunology Research and the Program for Cell Enhancement and Technologies for Immunotherapy at Children’s National, and colleagues tested this therapy in 26 patients treated at Children’s National or Baylor College of Medicine. They published these results online on Sept. 27, 2018, in the journal Blood. The study was a Phase I clinical trial, meaning that the therapy was tested primarily for safety, with efficacy as a secondary aim.

Seven patients who received the therapy had active disease that had not responded to conventional therapies. The other 19 were patients deemed to be at high risk for relapse.

Before each patient received their stem cell transplant, their donors gave an additional blood sample to generate the cancer-fighting T cells. Over the next 8 to 10 weeks, the researchers painstakingly manufactured the immune cells known as T-cells that specifically targeted EBV, growing these cells into numbers large enough for clinical use. Then, as early as 30 days after transplant, the researchers infused these T-cells into patients administering at least two doses, spaced two weeks apart.

Over the next several weeks, the researchers at CNMC and Baylor College of Medicine monitored patients with comprehensive exams to see how they fared after these transplants. The results showed that adverse effects from the treatment were exceedingly rare. There were no immediate infusion-related toxicities to the T-cell therapy and only one incident of dose-limiting toxicity.

This therapy may be efficacious, depending on the individual patients’ circumstances, Dr McLaughlin adds. For those in complete remission but at high risk of relapsing, the two-year survival rate was 78%, suggesting that the administration of this novel T-cell therapy may give the immune system a boost to prevent the lymphoma from returning after transplant. For patients with active T-cell lymphomas, two-year survival rates were 60%. However, even these lower rates are better than the historical norm of 30-50%, suggesting that the targeted T-cell therapies could help fight disease in patients with this poor prognosis lymphoma.

Dr. McLaughlin, the study’s lead author and a Lymphoma Research Foundation grantee, notes that researchers have more work to do before this treatment becomes mainstream. For example, this treatment will need to be tested in larger populations of patients with EBV-related lymphoma to determine who would derive the most benefit, the ideal dose and dose timing. It also may be possible to extend targeted T-cell treatments like this to other types of cancers. In the future, Dr. McLaughlin adds, it may be possible to develop T-cells that could be used “off the shelf”—in other words, they wouldn’t need to come from a matched donor and would be ready to use whenever a recipient needs them. Another future goal is using this therapy as one of the first lines of treatment rather than as a last resort.

“Our ultimate goal is to find a way to avoid chemotherapy and/or radiation therapy while still effectively treating a patient’s cancer,” she says. “Can you use the immune system to do that job? We’re working to answer that question.”

In addition to Drs. McLaughlin and Bollard, study co-authors include Rayne Rouce, Stephen Gottschalk, Vicky Torrano, George Carrum, Andrea M. Marcogliese, Bambi Grilley, Adrian P. Gee, Malcolm K. Brenner, Cliona M. Rooney and Helen E. Heslop, all of Baylor College of Medicine; Meng-Fen Wu from the Dan L. Duncan Comprehensive Cancer Center; and Fahmida Hoq and Patrick J. Hanley, Ph.D. from Children’s National in Washington, D.C.

germ cells in testicular tissues

Experimental fertility preservation provides hope for young men

germ cells in testicular tissues

Confirming the presence of germ cells in testicular tissues obtained from patients. Undifferentiated embryonic cell transcription factor 1 (UTF1) is an established marker of undifferentiated spermatogonia as well as the pan-germ cell marker DEAD-box helicase 4 (DDX4). UTF1 (green) and/or DDX4 (red) immunostaining was confirmed in 132 out of 137 patient tissues available for research, including patients who had received previous non-alkylating (B, E, H, K) or alkylating (C, F, I, L) chemotherapy treatment. © The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology.

Testicular tissue samples obtained from 189 males who were facing procedures that could imperil fertility were cryopreserved at one university, proving the feasibility of centralized processing and freezing of testicular tissue obtained from academic medical centers, including Children’s National, scattered around the world.

“It’s not surprising that the University of Pittsburgh would record the highest number of samples over the eight-year period (51 patients), given its role as the central processing facility for our recruiting network of academic medical centers,” says Michael Hsieh, M.D., Ph.D., director of transitional urology at Children’s National. “Children’s National recruited the third-highest number of patients, which really speaks to the level of collaboration I have with Jeff Dome’s team and their commitment to thinking about the whole patient and longer-term issues like fertility.”

An estimated 2,000 U.S. boys and young men each year receive treatments or have cancers or blood disorders that place them at risk for infertility. While older youths who have undergone puberty can bank their sperm prior to undergoing sterilizing doses of chemotherapy or radiation, there have been scant fertility preservation options for younger boys. However, some older adolescents and young men are too sick or stressed to bank sperm. For patients with no sperm to bank or who are too sick or stressed to bank sperm, the experimental procedure of freezing testicular tissue in anticipation that future cell- or tissue-based therapies can generate sperm is the only option.

Recent research in experimental models indicates that such testicular tissue biopsies contain stem cells, blank slate cells, hinting at the potential of generating sperm from biopsied tissue.

“This study demonstrates that undifferentiated stem and progenitor spermatogonia may be recovered from the testicular tissues of patients who are in the early stages of their treatment and have not yet received an ablative dose of therapy. The function of these spermatogonia was not tested,” writes lead author Hanna Valli-Pulaski, Ph.D., research assistant professor at the University of Pittsburgh, and colleagues in a study published online May 21, 2019, in Human Reproduction.

Right now, hematologists and oncologists discuss future treatment options with patients and families, as well as possible long-term side effects, including infertility. At Children’s National, they also mention the ongoing fertility preservation study and encourage families to speak with Dr. Hsieh. He meets with families, explains the study goals – which include determining better ways to freeze and thaw tissue and separating malignant cells from normal cells – what’s known about experimental fertility preservation and what remains unknown. Roughly half of patients decide to enroll.

“This study is unique in that there is definitely a potential direct patient benefit,” Dr. Hsieh adds. “One of the reasons the study is compelling is that it presents a message of hope to the families. It’s a message of survivorship: We’re optimistic we can help your child get through this and think about long-term issues, like having their own families.”

In this phase of the study, testicular tissue was collected from centers in the U.S. and Israel from January 2011 to November 2018 and cryopreserved. Patients designated 25% of the tissue sample to be used for the research study; 75 percent remains stored in liquid nitrogen at temperatures close to absolute zero for the patient’s future use. The fertility preservation patients ranged from 5 months old to 34 years old, with an average age of 7.9 years.

Thirty-nine percent of patients had started medical treatment prior requesting fertility preservation. Sixteen percent received non-alkylating chemotherapy while 23% received alkylating chemotherapy, which directly damages the DNA of cancer cells.

The research team found that the number of undifferentiated spermatogonia per seminiferous tubule increase steadily with age until about age 11, then rise sharply.

“We recommend that all patients be counseled and referred for fertility preservation before beginning medical treatments known to cause infertility. Because the decision to participate may be delayed, it is encouraging that we were able to recover undifferentiated spermatogonia from the testes of patients already in the early stages of chemotherapy treatments,” Dr. Hsieh says.

In addition to Dr. Hsieh, study co-authors include lead author, H. Valli-Pulaski, K.A. Peters, K. Gassei, S.R. Steimer, M. Sukhwani, B.P. Hermann, L. Dwomor, S. David, A.P. Fayomi, S.K. Munyoki, T. Chu, R. Chaudhry, G.M. Cannon, P.J. Fox, T.M. Jaffe, J.S. Sanfilippo, M.N. Menke and senior author, K.E. Orwig, all of University of Pittsburgh; E. Lunenfeld, M. Abofoul-Azab and M. Huleihel, Ben-Gurion University of the Negev; L.S. Sender, J. Messina and L.M. Klimpel, CHOC Children’s Hospital;  Y. Gosiengfiao, and E.E. Rowell, Ann & Robert H. Lurie Children’s Hospital of Chicago; C.F. Granberg, Mayo Clinic; P.P. Reddy, Cincinnati Children’s Hospital Medical Center; and J.I. Sandlow, Medical College of Wisconsin.

Financial support for the research covered in this post was provided by Eunice Kennedy Shriver National Institute for Child Health and Human Development under awards HD061289 and HD092084; Scaife Foundation; Richard King Mellon Foundation; University of Pittsburgh Medical Center; United States-Israel Binational Science Foundation and Kahn Foundation.

schistosome blood fluke

Therapy derived from parasitic worms downregulates proinflammatory pathways

schistosome blood fluke

A therapy derived from the eggs of the parasitic Schistosoma helps to protect against one of chemotherapy’s debilitating side effects by significantly downregulating major proinflammatory pathways, reducing inflammation.

A therapy derived from the eggs of parasitic worms helps to protect against one of chemotherapy’s debilitating side effects by significantly downregulating major proinflammatory pathways and reducing inflammation, indicates the first transcriptome-wide profiling of the bladder during ifosfamide-induced hemorrhagic cystitis.

The experimental model study findings were published online Feb. 7, 2019, in Scientific Reports.

With hemorrhagic cystitis, a condition that can be triggered by anti-cancer therapies like the chemotherapy drug ifosfamide and other oxazaphosphorines, the lining of the bladder becomes inflamed and begins to bleed. Existing treatments on the market carry their own side effects, and the leading therapy does not treat established hemorrhagic cystitis.

Around the world, people can become exposed to parasitic Schistosoma eggs through contaminated freshwater. Once inside the body, the parasitic worms mate and produce eggs; these eggs are the trigger for symptoms like inflammation. To keep their human hosts alive, the parasitic worms tamp down excess inflammation by secreting a binding protein with anti-inflammatory properties.

With that biological knowledge in mind, a research team led by Michael H. Hsieh, M.D., Ph.D., tested a single dose of IPSE, an Interleukin-4 inducing, Schistosoma parasite-derived anti-inflammatory molecule and found that it reduced inflammation, bleeding and urothelial sloughing that occurs with ifosfamide-related hemorrhagic cystitis.

In this follow-up project, experimental models were treated with ifosfamide to learn more about IPSE’s protective powers.

The preclinical models were given either saline or IPSE before the ifosfamide challenge. The bladders of the experimental models treated with ifosfamide had classic symptoms, including marked swelling (edema), dysregulated contraction, bleeding and urothelial sloughing. In contrast, experimental models “pre-treated” with IPSE were shielded from urothelial sloughing and inflammation, the study team found.

Transcriptional profiling of the experimental models’ bladders found the IL-1-B TNFa-IL-6 proinflammatory cascade via NFkB and STAT3 pathways serving as the key driver of inflammation. Pretreatment with IPSE slashed the overexpression of Il-1b, Tnfa and Il6 by 50 percent. IPSE drove significant downregulation of major proinflammatory pathways, including the IL-1-B TNFa-IL-6 pathways, interferon signaling and reduced (but did not eliminate) oxidative stress.

“Taken together, we have identified signatures of acute-phase inflammation and oxidative stress in ifosfamide-injured bladder, which are reversed by pretreatment with IPSE,” says Dr. Hsieh, a urologist at Children’s National Health System and the study’s senior author. “These preliminary findings reveal several pathways that could be therapeutically targeted to prevent ifosfamide-induced hemorrhagic cystitis in humans.”

When certain chemotherapy drugs are metabolized by the body, the toxin acrolein is produced and builds up in urine. 2-mercaptoethane sulfonate Na (MESNA) binds to acrolein to prevent urotoxicity. By contrast, IPSE targets inflammation at the source, reversing inflammatory changes that damage the bladder.

“Our work demonstrates that there may be therapeutic potential for naturally occurring anti-inflammatory molecules, including pathogen-derived factors, as alternative or complementary therapies for ifosfamide-induced hemorrhagic cystitis,” Dr. Hsieh adds.

In addition to Dr. Hsieh, study co-authors include Lead Author Evaristus C. Mbanefo and Rebecca Zee, Children’s National; Loc Le, Nirad Banskota and Kenji Ishida, Biomedical Research Institute; Luke F. Pennington and Theodore S. Jardetzky, Stanford University; Justin I. Odegaard, Guardant Health; Abdulaziz Alouffi, King Abdulaziz City for Science & Technology; and Franco H. Falcone, University of Nottingham.

Financial support for the research described in this report was provided by the Margaret A. Stirewalt Endowment, the National Institute of Diabetes and Digestive and Kidney Diseases under award R01DK113504, the National Institute of Allergy and Infectious Diseases under award R56AI119168 and a Urology Care Foundation Research Scholar Award.

Schistosoma haematobium egg

For hemorrhagic cystitis, harnessing the power of a parasite

Schistosoma haematobium egg

“Urogenital Schistosoma infestation, which is caused by S. haematobium, also causes hemorrhagic cystitis, likely by triggering inflammation when the parasite’s eggs are deposited in the bladder wall or as eggs pass from the bladder into the urinary stream. S. haematobium eggs secrete proteins, including IPSE, that ensure human hosts are not so sickened that they succumb to hemorrhagic cystitis,” says Michael H. Hsieh, M.D., Ph.D.

Every year, hundreds of thousands of U.S. patients – and even more throughout the world – are prescribed cyclophosphamide or ifosfamide. These two chemotherapy drugs can be life-saving for a wide range of pediatric cancers, including leukemias and cancers of the eyes and nerves. However, these therapies come with a serious side effect: Both cause hemorrhagic cystitis in up to 40 percent of patients. This debilitating condition is characterized by severe inflammation in the bladder that can cause tremendous pain, life-threatening bleeding, and frequent and urgent urination.

Infection with a parasitic worm called Schistosoma haematobium also causes hemorrhagic cystitis, but this organism has a fail-safe: To keep its host alive, the parasite secretes a protein that suppresses inflammation and the associated pain and bleeding.

In a new study, a Children’s-led research team harnessed this protein to serve as a new therapy for chemotherapy-induced hemorrhagic cystitis.

“Urogenital Schistosoma infestation, which is caused by S. haematobium, also causes hemorrhagic cystitis, likely by triggering inflammation when the parasite’s eggs are deposited in the bladder wall or as eggs pass from the bladder into the urinary stream. S. haematobium eggs secrete proteins, including IPSE, that ensure human hosts are not so sickened that they succumb to hemorrhagic cystitis,” says Michael H. Hsieh, M.D., Ph.D., senior author of the study published April 3, 2018, by The FASEB Journal. “This work in an experimental model is the first published report of exploiting an uropathogen-derived host modulatory molecule in a clinically relevant model of bladder disease, and it points to the potential utility of this as an alternate treatment approach.”

S. mansoni IPSE binds to Immunoglobulin E (IgE), an antibody produced by the immune system that is expressed on the surface of basophils, a type of immune cell; and mast cells, another immune cell that mediates inflammation; and sequesters chemokines, signaling proteins that alert white cells to infection sites. The team produced an ortholog of the uropathogen-derived protein. A single IV dose proved superior to multiple doses of 2-Mercaptoethane sulfonate sodium (MESNA), the current standard of care, in suppressing chemotherapy-induced bladder hemorrhaging in an experimental model. It was equally potent as MESNA in dampening chemotherapy-induced pain, the research team finds.

“The current array of medicines we use to treat hemorrhagic cystitis all have shortcomings, so there is a definite need for novel therapeutic options,” says Dr. Hsieh, a Children’s National Health System urologist. “And other ongoing research projects have the potential to further expand patients’ treatment options by leveraging other urogenital parasite-derived, immune-modulating molecules to treat inflammatory bowel diseases and autoimmune disorders.”

Future research will aim to describe the precise molecular mechanisms of action, as well as to generate other orthologs that boost efficacy while reducing side effects.

In addition to Dr. Hsieh, Children’s study co-authors include Lead Author, Evaristus C. Mbanefo; Loc Le and Luke F. Pennington; Justin I. Odegaard and Theodore S. Jardetzky, Stanford University; Abdulaziz Alouffi, King Abdulaziz City for Science and Technology; and Franco H. Falcone, University of Nottingham.

Financial support for this research was provided by National Institutes of Health under award number RO1-DK113504.

Study to evaluate heat-activated chemotherapy drug

Children’s National Health System and Celsion Corp., a leading oncology drug-development company, will be the first to launch a clinical study in the U.S. that evaluates the use of ThermoDox®, a heat-activated chemotherapy drug, in combination with noninvasive magnetic resonance-guided high-intensity focused ultrasound (MR-HIFU) to treat refractory or relapsed solid tumors in children and young adults.

The investigator-sponsored Phase I study, which is partially funded by an NIH R01 grant, will determine a safe and tolerable dose of ThermoDox, a lyso-thermosensitive liposomal doxorubicin (LTLD), which can be administered in combination with MR-HIFU. Under the guidance of an MRI, the high-intensity focused ultrasound directs soundwave energy to heat the tumor and the area around the tumor. When heated, the liposome rapidly changes structure and releases doxorubicin directly into and around the targeted tumor.

“There is currently no known cure for many patients with refractory recurring solid tumors, despite the use of intensive therapy, so we need to identify new, smarter therapies that can improve outcomes,” said AeRang Kim, M.D., Ph.D., oncologist and member of the Sheikh Zayed Institute for Pediatric Surgical Innovation at Children’s National, who is also principal investigator for the study. “Recent advances in the use of noninvasive MR-HIFU coupled with novel therapies, such as LTLD, may provide us with a mechanism to noninvasively administer high concentrations of the drug directly to the site where it is most needed and avoid toxicity to other areas of the body.”

A First to Treat Childhood Cancer

This is the first time LTLD is being combined with MR-HIFU and the first time it is being evaluated in children.

“Celsion’s experience in combining ThermoDox with HIFU, a noninvasive next generation heating technology, supports this very important research in childhood cancers. From a safe dose, ThermoDox’s proven ability to deliver high concentrations of an effective chemotherapy directly to a heated tumor makes it an ideal candidate for a trial involving children and young adults,” said Michael H. Tardugno, Celsion’s chairman, president and CEO. “This study will further elucidate ThermoDox’s potential in combination with ultrasound-induced hyperthermia, and highlight potential applications of ThermoDox in combination with a broad range of heating technologies that could address an even larger population of patients.”

A Multidisciplinary Approach

The study targeting the treatment of childhood sarcomas will be carried out as a multidisciplinary collaboration between Children’s National, Celsion, and Dr. Bradford Wood’s team at the National Institutes of Health.

This is the latest study from the Image-Guided Non-Invasive Therapeutic Energy (IGNITE) program, a collaboration of the Sheikh Zayed Institute for Pediatric Surgical Innovation at Children’s National and the pediatric health system’s Divisions of Radiology, Oncology, Surgery, and Anesthesiology. The goal of the IGNITE program is to improve the quality of life and outcomes for pediatric patients through the development and clinical introduction of novel minimally invasive and noninvasive surgery technologies and combination therapy approaches. In 2015, doctors from Children’s National were the first in the U.S. to treat osteoid osteoma, a benign and painful bone tumor, using MR-HIFU.

ThermoDox is currently in late-stage clinical trials in primary liver cancer and recurrent chest wall breast cancer. It is positioned for use with multiple heating technologies, and has the potential for applications in the treatment of other forms of cancer including metastatic liver and nonmuscle invading bladder cancers.

Finding new ways to fight hemorrhagic cystitis for cancer patients

Michael Hsieh

Children diagnosed with cancer face fear and uncertainty, a series of medical appointments, and multiple diagnostic tests and treatments.

Children diagnosed with cancer face fear and uncertainty, a series of medical appointments, and multiple diagnostic tests and treatments. On top of these challenges, says Children’s National Health System urologist Michael Hsieh, M.D., Ph.D., many patients contend with additional issues: Treatment side effects, discomforts, and dangers that nearly eclipse that of the cancer itself. One of the most common side effects is hemorrhagic cystitis (HC), a problem marked by extreme inflammation in the bladder that can lead to tremendous pain and bleeding.

HC often results from administering two common chemotherapy drugs, cyclophosphamide and ifosfamide, used to treat a wide variety of pediatric cancers, including leukemias and cancers of the eye and nerves. In the United States alone, nearly 400,000 patients of all ages receive these drugs annually. Of these, up to 40 percent develop some form of HC, from symptomatic disease characterized by pain and bloody urine to cellular changes to the bladder detected by microscopic analysis.

“Having to deal with therapy complications makes the cancer ordeal so much worse for our patients,” says Dr. Hsieh, Director of the Clinic for Adolescent and Adult Pediatric Onset Urology at Children’s National. “Being able to eliminate this extremely detrimental side effect once and for all could have an enormous impact on patients at our hospital and around the world.”

Preventing complications with mesna

The severity of side effects from cyclophosphamide and ifosfamide can vary from mild and fleeting to bladder bleeding so extensive that patients require multiple transfusions and surgery to remove blood clots that can obstruct urinary release, says Dr. Hsieh, who frequently treats patients with this condition. But HC isn’t inevitable, he adds. A drug called mesna has the potential to prevent this complication when prescribed before a patient receives chemotherapy.

The problem is for a fraction of patients, mesna simply doesn’t work. For others, mesna can cause its own serious side effects, such as life-threatening malfunctions of the heart’s electrical system or allergic reactions.

“These kids are often already very sick from their cancers and treatments, and then you compound it with these complications,” says Dr. Hsieh. “There’s a desperate need for alternatives to mesna.”

Looking at alternative treatments

In a new review of the scientific literature, published August 24 by Urology, senior author Dr. Hsieh and a colleague detail all the substitutes for this drug that researchers have examined over several years.

One of these is hyperhydration, or delivering extra fluid intravenously to help flush the bladder and keep dangerous chemotherapy drug metabolites from accumulating and causing damage. Hyperhydration, however, isn’t an option for some patients with kidney, lung, or liver problems, who can’t tolerate excess fluid.

Researchers also have invested heavily in antioxidants as alternative treatments. Because much of the damage caused by these chemotherapy agents is thought to result from a cascade of oxidizing free radicals that cyclophosphamide and ifosfamide launch in the bladder, antioxidants might prevent injury by halting the free radical attack. Antioxidants that researchers have explored for this purpose include cytokines, or immune-signaling molecules, known as interleukin-1 and tumor necrosis factor, and a compound called reduced glutathione. Other studies have tested plant-based antioxidants, including a component of red wine known as resveratrol; a compound called diallyl disulfide isolated from garlic oil; and extracts from Uncaria tomentosa, a woody vine commonly known as “cat’s claw” that grows in the jungles of Central and South America.

Researchers also have tested options that focus on reducing the intense inflammation that cyclophosphamide and ifosfamide cause in the bladder, including the corticoid steroid drug dexamethasone as well as another cytokine known as interleukin-4.

However, Dr. Hsieh says, studies have shown that each of these treatments is inferior to mesna. To truly combat HC, researchers not only need to find new drugs and methods that outperform mesna but also new ways to reverse HC after other measures fail—problems he’s working to solve in his own lab.