Center for Childhood Cancer Research

Philadelphia, PA, United States

Center for Childhood Cancer Research

Philadelphia, PA, United States
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SEATTLE - May 23, 2017 - In an effort to find new strategies to personalize treatment for pediatric patients, Seattle Children's has opened the first clinical trial applying next-generation T-cell receptor (TCR) sequencing and single-cell gene expression analysis to better understand how the immune system drives both inflammatory bowel disease (IBD) in pediatric autoimmunity patients and graft-versus host disease (GVHD) in pediatric bone marrow transplant (BMT) patients. The PREDICT (Precision Diagnostics in Inflammatory Bowel Disease, Cellular Therapy and Transplantation) trial is expected to first provide clinicians new information about why IBD arises in children, allowing them to tailor treatment plans to each patient. The trial will later expand to include BMT patients with the goal of identifying the immunologic changes that occur when a patient develops GVHD, the deadliest complication associated with BMT. BMT is used to treat a range of pediatric conditions from leukemia to inherited bone marrow failure syndromes, congenital metabolic disorders and other metabolic diseases. "PREDICT seeks to change the paradigm of treatment by first changing the paradigm of diagnosis," said Dr. Leslie Kean, the the trial's principal investigator who leads a lab focused on T-cell immunology and is the associate director of the Ben Towne Center for Childhood Cancer Research at Seattle Children's Research Institute. "By gaining foundational molecular diagnostic knowledge about a patient's T cells, we hope to ultimately discover better treatment approaches for IBD and GVHD." As part of the trial, Kean and her team will perform TCR sequencing and gene expression analysis on samples collected from 100 IBD and 250 BMT patients. The data resulting from the initial and follow-up analyses will help researchers pinpoint molecular pathways active within a patient's T cells that could serve as therapeutic targets in future studies. The researchers will collaborate with Adaptive Biotechnologies by implementing their immunoSEQ® platform for high-throughput TCR sequencing and conducting TCR repertoire analyses. The single-cell gene expression analysis will be performed using the Chromium™ Single Cell 3' Solution supplied by 10x Genomics, which will enable gene expression patterns to be discovered in each patient's individual T cells. Over the next two years, Kean will work in partnership with transplant, gastroenterology and immunology physicians to first enroll IBD patients who are undergoing their diagnostic evaluation and treatment at Seattle Children's, with plans to open the BMT cohort later this year. A bridge between the bowel and bone marrow GVHD occurs when the T cells of newly transplanted bone marrow begin to attack a patient's tissues, including those of the skin, liver and intestine. The impact to the gastrointestinal tract can be extremely difficult to overcome and is the most deadly complication of BMT. In patients with IBD, a similar pathogenesis is observed where components of the immune system, including T cells, react abnormally over time causing chronic inflammation in the digestive system. Standard treatments aimed at suppressing or modulating the immune response are often ineffective in managing diseases like IBD and GVHD. In both diseases, there is a need for new, targeted therapies able to prevent or treat the diseases without causing the side effects that plague current treatments. "IBD and GVHD have a lot more in common than meets the eye when it comes to the underlying immune response they trigger," said Kean. "PREDICT aims to bridge IBD and GVHD, shedding new light on the immunologic similarities they share and identifying the molecular causes of each patient's disease. This will create a unique opportunity to make significant headway in the treatment of both diseases, with the focus on each child and their unique disease signature." Initial funding for the PREDICT trial was provided through a Seattle Children's Research Institute pilot grant and made possible with support from biopharmaceutical collaborators. For more information on the PREDICT trial at Seattle Children's, please email predict@seattlechildrens.org. Seattle Children's mission is to provide hope, care and cures to help every child live the healthiest and most fulfilling life possible. Together, Seattle Children's Hospital, Research Institute and Foundation deliver superior patient care, identify new discoveries and treatments through pediatric research, and raise funds to create better futures for patients. Ranked as one of the top five children's hospitals in the country by U.S. News & World Report, Seattle Children's serves as the pediatric and adolescent academic medical center for Washington, Alaska, Montana and Idaho - the largest region of any children's hospital in the country. As one of the nation's top five pediatric research centers, Seattle Children's Research Institute is internationally recognized for its work in neurosciences, immunology, cancer, infectious disease, injury prevention and much more. Seattle Children's Hospital and Research Foundation works with the Seattle Children's Guild Association, the largest all-volunteer fundraising network for any hospital in the country, to gather community support and raise funds for uncompensated care and research. For more information, visit seattlechildrens.org or follow us on Twitter, Facebook, Instagram or on our On the Pulse blog.


"PREDICT seeks to change the paradigm of treatment by first changing the paradigm of diagnosis," said Dr. Leslie Kean, the trial's principal investigator who leads a lab focused on T-cell immunology and is the associate director of the Ben Towne Center for Childhood Cancer Research at Seattle Children's Research Institute. "By gaining foundational molecular diagnostic knowledge about a patient's T cells, we hope to ultimately discover better treatment approaches for IBD and GVHD." As part of the trial, Kean and her team will perform TCR sequencing and gene expression analysis on samples collected from 100 IBD and 250 BMT patients. The data resulting from the initial and follow-up analyses will help researchers pinpoint molecular pathways active within a patient's T cells that could serve as therapeutic targets in future studies. The researchers will collaborate with Adaptive Biotechnologies by implementing their immunoSEQ® platform for high-throughput TCR sequencing and conducting TCR repertoire analyses. The single-cell gene expression analysis will be performed using the Chromium™ Single Cell 3′ Solution supplied by 10x Genomics, which will enable gene expression patterns to be discovered in each patient's individual T cells. Over the next two years, Kean will work in partnership with transplant, gastroenterology and immunology physicians to first enroll IBD patients who are undergoing their diagnostic evaluation and treatment at Seattle Children's, with plans to open the BMT cohort later this year. A bridge between the bowel and bone marrow GVHD occurs when the T cells of newly transplanted bone marrow begin to attack a patient's tissues, including those of the skin, liver and intestine. The impact to the gastrointestinal tract can be extremely difficult to overcome and is the most deadly complication of BMT. In patients with IBD, a similar pathogenesis is observed where components of the immune system, including T cells, react abnormally over time causing chronic inflammation in the digestive system. Standard treatments aimed at suppressing or modulating the immune response are often ineffective in managing diseases like IBD and GVHD. In both diseases, there is a need for new, targeted therapies able to prevent or treat the diseases without causing the side effects that plague current treatments. "IBD and GVHD have a lot more in common than meets the eye when it comes to the underlying immune response they trigger," said Kean. "PREDICT aims to bridge IBD and GVHD, shedding new light on the immunologic similarities they share and identifying the molecular causes of each patient's disease. This will create a unique opportunity to make significant headway in the treatment of both diseases, with the focus on each child and their unique disease signature." Initial funding for the PREDICT trial was provided through a Seattle Children's Research Institute pilot grant and made possible with support from biopharmaceutical collaborators. For more information on the PREDICT trial at Seattle Children's, please email predict@seattlechildrens.org. About Seattle Children's Seattle Children's mission is to provide hope, care and cures to help every child live the healthiest and most fulfilling life possible. Together, Seattle Children's Hospital, Research Institute and Foundation deliver superior patient care, identify new discoveries and treatments through pediatric research, and raise funds to create better futures for patients. Ranked as one of the top five children's hospitals in the country by U.S. News & World Report, Seattle Children's serves as the pediatric and adolescent academic medical center for Washington, Alaska, Montana and Idaho – the largest region of any children's hospital in the country. As one of the nation's top five pediatric research centers, Seattle Children's Research Institute is internationally recognized for its work in neurosciences, immunology, cancer, infectious disease, injury prevention and much more. Seattle Children's Hospital and Research Foundation works with the Seattle Children's Guild Association, the largest all-volunteer fundraising network for any hospital in the country, to gather community support and raise funds for uncompensated care and research. For more information, visit seattlechildrens.org or follow us on Twitter, Facebook, Instagram or on our On the Pulse blog. To view the original version on PR Newswire, visit:http://www.prnewswire.com/news-releases/seattle-childrens-brings-first-of-its-kind-precision-medicine-clinical-trial-to-inflammatory-bowel-disease-bone-marrow-transplant-patients-300462186.html


After phase 1 results of Seattle Children's Pediatric Leukemia Adoptive Therapy (PLAT-02) trial have shown T-cell immunotherapy to be effective in getting 93 percent of patients with relapsed or refractory acute lymphoblastic leukemia (ALL) into complete initial remission, researchers have now opened a first-in-human clinical trial aimed at reducing the rate of relapse after the therapy, which is about 50 percent. The new phase 1 pilot study, PLAT-03, will examine the feasibility and safety of administering a second T-cell product intended to increase the long-term persistence of the patient's chimeric antigen receptor (CAR) T cells that were reprogrammed to detect and destroy cancer. The research team, led by Dr. Mike Jensen at the Ben Towne Center for Childhood Cancer Research at Seattle Children's Research Institute, is exploring this strategy after discovering that of the patients who relapse in the PLAT-02 trial, about half of them have lost their CAR T cells. Lasting persistence of the CAR T cells is critical in combating a recurrence of cancer cells. "While it's promising that we're able to get these patients who are very sick back into remission, we're also seeing that the loss of the CAR T cells in some patients may be opening the door for the cancer to return," said Dr. Colleen Annesley, an oncologist at Seattle Children's and the lead investigator of the PLAT-03 trial. "We're pleased to now be able to offer patients who have lost or are at risk of losing their cancer-fighting T cells an option that will hopefully lead to them achieving long-term remission." In the PLAT-03 trial, patients will receive "booster" infusions of a second T-cell product, called T antigen-presenting cells (T-APCs). The T-APCs have been genetically modified to express the CD19 target for the cancer-fighting CAR T cells to recognize. Patients will receive a full dose of T-APCs every 28 days for at least one and up to six doses. By stimulating the CAR T cells with a steady stream of target cells to attack, researchers hope the CAR T cells will re-activate, helping to ensure their persistence long enough to put patients into long-term remission. PLAT-03 is now open to patients who first enroll in phase 2 of Seattle Children's PLAT-02 trial and who are also identified as being at risk for early loss of their reprogrammed CAR T cells, or those who lose their reprogrammed CAR T cells within six months of receiving them. The PLAT-03 trial is one of several trials that Seattle Children's researchers are planning to open within the next year aimed at further improving the long-term efficacy of T-cell immunotherapy. In addition to the current T-cell immunotherapy trial that is open for children with neuroblastoma, researchers also hope to expand this promising therapy to other solid tumor cancers. "We are pleased to be at a pivotal point where we are now looking at several new strategies to further improve CAR T-cell immunotherapy so it remains a long-term defense for all of our patients," said Dr. Rebecca Gardner, Seattle Children's oncologist and the lead investigator of the PLAT-02 trial. "We're also excited to be working to apply this therapy to several other forms of pediatric cancer beyond ALL, with the hope that T-cell immunotherapy becomes a first line of defense, reducing the need for toxic therapies and minimizing the length of treatment to only weeks." To read about the experience of one of the patients in the PLAT-02 trial, please visit Seattle Children's On the Pulse blog. The T-cell immunotherapy trials at Seattle Children's are funded in part by Strong Against Cancer, a national philanthropic initiative with worldwide implications for potentially curing childhood cancers. If you are interested in supporting the advancement of immunotherapy and cancer research, please visit Strong Against Cancer's donation page. For more information on immunotherapy research trials at Seattle Children's, please call (206) 987-2106 or email immunotherapy@seattlechildrens.org. Seattle Children's mission is to provide hope, care and cures to help every child live the healthiest and most fulfilling life possible. Together, Seattle Children's Hospital, Research Institute and Foundation deliver superior patient care, identify new discoveries and treatments through pediatric research, and raise funds to create better futures for patients. Ranked as one of the top five children's hospitals in the country by U.S. News & World Report, Seattle Children's serves as the pediatric and adolescent academic medical center for Washington, Alaska, Montana and Idaho - the largest region of any children's hospital in the country. As one of the nation's top five pediatric research centers, Seattle Children's Research Institute is internationally recognized for its work in neurosciences, immunology, cancer, infectious disease, injury prevention and much more. Seattle Children's Hospital and Research Foundation works with the Seattle Children's Guild Association, the largest all-volunteer fundraising network for any hospital in the country, to gather community support and raise funds for uncompensated care and research. For more information, visit seattlechildrens.org or follow us on Twitter, Facebook, Instagram or on our On the Pulse blog.


Devoto M.,Children's Hospital of Philadelphia | Devoto M.,University of Pennsylvania | Devoto M.,University of Rome La Sapienza | Specchia C.,University of Brescia | And 5 more authors.
Human Heredity | Year: 2011

Background: Neuroblastoma (NB) is an important childhood cancer with a strong genetic component related to disease susceptibility. Approximately 1% of NB cases have a positive family history. Following a genome-wide linkage analysis and sequencing of candidate genes in the critical region, we identified ALK as the major familial NB gene. Dominant mutations in ALK are found in more than 50% of familial NB cases. However, in the families used for the linkage study, only about 50% of carriers of ALK mutations are affected by NB. Methods: To test whether genetic variation may explain the reduced penetrance of the disease phenotype, we analyzed genome-wide genotype data in ALK mutation-positive families using a model-based linkage approach with different liability classes for carriers and non-carriers of ALK mutations. Results: The region with the highest LOD score was located at chromosome 2p23-p24 and included the ALK locus under models of dominant and recessive inheritance. Conclusions: This finding suggests that variants in the non-mutated ALK gene or another gene linked to it may affect penetrance of the ALK mutations and risk of developing NB in familial cases. Copyright © 2011 S. Karger AG, Basel.


News Article | December 20, 2016
Site: www.eurekalert.org

Scientists have used systems biology tools to map out molecular pathways and signaling circuits that come into play when the immune system acts against infections and cancer. Important immune cells, called CD8+ T cells, play a pivotal role in immune response, but their gene regulatory circuits are not well understood. Researchers from Children's Hospital of Philadelphia (CHOP) and the University of Iowa used sophisticated sequencing and computational techniques to investigate the molecular mechanisms during each stage of the CD8+ T cells' responses. By identifying novel biological pathways and publishing details of these interactions, the study team aims to help uncover useful targets in developing better vaccines and cancer treatments. "We have revealed novel components and connections in the regulatory network underlying how these T cells mount an immune response," said study co-leader Kai Tan, PhD, of the Center for Childhood Cancer Research and the Departments of Pediatrics and Biomedical and Health Informatics at CHOP. "We found highly dynamic processes as these cells develop. In addition to adding to our knowledge of cell biology, these findings may help advance vaccine development and cancer immunotherapy." Tan and colleagues at CHOP co-authored the study with a team led by Hai-Hui Xue, MD, PhD, of the Carver College of Medicine at the University of Iowa. The research appeared online Dec. 13 in Immunity and in print today. The researchers investigated how CD8+ T cells in laboratory mice respond to infections. In mice, humans and other mammals, those cells begin in a naïve pre-infected state, but after encountering an antigen, differentiate into large quantities of effector cells to clear an infection. After the infection, cell numbers diminish, but central memory T cells retain a long-term ability to defend against reinfection by microorganisms that carry the same antigen. The three stages of CD8+ T cell development are well known, but the current study identifies a detailed map of the regulatory circuitry, such as interactions between enhancers and promoters--genetic regulatory regions that function together in driving genes to transcribe proteins to carry out biological processes. Using bioinformatics tools to identify and map out specific components and regulatory interconnections, the study team found highly dynamic activities during CD8+ T cell responses: a distinct repertoire of super enhancers -- groups of enhancers that interact with promoters to drive gene transcription, new groups of enhancers that jump into activity only in the memory cell stage, and extensive re-wiring of regulatory circuits from one cell stage to another. "Better understanding of these mechanisms is important because increasing the quantity and quality of memory CD8+ T cells is a key goal in developing more effective vaccines and immunotherapeutic strategies," said Tan. "In addition, although many shared properties exist between infection and cancer, future studies identifying distinct regulatory wiring in cancer-infiltrating T cells are essential for the continued progress of cancer immunotherapy." The researchers created a website to hold datasets resulting from this study, including a "roadmap" of methods for extracting useful clues for further study by other researchers. "We expect this resource will suggest novel targets for researchers in immunology and oncology," said Tan. He added that the immediate next step is to perform experimental testing and refining of the circuit models from this study. Primary support for this study came from the National Institutes of Health (grant AI115149), with additional support from 10 other NIH grants to various co-authors. The co-first authors are Bing He, PhD, from CHOP, and Shaojun Xing, PhD, from the University of Iowa. Bing He et al, "CD8+M/sup> T Cells Utilize Highly Dynamic Enhancer Repertoires and Regulatory Circuitry in Response to Infections," Immunity, published online Dec. 13, 2016, in print Dec.20. http://doi. About The Children's Hospital of Philadelphia: The Children's Hospital of Philadelphia was founded in 1855 as the nation's first pediatric hospital. Through its long-standing commitment to providing exceptional patient care, training new generations of pediatric healthcare professionals, and pioneering major research initiatives, Children's Hospital has fostered many discoveries that have benefited children worldwide. Its pediatric research program is among the largest in the country. In addition, its unique family-centered care and public service programs have brought the 535-bed hospital recognition as a leading advocate for children and adolescents. For more information, visit http://www.


Dews M.,Center for Childhood Cancer Research | Tan G.S.,Center for Childhood Cancer Research | Hultine S.,Center for Childhood Cancer Research | Raman P.,Children's Hospital of Philadelphia | And 7 more authors.
Journal of the National Cancer Institute | Year: 2014

Background The c-Myc oncoprotein is activated in the majority of colorectal cancers (CRCs), whereas the TGF-β pathway is frequently affected by loss-of-function mutations, for example in SMAD2/3/4 genes. The canonical model places Myc downstream of inhibitory TGF-β signaling. However, we previously demonstrated that Myc also inhibits TGF-β signaling through the miR-17∼92 microRNA cluster, raising the question about functional relationships between these two pathways. Methods We engineered a series of genetically complex murine and human CRC cell lines in which Myc and TGF-β activities could be manipulated simultaneously. This was achieved through retroviral expression of the Myc-estrogen receptor fusion protein and through Smad4 short hairpin RNA knockdown. Cell lines thus modified were injected subcutaneously in immunocompromised mice, and the resultant tumors (n = 5-10 per treatment group) were analyzed for overall growth and neovascularization. Additionally, the distribution of MYC and TGF-β pathway mutations was analyzed in previously profiled human CRC samples. Results In kras-mutated/trp53-deleted murine colonocytes, either Myc activation or TGF-β inactivation increased tumor sizes and microvascular densities approximately 1.5-to 2.5-fold, chiefly through downregulation of thrombospondin-1 and related type I repeat-containing proteins. Combining Myc activation with TGF-β inactivation did not further accelerate tumorigenesis. This redundancy and the negative effect of TGF-β signaling on angiogenesis were also demonstrated using xenografts of human CRC cell lines. Furthermore, the analysis of the Cancer Genome Atlas data revealed that in CRC without microsatellite instability, overexpression of Myc and inactivation of Smads (including acquired mutations in SMAD2) are mutually exclusive, with odds ratio less than 0.1. Conclusions In human CRC, gain-of-function alterations in Myc and loss-of-function alterations in TGF-β exhibit a masking epistatic interaction and are functionally redundant. © The Author 2014. Published by Oxford University Press. All rights reserved.


Fox J.L.,Center for Childhood Cancer Research | Fox J.L.,University of Pennsylvania | Dews M.,Center for Childhood Cancer Research | Minn A.J.,University of Pennsylvania | And 2 more authors.
RNA | Year: 2013

The miR-17~92 cluster is thought to be an oncogene, yet its expression is low in glioblastoma multiforme (GBM) cell lines. This could allow unfettered expression of miR-17~92 target genes such as connective tissue growth factor (CTGF; or CCN2), which is known to contribute to GBM pathogenesis. Indeed, microRNA-18a (but not other miR-17~92 members) has a functional site in the CTGF 3' UTR, and its forced reexpression sharply reduces CTGF protein and mRNA levels. Interestingly, it also reduces the levels of CTGF primary transcript. The unexpected effects of miR-18a on CTGF transcription are mediated in part by direct targeting of Smad3 and ensuing weakening of TGFβ signaling. Having defined the TGFβ signature in GBM cells, we demonstrate a significant anti-correlation between miR-18 and TGFβ signaling in primary GBM samples from The Cancer Genome Atlas. Most importantly, high levels of miR-18 combined with low levels of the TGFβ metagene correlate with prolonged patient survival. Thus, low expression of the miR-17~92 cluster, and specifically miR-18a, could significantly contribute to GBM pathogenesis. Copyright © 2013 RNA Society.

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