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Seattle Children's Trial Aims to ID Immune Pathways in IBD, Graft Versus Host Disease

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SAN FRANCISCO (GenomeWeb) – Researchers at Seattle Children's Hospital have launched a clinical trial that aims to identify the immune pathways involved in inflammatory bowel disease and in patients who undergo bone marrow transplantation and develop graft versus host disease of the gastrointestinal tract.

The goal is to identify immune system-related gene expression signatures that can lead to better diagnosis of the diseases, enabling subtyping to identify the most severe cases, and even to enable targeted treatment.

The researchers plan to enroll 100 patients with IBD and 250 patients who have had bone marrow transplants and will use a combination of immune sequencing technologies: Adaptive Biotechnologies' ImmunoSeq platform to do deep sequencing of T cell receptors and 10x Genomics' immune repertoire profiling technology to get gene expression at the single-cell level.

Leslie Kean, associate director of the Ben Towne Center for Childhood Cancer Research at Seattle Children's Hospital and principal investigator of the trial, said that currently, "patients are treated with a one-size-fits all approach and we have little insight into the molecular pathways that are disrupted in T cells" for both IBD and graft versus host disease, although both disorders are related to the immune system. In addition, both IBD patients and a certain subset of patients who have bone marrow transplants experience similar gastrointestinal symptoms.

For patients who undergo bone marrow transplants, about half end up developing some sort of graft versus host disease, she said, and about 15 percent of those patients experience a very severe form that affects the gastrointestinal system. Essentially, a patient's T cells attack the GI tract and the patient becomes unable to absorb nutrients. Patients also experience significant diarrhea and can have bleeding from their intestine. "It's the most deadly complication of bone marrow transplantation," Kean said, "and has a lot of commonalities with IBD."

Kean and her colleagues launched the clinical trial, Precision Diagnostics in Inflammatory Bowel Disease, Cellular Therapy and Transplantation (PREDICT), after years of both pre-clinical research in animals as well as clinical research in humans studying immune pathways.

"If we can understand the pathways that are dysregulated in each individual patient then that could lead to treatment decisions that are patient-specific, which would potentially be more targeted with fewer side effects and more efficacy," she said. "That's the goal of PREDICT."

Kean's previous research lends support to the idea. In a 2015 study published in Blood, the researchers collaborated with Adaptive Biotechnologies to use the ImmunoSeq assay to identify molecular mechanisms involved in cytomegalovirus reactivation in patients who experience immune disorders after a bone marrow transplant. In addition, animal research that evaluated the gene expression of T cells in primates and mouse models of graft-versus-host disease identified potential therapeutic pathways in those models, and in a study published in Science Translational Medicine, Kean and colleagues validated that inhibiting one of those targets, aurora kinase A, led to improved outcomes in mice.

Both of those studies laid the groundwork for developing the PREDICT trial, and the Science Translational Medicine study, in particular, lent support to the idea that the trial could uncover drug targets, Kean said. Separately, another group is now developing a molecule that inhibits aurora kinase A, she said, and the PREDICT trial could help determine which patients may benefit from such a drug.

Currently, the PREDICT trial does not include a pipeline through which researchers make treatment recommendations, but if this initial trial is successful, the study could later be expanded to include stratification of patients onto targeted therapies, Kean said.

Enrollment for both the IBD arm and the bone marrow transplantation arm are currently open, Kean said. For the IBD arm, Kean said the team is working closely with two physicians at Seattle Children's, Ghassan Wahbeh, director of the Inflammatory Bowel Disease Center and Betty Zheng, a gastroenterologist. Patients who come into the clinic will be given the option of enrolling into the trial. Both blood samples and samples from the diagnostic endoscopy will be taken, Kean said.

The pre-treatment samples will be "a huge advantage in terms of being able to see a signal," she added. In addition, she said, getting these early pre-treatment, pre-diagnosis samples will enable researchers to also collect control samples. Often children come to the clinic who have all the symptoms of IBD, but the cause is not immune related. "Those will be a really important comparator to the IBD group and will lend a lot of strength to the study," she said.

The other cohort — bone marrow transplant patients — will be recruited at the time they are receiving their transplant. This will enable the researchers to compare patients who do not develop graft versus host disease, patients who develop very severe GI-related GVHD, and patients who develop a different form of GVHD. GVHD can affect three different tissues, Kean said: the skin, liver, and the GI tract.

Blood samples will be collected from all patients and endoscopy samples will be taken from just those patients who end up with severe GI tract disorders.

For both cohorts, Kean said the team hopes to uncover gene expression signatures that can enable molecular diagnoses of these disorders, as well as identify targeted therapies to better treat the disorders.

There are already a number of targeted therapies available, Kean said, but it is currently difficult to determine who should receive which therapy. For instance, she said, there are known antibodies that target specific pathways, like the alpha 1 homing receptor pathway or the CCR5 chemokine receptor pathway. The goal of the study is that it will identify subsets of patients with active, targetable pathways.

Kean said the group chose to use both the Adaptive ImmunoSeq technology as well as 10x Genomics' single T-cell technology because they both had the potential to offer important insights. Based on her previous work with Adaptive, Kean said she realized the potential of that technology to do deep immune repertoire profiling. "That's been really impactful for understanding what pathways are disrupted," she said. However, "when you do bulk RNA-seq, one thing you have to contend with is the error of the mean. Because you have millions of cells, sometimes the signal is overwhelmed by the majority." The single-cell sequencing aspect will enable the researchers to look for T cells that may be critical, but only present at a low frequency.

Kean said she expected to finish enrollment for PREDICT in the next two to three years, with final results available about one year after that.

Seattle Children's Hospital is providing the bulk of the funding for the trial, but the group also has some philanthropic support. Both Adapative and 10x Genomics have been providing significant support for their respective technologies, Kean said. In addition, she said she is applying for funding from the National Institutes of Health.

If this initial phase is successful, Kean said a second phase that aims to make treatment recommendations based on patients' TCR profiles could launch in around three years.  

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