Tag Archive for: hemorrhagic cystitis

t-cells

Tailored T-cell therapies neutralize viruses that threaten kids with PID

t-cells

Tailored T-cells specially designed to combat a half dozen viruses are safe and may be effective in preventing and treating multiple viral infections, according to research led by Children’s National Hospital faculty.

Catherine Bollard, M.B.Ch.B., M.D., director of the Center for Cancer and Immunology Research at Children’s National and the study’s senior author, presented the teams’ findings Nov. 8, 2019, during a second-annual symposium jointly held by Children’s National and the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH). Children’s National and NIAID formed a research partnership in 2017 to develop and conduct collaborative clinical research studies focused on young children with allergic, immunologic, infectious and inflammatory diseases. Each year, they co-host a symposium to exchange their latest research findings.

According to the NIH, more than 200 forms of primary immune deficiency diseases impact about 500,000 people in the U.S. These rare, genetic diseases so impair the person’s immune system that they experience repeated and sometimes rare infections that can be life threatening. After a hematopoietic stem cell transplantation, brand new stem cells can rebuild the person’s missing or impaired immune system. However, during the window in which the immune system rebuilds, patients can be vulnerable to a host of viral infections.

Because viral infections can be controlled by T-cells, the body’s infection-fighting white blood cells, the Children’s National first-in-humans Phase 1 dose escalation trial aimed to determine the safety of T-cells with antiviral activity against a half dozen opportunistic viruses: adenovirus, BK virus, cytomegalovirus (CMV), Epstein-Barr virus (EBV), Human Herpesvirus 6 and human parainfluenza-3 (HPIV3).

Eight patients received the hexa-valent, virus-specific T-cells after their stem cell transplants:

  • Three patients were treated for active CMV, and the T-cells resolved their viremia.
  • Two patients treated for active BK virus had complete symptom resolution, while one had hemorrhagic cystitis resolved but had fluctuating viral loads in their blood and urine.
  • Of two patients treated prophylactically, one developed EBV viremia that was treated with rituximab.

Two additional patients received the T-cell treatments under expanded access for emergency treatment, one for disseminated adenoviremia and the other for HPIV3 pneumonia. While these critically ill patients had partial clinical improvement, they were being treated with steroids which may have dampened their antiviral responses.

“These preliminary results show that hexaviral-specific, virus-specific T-cells are safe and may be effective in preventing and treating multiple viral infections,” says Michael Keller, M.D., a pediatric immunologist at Children’s National and the lead study author. “Of note, enzyme-linked immune absorbent spot assays showed evidence of antiviral T-cell activity by three months post infusion in three of four patients who could be evaluated and expansion was detectable in two patients.”

In addition to Drs. Bollard and Keller, additional study authors include Katherine Harris M.D.; Patrick J. Hanley Ph.D., assistant research professor in the Center for Cancer and Immunology; Allistair Abraham, M.D., a blood and marrow transplantation specialist; Blachy J. Dávila Saldaña, M.D., Division of Blood and Marrow Transplantation; Nan Zhang Ph.D.; Gelina Sani BS; Haili Lang MS; Richard Childs M.D.; and Richard Jones M.D.

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Children’s National-NIAID 2019 symposium presentations

“Welcome and introduction”
H. Clifford Lane, M.D., director of NIAID’s Division of Clinical Research

“Lessons and benefits from collaboration between the NIH and a free-standing children’s hospital”
Marshall L. Summar, M.D., director, Rare Disease Institute, Children’s National

“The hereditary disorders of PropionylCoA and Cobalamin Metabolism – past, present and future”
Charles P. Venditti, M.D., Ph.D., National Human Genome Research Institute Collaboration

“The road(s) to genetic precision therapeutics in pediatric neuromuscular disease: opportunities and challenges”
Carsten G. Bönnemann, M.D., National Institute of Neurological Disorders and Stroke

“Genomic diagnostics in immunologic diseases”
Helen Su, M.D., Ph.D., National Institute of Allergy and Infectious Diseases

“Update on outcomes of gene therapy clinical trials for X-SCID and X-CGD and plans for future trials”
Harry Malech, M.D., National Institute of Allergy and Infectious Diseases

“Virus-specific T-cell therapies: broadening applicability for PID patients”
Catherine Bollard, M.D., Children’s National 

“Using genetic testing to guide therapeutic decisions in Primary Immune Deficiency Disease”
Vanessa Bundy, M.D., Ph.D., Children’s National 

Panel discussion moderated by Lisa M. Guay-Woodford, M.D.
Drs. Su, Malech, Bollard and Bundy
Morgan Similuk, S.C.M., NIAID
Maren Chamorro, Parent Advocate

“Underlying mechanisms of pediatric food allergy: focus on B cells
Adora Lin, M.D., Ph.D., Children’s National 

“Pediatric Lyme outcomes study – interim update”
Roberta L. DeBiasi, M.D., MS, Children’s National 

“Molecular drivers and opportunities in neuroimmune conditions of pediatric onset”
Elizabeth Wells, M.D., Children’s National 

 

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.

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.