Publications by Adaptive Scientists

Digital Genomic Quantification of Tumor-Infiltrating Lymphocytes. Science Translational Medicine December 2013. Harlan S Robins, Nolan G Ericson, Jamie Guenthoer, Kathy C O’Briant, Muneesh Tewari, Charles W Drescher, Jason H Beilas

Infiltrating T lymphocytes are frequently found in malignant tumors and are suggestive of a host cancer immune response. Multiple independent studies have documented that the presence and quantity of tumor-infiltrating lymphocytes (TILs) are strongly correlated with increased survival. However, because of methodological factors, the exact effect of TILs on prognosis has remained enigmatic, and inclusion of TILs in standard prognostic panels has been limited. For example, some reports enumerate all CD3+ cells, some count only cytotoxic CD8+ T cells, and the criteria used to score tumors as TIL-positive or TIL-negative are inconsistent among studies. To address this limitation, we introduce a robust digital DNA-based assay, termed QuanTILfy, to count TILs and assess T cell clonality in tissue samples, including tumors. We demonstrate the clonal specificity of this approach by the diagnosis of T cell acute lymphoblastic leukemia and the accurate, sensitive, and highly reproducible measurement of TILs in primary and metastatic ovarian cancer. Our experiments demonstrate an association between higher TIL counts and improved survival among women with ovarian cancer, and are consistent with previous observations that the immune response against ovarian cancer is a meaningful and independent prognostic factor. Surprisingly, the TIL repertoire is diverse for all tumors in the study with no notable oligoclonal expansions. Furthermore, because variability in the measurement and characterization of TILs has limited their clinical utility as biomarkers, these results highlight the significant translational potential of a robust, standardizable DNA-based assay to assess TILs in a variety of cancer types.

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Using synthetic templates to design an unbiased multiplex PCR assay. Nature Communications October 2013. Christopher S Carlson, Ryan O Emerson, Anna M Sherwood, Cindy Desmarais, Moon-Wook Chung, Joseph M Parsons, Michelle S Steen, Marissa A LaMadrid-Herrmannsfeldt, David W Williamson, Robert J Livingston, David Wu, Brent L Wood, Mark J Rieder & Harlan Robins

T and B cell receptor loci undergo combinatorial rearrangement, generating a diverse immune receptor repertoire, which is vital for recognition of potential antigens. Here we use a mul- tiplex PCR with a mixture of primers targeting the rearranged variable and joining segments to capture receptor diversity. Differential hybridization kinetics can introduce significant amplification biases that alter the composition of sequence libraries prepared by multiplex PCR. Using a synthetic immune receptor repertoire, we identify and minimize such biases and computationally remove residual bias after sequencing. We apply this method to a multiplex T cell receptor gamma sequencing assay. To demonstrate accuracy in a biological setting, we apply the method to monitor minimal residual disease in acute lymphoblastic leukaemia patients. A similar methodology can be extended to any adaptive immune locus.

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Immunosequencing: applications of immune repertoire deep sequencing. Current Opinion in Immunology October 2013. Harlan Robins

Advances in high-throughput sequencing have enabled the development of a powerful new technology for probing the adaptive immune system. Millions of B or T cell receptor sequences can be read in parallel from a single sample. The dynamics of an adaptive immune response, which is based on clonal expansion and contraction, can be monitored in real time at high sensitivity and the global properties of the adaptive immune repertoires can be studied. A large set of clinical applications for this technology are presently under study, with a few diagnostic applications for hematological malignancies already available. A review of this new field termed immunosequencing is presented.

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Tumor-infiltrating lymphocytes in colorectal tumors display a diversity of T cell receptor sequences that differ from the T cells in adjacent mucosal tissue. Cancer Immunology, Immunotherapy June 2013. Anna M. Sherwood, Ryan O. Emerson, Dominique Scherer, Nina Habermann, Katharina Buck, Jürgen Staffa, Cindy Desmarais, Niels Halama, Dirk Jaeger, Peter Schirmacher, Esther Herpel, Matthias Kloor, Alexis Ulrich, Martin Schneider, Cornelia M. Ulrich, Harlan Robins

Tumors from colorectal cancer (CRC) are generally immunogenic and commonly infiltrated with T lymphocytes. However, the details of the adaptive immune reaction to these tumors are poorly understood. We have accrued both colon tumor samples and adjacent healthy mucosal samples from 15 CRC patients to study lymphocytes infiltrating these tissues. We apply a method for detailed sequencing of T-cell receptor (TCR) sequences from tumor-infiltrating lymphocytes (TILs) in CRC tumors at high throughput to probe T-cell clones in comparison with the TCRs from adjacent healthy mucosal tissue. In parallel, we captured TIL counts using standard immunohistochemistry. The variation in diversity of the TIL repertoire was far wider than the variation of T-cell clones in the healthy mucosa, and the oligoclonality was higher on average in the tumors. However, the diversity of the T-cell repertoire in both CRC tumors and healthy mucosa was on average 100-fold lower than in peripheral blood. Using the TCR sequences to identify and track clones between mucosal and tumor samples, we determined that the immune response in the tumor is different than in the adjacent mucosal tissue, and the number of shared clones is not dependent on distance between the samples. Together, these data imply that CRC tumors induce a specific adaptive immune response, but that this response differs widely in strength and breadth between patients.

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Estimating the ratio of CD4 + to CD8 + T cells using high-throughput sequence data. Journal of Immunological Methods 18 February 2013. Ryan Emerson, Anna Sherwood, Cindy Desmarais, Sachin Malhotra, Deborah Phippard, Harlan Robins

Mature T cells express either CD8 or CD4, defining two physiologically distinct populations of T cells. CD8+ T cells, or Killer T-cells, and CD4+ T cells, or Helper T cells, effect different aspects of T cell mediated adaptive immunity. Currently, determining the ratio of CD4+ to CD8+ T cells requires flow cytometry or immunohistochemistry. The genomic T cell receptor locus is rearranged during T cell maturation, generating a highly variable T cell receptor locus in each mature T cell. As part of thymic maturation, T cells that will become CD4+ versus CD8+ are subjected to different selective pressures. In this study, we apply high-throughput next-generation sequencing to T cells from both a healthy cohort and a cohort with an autoimmune disease (multiple sclerosis) to identify sequence features in the variable CDR3 region of the rearranged T cell receptor gene that distinguish CD4+ from CD8+ T cells. We identify sequence features that differ between CD4+ and CD8+ T cells, including Variable gene usage and CDR3 region length. We implement a likelihood model to estimate relative proportions of CD4+ and CD8+ T cells using these features. Our model accurately estimates the proportion of CD4+ and CD8+ T cell sequences in samples from healthy and diseased immune systems, and simulations indicate that it can be applied to as few as 1000 T cell receptor sequences; we validate this model using in vitro mixtures of T cell sequences, and by comparing the results of our method to flow cytometry using peripheral blood samples. We believe our computational method for determining the CD4:CD8 ratio in T cell samples from sequence data will provide additional useful information for any samples on which high-throughput TCR sequencing is performed, potentially including some solid tumors.

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Palindromic Nucleotide Analysis in Human T Cell Receptor Rearrangements. PLOS One December 2012. Santosh K Srivastava, Harlan S Robins

Diversity of T cell receptor (TCR) genes is primarily generated by nucleotide insertions upon rearrangement from their germ line-encoded V, D and J segments. Nucleotide insertions at V-D and D-J junctions are random, but some small subsets of these insertions are exceptional, in that one to three base pairs inversely repeat the sequence of the germline DNA. These short complementary palindromic sequences are called P nucleotides. We apply the ImmunoSeq deep-sequencing assay to the third complementarity determining region (CDR3) of the b chain of T cell receptors, and use the resulting data to study P nucleotides in the repertoire of na ̈ıve and memory CD8+ and CD4+ T cells. We estimate P nucleotide distributions in a cross section of healthy adults and different T cell subtypes. We show that P nucleotide frequency in all T cell subtypes ranges from 1% to 2%, and that the distribution is highly biased with respect to the coding end of the gene segment. Classification of observed palindromic sequences into P nucleotides using a maximum conditional probability model shows that single base P nucleotides are very rare in VDJ recombination; P nucleotides are primarily two bases long. To explore the role of P nucleotides in thymic selection, we compare P nucleotides in productive and non-productive sequences of CD8+ na ̈ıve T cells. The na ̈ıve CD8+ T cell clones with P nucleotides are more highly expanded.

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Shaping of Human Germline IgH Repertoires Revealed by Deep Sequencing. The Journal of Immunology 14 August 2012. Kevin Larimore, Michael W. McCormick, Harlan S. Robins and Philip D. Greenberg

To understand better how selection processes balance the benefits of Ig repertoire diversity with the risks of autoreactivity and nonfunctionality of highly variable IgH CDR3s, we collected millions of rearranged germline IgH CDR3 sequences by deep sequencing of DNA from mature human naive B cells purified from four individuals and analyzed the data with computational methods. Long HCDR3 regions, often components of HIV-neutralizing Abs, appear to derive not only from incorporation of long D genes and insertion of large N regions but also by usage of multiple D gene segments in tandem. However, comparison of productive and out-of-frame IgH rearrangements revealed a selection bias against long HCDR3 loops, suggesting these may be disproportionately either poorly functional or autoreactive. Our data suggest that developmental selection removes HCDR3 loops containing patches of hydrophobicity, which are commonly found in some auto-antibodies, and at least 69% of the initial productive IgH rearrangements are removed from the repertoire during B cell development. Additionally, we have demonstrated the potential utility of this new technology for vaccine development with the identification in all four individuals of related candidate germline IgH precursors of the HIV-neutralizing Ab 4E10.

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High-Throughput Sequencing Detects Minimal Residual Disease in Acute T Lymphoblastic Leukemia. Science Translational Medicine 16 May 2012. David Wu, Anna Sherwood, Jonathan R. Fromm, Stuart S. Winter, Kimberly P. Dunsmore, Mignon L. Loh, Harvey A. Greisman, Daniel E. Sabath, Brent L. Wood and Harlan Robins

High-throughput sequencing (HTS) of lymphoid receptor genes is an emerging technology that can comprehensively assess the diversity of the immune system. Here, we applied HTS to the diagnosis of T-lineage acute lymphoblastic leukemia/lymphoma. Using 43 paired patient samples, we then assessed minimal residual disease (MRD) at day 29 after treatment. The variable regions of TCRB and TCRG were sequenced using an Illumina HiSeq platform after performance of multiplexed polymerase chain reaction, which targeted all potential V-J rearrangement combinations. Pretreatment samples were used to define clonal T cell receptor (TCR) complementarity-determining region 3 (CDR3) sequences, and paired posttreatment samples were evaluated for MRD. Abnormal T lymphoblast identification by multiparametric flow cytometry was concurrently performed for comparison. We found that TCRB and TCRG HTS not only identified clonality at diagnosis in most cases (31 of 43 for TCRB and 27 of 43 for TCRG) but also detected subsequent MRD. As expected, HTS of TCRB and TCRG identified MRD that was not detected by flow cytometry in a subset of cases (25 of 35 HTS compared with 13 of 35, respectively), which highlights the potential of this technology to define lower detection thresholds for MRD that could affect clinical treatment decisions. Thus, next-generation sequencing of lymphoid receptor gene repertoire may improve clinical diagnosis and subsequent MRD monitoring of lymphoproliferative disorders.

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Ultra-Sensitive Detection of Rare T Cell Clones. Journal of Immunological Methods 31 Jan 2012. HS Robins, C Desmarais, J Matthis, R Livingston, J Andriesen, H Reijonen, CS Carlson, G Nepom, C Yee, K Cerosaletti

To test the precision, accuracy, and sensitivity of our immune profiling assay, T cell clones, with one fixed TCR rearrangement are doped into complex blood cell samples, with the doped T cell clones ranging from 10% of the total sample to 0.001% (one cell in 100,000). Results show precision across five orders of magnitude, and accuracy within an overall factor of three across the 100,000 fold dynamic range. Additionally, the assay is shown to be highly repeatable.

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Deep Sequencing of the Human TCRγ and TCRβ Repertoires Suggests that TCRβ Rearranges After αβ and γδ T Cell Commitment. Sci Transl Med. 6 July 2011. Sherwood AM, Desmarais C, Livingston RJ, Andriesen J, Haussler M, Carlson CS, Robins HS

Our data suggest that TCRγ rearranges in all T cells before T lineage commitment, however, rearrangement of the TCRβ locus appears to be restricted after T cell precursors commit to the αβ T lineage. In T cell leukemias and lymphomas, TCRγ is almost always rearranged, and TCRβ is only rearranged in a subset, suggesting the target for monitoring minimal residual disease should be TCRγ.

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Detecting and monitoring lymphoma with high-throughput sequencing. Oncotarget April 2011. Harlan S Robins

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Overlap and Effective Size of the Human CD8+ T Cell Receptor Repertoire. Sci Transl Med. 1 Sept 2010. Robins HS, Srivastava SK, Campregher PV, Turtle CJ, Andriesen J, Riddell SR, Carlson CS, Warren EH

We sequenced the CDR3 regions from millions of TCRβ chain genes in naïve and memory CD8+ T cells of 7 adults. The CDR3 repertoire in each individual is strongly biased toward specific Vβ-Jβ pair utilization, dominated by sequences containing few inserted nucleotides, and drawn from a defined subset comprising less than 0.1% of the estimated 5 × 1011 possible sequences. The overlap in the naïve CD8+ CDR3 sequence repertoires of any 2 of the individuals is ~7000-fold larger than predicted and appears to be independent of the degree of HLA matching.

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Comprehensive assessment of T-cell receptor β-chain diversity in αβ T cells. Blood 5 Nov 2009. Robins HS, Campregher PV, Srivastava SK, Wacher A, Turtle CJ, Kahsai O, Riddell SR, Warren EH, Carlson CS.

We determine the CDR3 sequence in millions of rearranged TCRβ genes of 2 adults. We find that total TCRβ receptor diversity is at least 4-fold higher than previous estimates, and the diversity in the subset of CD45RO(+) antigen-experienced αβ T cells is at least 10-fold higher than previous estimates. These methods should prove valuable for assessment of αβ T-cell repertoire diversity after hematopoietic cell transplantation, in congenital or acquired immunodeficiency, and during normal aging.

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Publications by Adaptive Customers

Cornell University Library 2014.
Quantifying selection in immune receptor repertoires.
Elhanati Y1, Murugan A2, Callan CG3, Mora T4, Walczak AM1
Labaratoire de physique theorique UMR8549, NCRS and Ecole normale superieure, Paris, France1; Department of Applied Physics, Stanford University, Stanford, CA2; Joseph Henry Laboratories, Princeton University, Princeton NJ3; Labaratoire de physique statistique, UMR8550, NCRS and Ecole normale superieure, Paris, France4
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Clinical Cancer Research 2014.
CTLA4 blockade broadens the peripheral T cell receptor repertoire.
Robert L1, Tsoi J2, Wang X3, Emerson RO4, Homet B1, Chodon T5, Mok S6, Huang R-R7, Cochran AJ8, Comin-Anduix B9, Koya RC10, Graeber T11, Robins HS12, Ribas A1
Medicine, UCLA, Los Angeles, CA1; Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, CA2; School of Public Health at the University of California, Department of Biostatistics, Los Angeles, CA3; Bioinformatics, Adaptive Biotechnologies, Seattle, WA4; Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY5; Department of Molecular and Medical Pharmacology, UCLA Medical Center, Los Angeles, CA6; Department of Pathology and Laboratory Medicine, UCLA, Los Angeles, CA7; Path & Lab Med-Anatomic Path, UCLA, Los Angeles, CA8; Surgery, Division of Surgical Oncology, University of California Los Angeles, Los Angeles, CA9; Surgery, UCLA, Los Angeles, CA10; Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA11; Computational Biology Program, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA12
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American Journal of Transplantation 2014.
Novel GMP-Compatible Protocol Employing an Allogeneic B Cell Bank for Clonal Expansion of Allospecific Natural Regulatory T Cells.
Landwehr-Kenzel S1,2,3, Issa F4, Luu S-H1,2,5, Schmuck M1,6, Lei H1,2,6, Zobel A1, Thiel A1, Babel N1,5, Wood K4, Volk H-D1,6, Reinke P1,5
Berlin-Brandenburg Center for Regenerative Therapies, Charite University Medicine Berlin, Berlin, Germany1; Berlin-Brandenburg School for Regenerative Therapies, Charite University Medicine Berlin, Berlin, Germany2; Department of Pediatric Pulmonology and Immunology, Charite University Medicine Berlin, Berlin, Germany3; Transplantation Research Immunology Group, Nuffield Department of Surgical Sciences, John Radcliffe Hospital, Oxford, UK4; Renal and Transplant Research Unit, Department of Nephrology and Internal Intensive Care, Charite University Medicine Berlin, Berlin, Germany5; Institute of Medical Immunology, Charite University Medicine Berlin, Berlin, Germany6
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Journal of Clinical Investigation 2014.
T cell repertoire following autologous stem cell transplantation for multiple sclerosis.
Muraro PA1, Robins H2, Malhotra S3, Howell M3, Phippard D3, Desmarais C4, de Paula Alves Sousa A1, Griffith LM5, Lim N3, Nash RA6, Turka LA3,7
Division of Brain Sciences, Department of Medicine, Imperial College London, London, UK1; Fred Hutchinson Cancer Research Center, Seattle, WA2; Immune Tolerance Network, Bethesda, MD3; Adaptive Biotechnologies, Seattle, WA4; Division of Allergy, Immunology, and Transplantation, National Institute of Allergy and Infectious Diseases, Bethesda, MD5; Colorado Blood Cancer Institute at PSL, Denver, CO6; Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA7
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Science Translational Medicine 2014.
Intramuscular Therapeutic Vaccination Targeting HPV16 Induces T Cell Responses That Localize in Mucosal Lesions.
Maldonado L1, Teague JE2, Morrow MP3, Jotova I4, Wu TC5, Wang C6, Desmarais C7, Boyer JD8, Tycko B4, Robins HS9, Clark RA4, Trimble CL1,5,10
Department of Gynecology and Obstetrics, Johns Hopkins Medical Institutions, Baltimore, MD1; Harvard Skin Disease Research Center and the Department of Dermatology, Brigham and Women’s Hospital, Boston, MA2; Inovio Pharmaceuticals Inc, Blue Bell, PA3; Department of Pathology and cell Biology and Institute for Cancer Genetics, Columbia University Medical Center, New York, NY4; Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD5; Oncology Biostatistics, Johns Hopkins Medical Institutions, Baltimore, MD6; Adaptive Biotechnologies, Seattle, WA7; Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA8; Program in Computational Biology, Fred Hutchinson Cancer Research Center, Seattle, WA9; Department of Oncology, Johns Hopkins Medical Institutions, Baltimore, MD10
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eLIFE 2014.
T cell immunodominance is dictated by the positively selecting self-peptide.
Lo WL1, Solomon BD1, Donermeyer DL1, Hsieh CS2, Allen PM1
Department of Immunology and Pathology, Washington University School of Medicine, St. Louis, MO1; Department of Internal Medicine, Division of Rheumatology, Washington University School of Medicine, St. Louis, MO2
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Science Translational Medicine 2013.
Minimal Residual Disease Monitoring with High-Throughput Sequencing of T Cel Receptors in Cutaneous T Cell Lymphoma.
Weng W1, Armstrong R1, Arai S1, Desmarais C2, Hoppe R3, Kim YH4
Division of Blood and Marrow Transplantation, Department of Medicine, Stanford University School of Medicine, Stanford CA1; Adaptive Biotechnologies, Seattle WA2; Department of Radiation Oncology, Stanford University School of Medicine, Stanford CA3; Department of Dermatology, Stanford University School of Medicine, Stanford CA4
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Science Translational Medicine 2013.
Tumor-Associated Immune Parameters for Personalized Patient Care.
Pages F1
Laboratory of Immunology, Immunomonitoring Platform, Georges Pompidou European Hospital, AP-HP, Paris Descartes University, Laboratory of Integrative Cancer Immunology, INSERM, Cordeliers Research Center, Paris France1
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PNAS 2013.
Human autoimmunity after lymphocyte depletion is caused by homeostatic T-cell proliferation.
Jones JL1, Thompson SAJ1, Loh P2, Davies JL1, Tuohy OC1, Curry AJ1, Azzopardi L1, Hill-Cawthorne G1,3, Fahey MT2,4, Compston A1, Coles AJ1
Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK1; Division of Mathematics, Informatics and Statistics, Commonwealth Scientific and Industrial Research Organization, Clayton South, Australia2; Sydney Institute for Emerging Infections and Biosecurity, University of Sydney, Sydney, Australia3; Biostatistics Unit, Monash University, Melbourne, Australia4
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Blood 2013.
Deep sequencing of the T cell receptor repertoire in CD8+ T-large granular lymphocyte leukemia identifies signature landscapes.
Clemente MJ1, Przychodzen B1, Jerez A1, Dienes BE1, Afable MG1, Husseinzadeh H1, Rajala HLM3, Wlodarski MW2, Mustjoki3, Maciejewski JP1
Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH1; University of Freiburg, Department of Pediatrics and Adolescent Medicine, Germany2; Hematology Research Unit, Department of Medicine, University of Helsinki and Helsinki University Central Hospital, Finland3
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Journal of Clinical Investigation 2013.
Human Treg responses allow sustained recombinant adeno-associated virus-mediated transgene expression.
Mueller C1, Chulay JD2, Trapnell BC3, Humphries M1, Carey B3, Sandhaus RA4, McElvaney NG5, Messina L1, Tang Q1, Rouhani FN6, Campbell-Thompson M6, Fu AD6, Yachnis A6, Knop DR8, Ye G2, Brantly M6, Calcedo R7, Somanathan S7, Richman LP8, Vonderheide RH8, Hulme MA6, Brusko TM6, Wilson JM7, Flotte TR1,8
University of Massachusetts Medical School, Worchester, MA1; Applied Genetic Technologies Corp, Alachua FL2; Cincinnati Children’s Hospital, Cincinnati, OH3; National Jewish Health, Denver, CO4; Beaumont Hospital, Dublin, Ireland5; University of Florida College of Medicine, Gainesville, FL6; Gene Therapy Program7; Abramson Family Cancer Research Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA8
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Breast Cancer Res Treat 2013.
Peripheral blood mononuclear cells of patients with breast cancer can be reprogrammed to enhance anti-HER-2/neu reactivity and overcome myeloid-derived suppressor cells.
Payne KK1, Zoon CK2, Wan W3, Marlar K4, Keim RC1, Kenari MN5, Kazim AL4, Bear HD2, Manjili MH1
Department of Microbiology & Immunology, Virginia Commonwealth University, Massey Cancer Center, Richmond, VA1; Division of Surgical Oncology, Department of Surgery, Virginia Commonwealth University, Massey Cancer Center, Richmond, VA2; Department of Biostatistics, Virginia Commonwealth University, Massey Cancer Center, Richmond, VA3; Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY4; Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, NY5
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Journal of Immunology 2013.
A Novel Approach to Tracking Antigen-Experienced CD4 T Cells into Functional Compartments via Tandem Deep and Shallow TCR Clonotyping.
Estorninho M1, Gibson VB1, Kronenberg-Versteeg D1, Liu YF1, Ni C2, Cerolasetti K2, Peakman M1
Department of Immunology, Kings College London, London, UK1; Translational Research Program, Benaroya Research Institute at Virginia Mason, Seattle WA2
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PLOS One 2013.
High-Throughput Sequencing of Islet-Infiltrating Memory CD4+ T Cells Reveals a Similar Pattern of TCRB VB Usage in Prediabetic and Diabetic NOD Mice.
Marrero I1, Hamm D2, Davies JD1
Torrey Pines Institute for Molecular Studies, San Diego CA1; Adaptive Biotechnologies, Seattle WA2
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New England Journal of Medicine 2013.
Chimeric Antigen Receptor-Modified T Cells for Acute Lymphoid Leukemia.
Grupp SA1,2,3, Kalos M3,4, Barrett D1,2, Aplenc R1,2,3, Porter DL3,5, Rheingold SR1,2,3, Teachey DT1,2,3, Chew A4, Hauck B1,4, Wright JF1,4, Milone MC 3,4, Levine BL3,4, June CH 3,4
The Children’s Hospital of Philadelphia1; Department of Pediatrics2, Abramson Cancer Center3, Philadelphia, PA; The Departments of Pathology and Laboratory Medicine4 and Medicine5, University of Pennsylvania, Philadelphia, PA6
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Nature 2013.
Immune surveillance by CD8AA+ skin-resident T cells in human herpes virus infection.
Zhu J1,2, Peng T2,3, Johnston C3, Phasouk K2, Kask AS1, Klock A1, Jin L1, Diem K1, Koelle DM1,2,3,4,5, Wald A1,2,3,6, Robins H7, Corey L1,2,3,4
Department of Laboratory Medicine, University of Washington, Seattle, WA1; Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA2; Department of Medicine, University of Washington, Seattle, WA3; Department of Pathobiology, University of Washington, Seattle, WA4; Benaroya Research Institute, Seattle, WA5; Department of Epidemiology, University of Washington, Seattle, WA6; Program in Computational Biology, Fred Hutchinson Cancer Research Center, Seattle, WA7
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Journal of Pathology 2013.
Ultra-deep T-cell receptor sequencing reveals the complexity and intratumour heterogeneity of T-cell clones in renal cell carcinomas.
Gerlinger M1, Quezada SA3, Peggs KS3, Furness AJS1, Fisher R4, Marafioti T5, Shende VH5, McGranahan N1,6, Rowan AJ1, Hazell S4, Hamm D7, Robins HS7, Pickering L4, Gore M4, Nicol DL4, Larkin J2, Swanton C1
Cancer Research UK, London Research Institute, London, UK1; Barts Cancer Institute, Barts and The London School of Medicine and Dentistry, London, UK2; UCL Cancer Institute, London, UK3; Royal Marsden Hospital, London, UK4; Departments of Pathology and Histopathology, University College Hospital, London, UK5; Centre for Mathematics & Physics in the Life Sciences & experimental Biology, University College London, London, UK6
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American Journal of Transplantation 2013.
Clinical Grade Manufacturing of Human Alloantigen-Reactive Regulatory T Cells for Use in Transplantation.
Putnam AL1, Safinia N1, Medvec A1, Laszkowska M1, Wray M1, Mintz MA2, Trotta E3, Szot GL3, Liu W2, Lares A1, Lee K3, Laing A3, Lechler RI2, Riley JL1, Bluestone JA3, Lombardi G2, Tang Q1
CSF Diabetes Center, University of California, San Francisco, San Francisco CA1; MRC Centre for Transplantation, King’s College London, London, UK2; Department of Microbiology, University of Pennsylvania, Philadelphia, PA3; Department of Surgery, University of California, San Francisco, San Francisco CA4
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Blood 2013.
Cytomegalovirus-specific T cells are primed early after cord blood transplant but fail to control virus in vivo.
McGoldrick SM1,2, Bleakley ME1,2, Guerrero A1, Turtle CJ1,2,Yamamoto TN1, Pereira SE1,2, Delaney CS1,2, Riddell SR1,3
Fred Hutchinson Cancer Research Center, Clinical Research Division, Seattle, WA1; University of Washington, School of Medicine, Seattle, WA2; Institute for Advanced Study, Technical University of Munich, Munich, Germany3
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Acta Neuropathol 2013.
Peripheral T-cell lymphoma emerging in a patient with aggressive polymyositis: molecular evidence for neoplastic transformation of an oligoclonal T-cell infiltrate.
Tsankova NM, Bevan C, Jobanputra V, Ko YCK, Mayer EW, Lefkowitch JH, Mansukhani M, Rowland LP, Bhagat G, Tanji K
Columbia University Medical Center and New York Presbyterian Hospital, New York, USA
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PNAS Plus 2013.
Unifying Model for Molecular Determinants of the Preselection VBeta Repertoire.
Gopalakrishnan S1, Majumder K1, Predeus A1, Huang Y1, Koues O1, Verma-Gaur J2, Loguercio S3, Su A3, Feeney A2, Artyomov M1, Oltz E1
Department of Pathology & Immunology, Washington University School of Medicine in St. Louis, St. Louis, MO1; Department of Immunology & Microbial Science, The Scripps Research Institute, La Jolla, CA2; Department of Molecular & Experimental Medicine, The Scripps Research Institute, La Jolla, CA3
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Plos One 2013.
ATM Influences the Efficiency of TCRB Rearrangement, Subsequent TCRB-Dependent T Cell Development, and Generation of the Pre-Selection TCRB CDR3 Repertoire.
Hathcock KS1, Bowen S1, Livak F2, Hodes RJ1
Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD1; Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD2
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J. Immunol. 2013.
The Restricted DH Gene Reading Frame Usage in the Expressed Human Antibody Repertoire Is Selected Based upon its Amino Acid Content.
Benichou J1, Glanville J2, Prak ET3, Azran R4, Kuo TC2, Pons J2, Desmarais C5, Tsaban L4, Louzoun Y4
Mina and Everard Goodman Faculty of Life Sciences, Bar Illan University, Ramat Fan, Israel1; Protein Engineering and Applied Quantitative Genotherapeutics, Rinat-Pfizer, South San Francisco, CA2; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA3; Department of Mathematics and Gonda Brain Research Center, Bar Illan University, Ramat Gan, Israel4; Adaptive Biotechnologies, Seattle, WA5
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J. Virol 2013.
High Frequency of Herpesvirus-Specific Clonotypes in the Human T cell Repertoire Can Remain Stable over Decades with Minimal Turnover.
Neller MA1, Burrows JM1, Rist MJ1,2, Miles JJ1,2,3, Burrows SR1,2
Australian Centre for Vaccine Development, Queensland Institute of Medical Research, Brisbane, Australia1; The University of Queensland, Brisbane, Australia2; Institute of Infection and Immunity, Cardiff University School of Medicine, Cardiff, UK 3
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Mol. Ther. 2013.
Allelic Exclusion and Peripheral Reconstitution by TCR Transgenic T cells Arising from Transduced Human Hematopoietic Stem/Progenitor Cells.
Giannoni F, Hardee CL, Wherley J, Gschweng E, Senadheera S, Kaufman ML, Chan R, Bahner I, Gersuk V, Wang X, Gjertson D, Baltimore D, Witte ON, Economou JS, Ribas A,Kohn DB
Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, California, USA
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Biol. Blood Marrow Transplant 2013.
Fractal Organization of the Human T Cell Repertoire in Health and After Stem Cell Transplantation.
Meier J, Roberts C, Avent K, Hazlett A, Berrie J, Payne K, Hamm D, Desmarais C, Sanders C, Hogan KT, Archer KJ, Manjili MH, Toor AA.
Bone Marrow Transplant Program, Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia
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Science Translational Medicine 2013.
CD19-Targeted T Cells Rapidly Induce Molecular Remissions in Adults with Chemotherapy-Refractory Acute Lymphoblastic Leukemia.
Brentjens R 1,2,3, Davila M1, Riviere I 1,2,3,4, Park J 1, Wang X 3,4, Cowell LG 5, Bartido S 4, Stefanski J 4, Taylor C 4, Olszewska M 4, Borquez-Ojeda O 4, Qu J 4, Wasielewska T 4, He Q 4, Bernal Y 1, Rijo IV 6, Hedvat C 6, Kobos R 7, Curran K 7, Steinherz P 7, Jurcic J1, Rosenblat T 1, Maslak P 1, Frattini M 1, Sadelain M 1,2,3
Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA 1; Center for Cell Engineering, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA2; Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA 3; Cell Therapy and Cell Engineering Facility, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA 4; Department of Clinical Sciences, UT Southwestern, Dallas, TX 75390, USA 5; Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA 6; Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA 7
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PNAS 2012.
Statistical Inference of the Generation Probability of T-cell Receptors from Sequence Repertoires.
Murugan A 1, Mora T2, Walczak AM3, Callan CG1,4
Joseph Henry Laboratories, Princeton University, Princeton, NJ 1; Laboratoire de Physique Statistique, UMR8550, Centre National de la Recherche Scientifique and Ecole Normale Superieure, Paris, France 2; Laboratoire de Physique Theorique, UMR8549, Centre National de la Recherche Scientifique and Ecole Normale Superieure, Paris, France 3; Simons Center for Systems Biology, Institue for Advanced Study, Princeton, NJ4

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Biol. Blood and Bone Marrow Transplant 2012.
Immune Recovery in Adult Patients Following Myeloablative Dual Umbilical Cord Blood, Matched Sibling, and Matched Unrelated Donor Hematopoietic Cell Transplantation.
Kanda J, Chiou LW, Szabolcs P, Sempowski GD, Rizzieri DA, Long GD, Sullivan KM, Gasparetto C, Chute JP, Morris A, McPherson J, Hale J, Livingston JA, Broadwater G, Niedzwiecki D, Chao NJ, Horwitz ME
Division of Cellular Therapy, Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA.
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JCI 2012.
Thymocyte responsiveness to endogenous glucocorticoids is required for immunological fitness.
Mittelstadt PR, Monteiro JP, Ashwell JD
Center for Cancer Research, NCI and NIAID, NIH, Bethesda, Maryland, USA
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Clinical Cancer Research 2012.
Adoptive Transfer of Autologous T Cells Improved T-Cell Repertoire Diversity and Long-term B-cell Function in Pediatric Patients with Neuroblastoma.
Grupp SA1, Prak EL4, Boyer J4,5, McDonald KR2, Shusterman S6, Thompson E4,5, Callahan C1, Jawad AF3, Levine BL4,5, June CH4,5, Sullivan KE 2
Division of Oncology1, Division of Allergy Immunology2, Department of Pediatrics3, The Children’s Hospital of Philadelphia; Department of Pathology & Laboratory Medicine4, Abramson Cancer Center5, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA; Pediatric Oncology, Dana Farber Cancer Institute, Boston MA6; Program in Computational Biology, Fred Hutchinson Cancer Research Center, Seattle, WA
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New England Journal of Medicine 2011.
Chimeric Antigen Receptor-Modified T Cells in Chronic Lymphoid Leukemia.
DL Porter1,2, BL Levine1,3,4, M Kalos1,3,4, A Bagg1,3, CH June1,3,4
Abramson Cancer Center1; Dthe Department of Medicine2; the Department of Pathology & Laboratory Medicine3; and the Abramson Family Cancer Research Institute4, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
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Science Translational Medicine 2011.
T Cells with Chimeric Antigen Receptors Have Potent Antitumor Effects and Can Establish Memory in Patients with Advanced Leukemia.
Kalos M1,2, Levine BL1,2, Porter DL1,3, Katz S4, Grupp SA5,6, Bagg A1,2, June CH1,2
Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA1; Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA2; Department of Medicine, University of Pennsylvania, Philadelphia, PA3; Department of Radiology, University of Pennsylvania, Philadelphia, PA4; Department of Pediatrics, University of Pennsylvania, Philadelphia, PA5; Division of Oncology, Children’s Hospital of Philadelphia, Philadelphia, PA6
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