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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 

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Also read: Johan’s story
View: Safeguarding Johan’s future

antibodies-illustration

Detecting and treating dnDSA early preserves allograft function

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Monitoring and treating de novo donor-specific antibodies (dnDSA) before they could cause graft damage helped to decrease dnDSA in a majority of pediatric kidney transplant recipients at Children National Health System and prevented graft failure in the first few years.

Development of de novo donor-specific antibodies (dnDSA) is known to cause graft failure. Therefore, a protocol aimed at prospective monitoring and treating dnDSA – before they can cause graft damage – was developed for kidney transplant recipients at Children National Health System. This helped to decrease dnDSA in 76 percent of pediatric patients and prevented graft failure in the first few years, indicates a longitudinal cohort study published online Jan. 22, 2018, in Pediatric Transplantation. However, the benefit of preserving function of transplanted kidneys came at a price: Heightened hospitalization rates for infection.

An estimated 20 percent to 30 percent of children develop dnDSA and many of these patients go on to develop allograft failure after three to six years, write the study authors.

Clinical signs of graft failure due to antibodies appear too late to safeguard long-term graft survival. According to the study authors, developing earlier methods to detect dnDSA offers the opportunity to intervene before irreversible graft injury occurs.

“Children’s National Health System instituted a routine protocol that standardizes monitoring and treatment of dnDSA,” says Asha Moudgil, M.D., FASN, associate chief of the Division of Nephrology at Children’s National and the study’s senior author. “We followed this protocol as we monitored and treated all children younger than 19 who received a kidney transplant at Children’s National from Jan. 1, 2008, to Dec. 31, 2013.”

After transplant, these children were monitored for development of dnDSA at six months and then yearly. Upon detection of DSA, these children underwent kidney biopsy to assess for acute rejection. Additionally, monitoring was intensified to every two months.

“Our patients did not have a statistically significant increase in graft loss or dysfunction, suggesting that early and targeted treatment of dnDSA may benefit patients,” says Asha Moudgil, M.D., FASN.

Sixty-seven of the 72 children who received kidney transplants during that six-year period were included in this retrospective analysis. Their mean age was 14.1 years. Acute cellular rejection was treated according to a prespecified protocol.

  • The team treated de novo DSA with high-dose intravenous immunoglobulin (IVIG) if antibody titers were low and added two doses of rituximab to that treatment regimen if antibody titers were high.
  • If either C1q binding of immunodominant DSA was present or C4d+ were seen on biopsy, six sessions of plasma exchange were added to the above protocol.
  • Kids who were resistant to such treatment approaches received an additional four doses of IVIG monthly.

Nearly 39 percent of the children developed dnDSA within a median of 1.36 years. Ten of these 26 children had increased creatinine, 12 had new onset proteinuria and six had newly diagnosed hypertension at the time the dnDSA was detected. The multivariate analysis found that the coefficient of variance of tacrolimus, which measures adherence to immunosuppressive drugs, was the only statistically significant predictor for developing dnDSA.

DSA-positive patients had a higher rate of admissions (1.23 hospital admissions for infectious- or immunosuppressive-related side effects per patient, compared with 0.59 hospital admissions for the DSA-negative patients), which the study team attributes to aggressive treatment of dnDSA.

“Our patients did not have a statistically significant increase in graft loss or dysfunction, suggesting that early and targeted treatment of dnDSA may benefit patients,” Dr. Moudgil adds. “There was a higher risk of treatment-related complications, however, and this risk must be balanced against the short-term benefit of prolonging allograft function.”

Study co-authors include Olga Charnaya, M.D., a Children’s fellow when the study was designed and the article was drafted, now at Johns Hopkins; and Children’s Nephrologist, Shamir Tuchman, M.D.