Virus World

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. 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." Michael Keller, M.D., pediatric immunologist at Children's National and the lead study author.

In recent years we’ve seen the power of analyzing cell-free DNA to diagnose and track the progression of cancer. Yet, using this technology as a diagnostic tool for infectious diseases required scientists to overcome numerous hurdles. For instance, a common problem in diagnosing infectious disease is that the presence of a potential pathogen in the body does not necessarily mean the patient is sick. This scenario can be particularly challenging when treating organ transplant recipients, who often grapple with infection as well as complications related to immunosuppression.

Now, a new study by investigators at Cornell University describes a technique to identify viruses and bacteria in the human body and quantify injuries to organs by using dead fragments of DNA, called cell-free DNA, that roam throughout the bloodstream and urine. Findings from the new study were published recently in PNAS. The resulting test is simple, fast, low cost, and generalizable enough to identify thousands of bacteria and viruses. 

“This really came about through collaboration with clinicians who explained to us this common problem in infectious disease diagnosis,” explained senior study investigator Iwijn De Vlaminck, PhD, a professor in the Meinig School of Biomedical Engineering at Cornell. “So, we developed an assay that would simultaneously inform us about the presence or absence of a wide range of pathogens, but at the same time would also tell us about the injury of different host tissues. The combined information enables us to more definitively say whether a person is dealing with disease or not.” In the current study, the researchers used high-throughput DNA sequencing to identify any microorganisms that were present in clinical samples and distinguish them from the host DNA via bisulfite sequencing, a process in which the cell-free DNA is treated with salt to reveal methylation marks. These marks helped the researchers trace the cell-free DNA’s tissues of origin and measure the degree of injury to different host tissues.

Study co-author Manikkam Suthanthiran, MD, chief of nephrology, hypertension, and transplantation medicine at Cornell added that “transplant recipients, because of the lifelong drug therapy needed to protect their transplanted organs, are ever at risk for infection-related complications. A precise test that informs not only the presence of infectious agents but also the presence or absence of tissue injury is a major step toward personalizing therapy and making organ transplantation safer.”  Interestingly, the test was especially helpful in diagnosing damage due to BK polyomavirus (BKV) infection. While 25–30% of kidney transplant recipients have the virus in their blood or urine, only 5% experience nephropathy, or kidney disease, from the virus. “In this investigation, we were able to demonstrate that the kidney-specific urine cell-free DNA is higher in individuals with BKV nephropathy as compared to those with BKV replication alone and those with no BKV replication, suggesting a role for this assay to monitor kidney damage in the face of active viral replication and infection,” concluded co-senior study investigator Darshana Dadhania, MD, associate professor of medicine at Weill Cornell Medicine and a nephrologist at NewYork-Presbyterian/Weill Cornell Medical Center said. “This is particularly important because there is no specific therapy for active BKV replication.”

Original findings published on  August 5, 2019 in P.N.A.S.:

https://doi.org/10.1073/pnas.1906320116