Congratulations to the 2014 November recipients.
Adaptive has selected 2 winners for the Young Investigator Award. Each recipient will receive $5,000 to use for sequencing to assist in his/her research in immunology. The next group of winners will be chosen from applications due January 31. Click here to apply »
Iwona Konieczna, Northwestern University
Research Summary: Achievement of donor-specific immunologic tolerance is key to eliminating the need for chronic immuno-supression in transplant recipients. Recent advances in transplant tolerance research have indicated that the use of ex vivo expanded regulatory T cells (Tregs) may achieve this elusive goal. Their increased presence have been associated with immunologic tolerance to organ transplants and with improved outcome in allograft rejection. Under physiological conditions these Tregs, however, are of low abundance. Therefore, ex vivo expansion is required to harness their therapeutic potential. By T cell receptor repertoire screening we will be able to more reliably monitor changes in cellular make up during the Treg culture, to track cell plasticity and help identify inflammatory cell subsets that would otherwise be deleterious to organ transplants. Key to the success of this project is identification of a TCR repertoire as a Treg signature that defines effective Treg population.
Spyros Chalkias, Beth Israel Deaconess Medical Center
Research Summary: Public T cell responses to a specific epitope are the result of shared T cell receptor (TCR) sequences among multiple individuals. Public TCR were previously regarded as an unusual phenomenon, owing to the apparent low probability of the same TCR being observed in multiple individuals responding to the same epitope. We will use ImmunoSEQ in order to screen for human leukocyte antigen – restricted public TCR sequences in response to polyoma virus JC, which is the etiologic agent of progressive multifocal leukoencephalopathy. Our goal is to understand the significance of public TCR against viruses and translate our findings into clinically useful applications
2014 August recipients.
Reetta Vanhanen, Haartman Institute, University of Helsinki
Research Summary: The enormous diversity of our immune system is created in thymus by genetic rearrangement of TCR alpha and beta chains. We would like to perform a deep sequencing analysis of human thymic TCR beta repertoire. The aim is to estimate what is the number and diversity of TCR beta repertoire in human thymus.
Elisa Masat, University Pierre and Marie Curie, INSERM U974
Research Summary: Therapeutic efficacy following in vivo gene transfer has been demonstrated in several clinical trials. However, the scope of this approach in humans appears to be limited by T cell responses directed against the viral vector used as gene delivery vehicle. We plan to use to the Immunoseq technology to follow the TCR repertoire in humans undergoing gene transfer and track T cell clonality in different tissues at baseline and following vector administration.
2014 April recipients.
Yves T. Falanga, Ph.D., University of Massachusetts Medical School
Research Summary: Approximately 90-95% of adult individuals have latent Epstein-Barr virus (EBV) infection. In immune-sufficient patients, numerous factors contribute to the containment of EBV, such as the ability of EBV-specific CD8+ T cells to appropriately respond upon cognate antigen stimulation. Generally, infected individuals remain seropositive for EBV throughout their entire life. Although EBV reactivation from latency is not frequent and often causes no harm, it is associated with lymphoproliferative diseases like Burkitt’s lymphoma in rare cases. Recent studies demonstrate increased incidence in Burkitt’s lymphoma in EBV-infected patients residing in malaria-endemic areas, suggesting an association between malaria infection, EBV reactivation and the development of Burkitt’s lymphoma. Using the ImmunoSEQ technology platform, we aim to study the diversity of the T cell repertoire in single individuals over time using malaria infection as an ecological variable. This will allow us to assess not only patient-specific variations of the T cell repertoire over time but also inter-patient variations. Furthermore, we will study longitudinal variations of the T cell repertoire in Burkitt’s lymphoma patients before and after chemotherapy treatment.
Nicholas Gulati, The Rockefeller University
Research Summary: Diphencyprone (DPCP) is a hapten that causes delayed-type hypersensitivity reactions upon conjugation with endogenous proteins and is widely used to test immune status, yet the antigen(s) responsible are unknown. We plan to study the TCR repertoire of human skin samples at various time points following the inflammation induced by DPCP, with the hope of better understanding the clonality of these reactions as well as how long the T cells persist.
Kinjal Majumder, Washington University St. Louis
Research Summary: Generation of the pre-selection T cell repertoire is a multifactorial process, driven by genetic, epigenetic and structural components. It is essential to develop a deeper understanding of the mechanisms that sculpt V segment selection during VDJ recombination. We have developed mouse models which separate the phenomenon of long range interaction from the epigenetic landscape. Using Immunoseq, we plan to dissect how changes in chromosome looping alter the fine-tuning of the T cell receptor beta repertoire.
2014 February recipients.
Ioannis Politikos, M.D., Beth Israel Deaconess Medical Center
Research Summary: Patients undergoing umbilical cord blood transplantation (UCBT) have increased risk for reactivation of human herpesvirus 6 (HHV-6), which is the leading cause of central nervous system complications after UCBT. In order to understand the immunologic mechanisms responsible for HHV-6 reactivation, we will use the ImmunoSEQ technology to characterize and monitor the TCR repertoire in response to HHV6. First, we will use T cells from patients with high levels of HHV-6 viremia for in vitro stimulation with immunogenic HHV-6-specific peptides and we will identify TCR dominant clones by deep sequencing of the Vb TCR locus. Subsequently, we will perform deep sequencing analysis in the T cells of UCBT recipients with and without HHV-6 viremia, in order to investigate the existence and dominance of HHV6-specific clones in vivo. These studies will determine the quantitative and qualitative profile of the HHV-6-specific responses overtime. Furthermore, by correlation with clinical outcomes, our studies may enable the identification of UCBT recipients at high risk for uncontrolled reactivation of HHV-6, which represents the most serious cause of post-transplant encephalitis.
Wade Iams, M.D., Vanderbilt University Medical Center
Research Summary: Small cell lung cancer (SCLC) is an aggressive form of lung cancer with a poor prognosis. Since treatments and outcomes for patients with SCLC have not significantly changed over the past 30 years, there is an urgent need to define novel therapeutic strategies. Recently, immune checkpoint inhibitors have successfully been used to treat patients with SCLC. However, there are limited data supporting biomarkers of response to these agents. We hypothesize that characterization of the immune repertoire of T cells infiltrating tumors in patients with SCLC will provide insight into an underlying immunologic signature that predicts response to immune checkpoint inhibition.
Natalie Miller, University of Washington School of Medicine
Research Summary: Merkel cell carcinoma (MCC) is a highly aggressive neuroendocrine skin cancer caused by Merkel Cell Polyomavirus (MCPyV). Over half of MCC patients mount an adaptive immune response to the MCPyV T-Antigen, and patient survival is positively correlated with tumor infiltration by CD8+ T cells. We propose to tetramer sort HLA*A02:01-restricted T cells recognizing one commonly immunogenic MCPyV epitope from PBMC of MCC patients and use the immunoSEQ platform to determine the TCR alpha and beta repertoire of these CD8+ cells. We hope to detect any public TCRs among this cohort, as well as possible differences in repertoire among patients with different disease courses.
Daniel Lowther, Yale
Research Summary: Using TCRbeta sequencing to understand how the anti-tumor immune response infiltrating meningiomas impacts tumor progression and predicts malignancy.
2013 November recipients.
David B. Page, Ph.D., Memorial Sloan-Kettering Cancer Center
Research Summary: In locally advanced breast cancer, lymphocytic tumor infiltration correlates with long-term survival following neoadjuvant chemotherapy. We will utilize the platform to test the hypothesis that chemotherapy serves to ‘auto-vaccinate’ against tumor antigens, generating a clonal T-cell response that might be protective against recurrence.
Xiaoti Guo, Ph.D., North Shore-LIJ Health System
Research Summary: Natural antibodies bind and eliminate infectious microbes, but also can bind self components and help dispose of cellular debris, thereby avoid activation of the immune system and initiation of autoimmune disease, including lupus. We will study human anti-phosphorylcholine (PC) autoantibody that we propose works to prevent lupus, to learn what B lymphocytes produce this antibody, how the antibody binds PC, whether the antibody is different when it comes from healthy individuals vs patients with lupus, and whether the antibody protects animals predisposed to develop lupus. We will perform next-generation sequencing with the Immunoseq platform to examine the repertoire and structure of anti-PC antibodies. The deep sequencing data will tell us whether B1 cell-derived anti-PC Ab is distinct in terms of VDJ usage, CDRH3 properties, N-addition and VH mutation when compared with other B cell subsets; and whether B cells of autoimmune patients produce qualitatively and quantitatively distinct anti-PC Abs.
Krithika Kodumudi, Ph.D., H. Lee Moffitt Cancer Center
Research Summary: Adoptive transfer of tumor infiltrating lymphocytes (TIL) has emerged as a promising approach to induce effective anti-tumor immunity and tumor regression. Although T cells are able to infiltrate tumors, studies have shown that TIL are inactivated in vivo due to various suppressive factors in the local tumor microenvironment, including regulatory T cells, myeloid derived suppressor cells, and co-inhibitory receptors such as CTLA-4 and PD-1. We hypothesize that blockade of the PD-1/ PD-L1 pathway will lead to increased T cell diversity within tumors. Our aim is to characterize the immune repertoire of T cells (TCRbeta) infiltrating tumors. Using ImmunoSEQ technology, characterization of TIL will reveal the clonal composition of T cell populations and provide insight into the clonality and heterogeneity of the TIL in solid tumors after PD-L1 blockade.
Vinay S Mahajan, M.D., Ph.D., Center for Cancer Research, Massachusetts General Hospital
Research Summary: IgG4-related disease is a chronic immune-mediated condition characterized by extensive tissue fibrosis and is treatable by rituximab with an excellent clinical response in nearly all patients. However, the disease relapses after 6-12 months in a subset of individuals and we have found that relapse is heralded by the reemergence of specific disease-associated T and B cell populations. We intend to use the ImmunoSeq platform for quantitative repertoire analysis of these lymphocyte subsets to assess the mechanism of post-rituximab disease relapse in these patients.
Catherine Meador, Vanderbilt University
Research Summary: Lung cancer is the leading cause of cancer-related death worldwide. To gain insights into how the immune system plays a role in lung tumorigenesis, we propose to use immunoSEQ technology to study the T cell repertoire in human lung cancer specimens.
2013 July recipients.
Matthew Rausch, Ph.D., University of Arizona College of Medicine Phoenix
Research Summary: The processing and presentation of peptide antigens by professional antigen presenting cells is a critical first step in the initiation of T cell-mediated immune responses. Studies in mice have revealed that altering the cellular antigen processing machinery of antigen presenting cells can significantly change the self peptide repertoire presented under steady state conditions. However, the impact of this altered antigen presentation on the T cell repertoire has not been investigated. I will use the immunoSEQ technology to analyze how altering the antigen processing machinery of mouse antigen presenting cells impacts the T cell repertoire. The results of this project are anticipated to provide us with new insights into how antigen processing and presentation affects T cell responses with implications for the treatment of autoimmunity and cancer.
Lauren Henderson, Ph.D., Boston Children’s Hospital
Research Summary: Juvenile Idiopathic Arthritis (JIA) is the most common rheumatologic disorder affecting children yet the cause of this disease is unknown. Past studies have demonstrated the importance of T lymphocytes in JIA. By characterizing the T cell repertoire in the synovial fluid and peripheral blood of patients with JIA, I hope to further elucidate the pathogenesis of this disease.
2013 May Recipients
David Bernal, Ph.D., Universidad Nacional de Colombia
Research Summary: In our laboratory we are working on the immunogenicity of tumors in breast cancer patients. With immunoSEQ we will sequence CD8 specific tumor antigen TCR from those patients and total CD8 TCR before and after chemotherapy to evaluate if the repertoire frequency of specific T cells is altered by cancer treatment and correlate these results with their clinical response.
Kirstin Heutinck, Ph.D., Academic Medical Center Amsterdam
Research Summary: In kidney transplant recipients, the presence of virus-specific T cells with cross-reactivity to allogeneic-HLA molecules of donor origin, may negatively influence transplant outcome. To characterize cross-reactive T cell responses in transplant recipeints, I will the immunoSEQ technology to analyse the clonality of the response and to follow cross-reactive T cell clones in time.
Jamie Lynn Harden, Ph.D., The Rockefeller University
Research Summary: Psoriasis is a chronic, debilitating inflammatory skin disease characterized by red, scaly plaques. Although the role of T cells in this disease has been well established, the antigen specificity of the pathogenic T-cells in psoriasis is largely unknown. Additionally, gamma-delta T-cells have been gaining interest as a cellular contributor to psoriasis. In this pilot study, both the gamma and the beta human T-cell immunoSEQ platforms will be utilized to compare the Tcell repertoire in normal and psoriatic skin. A more detailed understanding of the Tcell populations in psoriasis is a critical next step to elucidating the etiology of this disease, as well as possible new therapeutic targets.
2013 February Recipients
Alan Watson, Ph.D., University of Pittsburgh
Research Summary: T cell responses elicited by the live-attenuated Yellow Fever Virus (YFV) Vaccine play a role in protecting the host against infection with wild-type (wt)YFV in our mouse model; however, non-vaccinated mice succumb to disease following wtYFV infection despite eliciting surprisingly high numbers of polyfunctional T cells. I will use the immunoSEQ system to compare the clonotypic diversity of T cells elicited following vaccination or infection with wtYFV and ask whether differences in T cell repertoire may explain immune control of the YFV vaccine and immune evasion by wtYFV.
Sven Malchow, Ph.D., University of Chicago, Dept. of Pathology
Research Summary: In a recent study, we demonstrated that the thymic development of some naturally occurring Foxp3+ regulatory T cells (Tregs) is dependent on the transcriptional regulator Aire (autoimmune-regulator). Aire expression in the thymus drives the ectopic expression of peripheral tissue self antigens, and Aire-deficiency in mice and humans results in multi-organ autoimmunity. The relative contribution of Aire-dependent Tregs to the peripheral Treg pool is unknown. I will use the immunoSEQ technology to elucidate the prevalence of Aire-dependent Tregs within the peripheral repertoire by determining the extent of TCR β chain repertoire overlap between CD4+Foxp3neg and CD4+Foxp3+ T cell populations derived from wild-type and Aire-deficient mice. The results of this study are anticipated to provide new insights into the antigen specificities and development of Tregs, with implications for the treatment of autoimmunity and cancer.
Marta Pasikowska, King’s College London
Research Summary: We would like to perform analysis of TCR beta repertoire diversity of CD4+ T cell found in non-reactive lymph nodes from healthy individuals. These studies would broaden our understanding of the dynamics of T cell circulation and retention in lymph nodes in normal health. In addition, they would serve as reference point for our studies looking into the changes in the TCR beta diversity in chronic lymphocytic leukaemia and will hopefully help other researchers to interpret the results of their studies on TCR diversity in other disease-involved lymph nodes.
Michela Bardini, Centro Ricerca Tettamanti University of Milan Bicocca
Research Summary: Acute lymphoblastic leukemia with the Mixed-Lineage Leukemia gene rearrangement occurring within the first year of age (MLL+ Infant ALL) is a very aggressive disease, associated to an overall dismal prognosis, in which the MLL gene rearrangement is the pre-natal and powerful genetic event driving and hastening the leukemia initiation.
By clonal studies in relapsed patients, and serial xeno-trasplantation assays into immunedeficient NOD/SCID mice, we have uncovered an exceptional clonal diversity and competition/selection of multiple co-existing leukemic clones (as for example we have observed that dominant clones at disease presentation might persist or extinguish at relapse; whilst ‘new’ clones, which were indeed minor component of the leukemic bulk but quiescent at diagnosis, might reactivate and take over at relapse).
In the proposed study we will perform next-generation profiling of Ig/TCR gene rearrangements in order to i. further dissect the clonal composition of MLL+ leukemia and ii. follow the dynamics of competition/selection of multiple pre- existing leukemia-initiating clones during disease progression; both in paired diagnosis/relapse samples from MLL+ infant ALL patients, as well as in xenograft leukemia samples from serially transplanted mice.
2012 November Recipients
Jennifer Sims, Ph.D., Columbia University Medical Center
Research Summary: Glioblastoma multiforme (GBM) remains the most aggressive and prognostically devastating primary brain tumor, unusually persistent in the face of surgical, chemotherapeutic, radiological intervention. We are studying the links between glioma progression (and suppression) and perturbation of the T cell population within the tumor and the periphery with both human patient samples and our murine model.
Gaurav Gaiha, Ph.D., Ragon Institute of MGH, MIT and Harvard
Research Summary: Given recent findings implicating the role of CD8+ T cell receptor clonotypes in HIV control, we propose using the immunoSEQ platform to profile the entire TCR beta repertoire of HIV-specific CD8+ T cells from patients with known periods of controlled and progressive infection. This unique intra-patient comparative approach would provide a first in-kind perspective on the global changes in HIV-specific TCR repertoires that account for these divergent clinical presentations, ultimately guiding further development and monitoring of efficacious T cell based vaccines.
Eric Allenspach, Ph.D., Seattle Children’s Hospital
Research Summary: My project proposal is to compare the naïve B cell IgH repertoire of normal human control samples with patients with human primary immunodeficiency syndromes. Many patients have autoimmunity symptoms that may be explained by a shift in the peripheral B cell repertoire.
Taizo Nakano, M.D., Children’s Hospital Colorado
Research Summary: Neuroblastoma, the most common extracranial solid tumor in infants and young children, accounts for 15% of childhood cancer mortality. We hypothesize that T cells actively undergo clonal expansion in response to neuroblastoma and that overrepresented T cell receptor repertoire sequences will act as diagnostic and/or prognostic tools that will influence treatment decisions and lead to novel antigen discovery. Variations in the diversity of the anti-tumor immune repertoire amongst patients with stage IV neuroblastoma, between patients of low stage and high stage disease, and after the administration of induction chemotherapy will greatly expand our current understanding of neuroblastoma immunology.
2012 August Recipients
Evaggelia Liaskou, University of Birmingham, UK
Research Summary: Primary sclerosing cholangitis (PSC) is a chronic liver disease, characterized by progressive inflammation, fibrosis and destruction of the bile ducts. Studies suggest that T cells play a pivotal role in the progression of PSC disease. In this project, we propose to isolate T cells from human PSC liver tissue and matched peripheral blood and using the immunoSEQ technology to profile the human T cell receptor beta, in order to investigate the presence of specific TCRs in PSC patients that will help us understand what antigens might be able to interact with the variable regions and thus identify what causes the activation of T cells in human PSC liver.
Kyle K. Payne, Virginia Commonwealth University – Massey Cancer Center
Research Summary: Through the use of ultrahigh-throughput sequence analysis, this project proposes to determine whether the T cells of patients with breast cancer exhibit a unique molecular signature in VDJ gene recombination of the TcR Vβ following an ex vivo T cell expansion and re-programming protocol developed by our group. The existence of distinct TcR clonotypes in re-programmed T cells would provide rationale for future immunomonitoring of TcR Vβ recombination in breast cancer patients in order to predict objective responses following initial therapy.
Alison Smith, Tulane University
Research Summary: Obesity is a chronic inflammatory condition characterized by activation and infiltration of T cells into adipose tissues, which is an integral step in the development of associated metabolic syndromes such as diabetes. The goal of this project is to analyze the variable region of T cells in adipose tissue from obese patients with type-2 diabetes using a high-throughput sequencing method in order to better understand the role of T cells in the pathophysiology of this disease.
Patrick Hanley, Baylor College of Medicine
Research Summary: We have an ongoing clinical trial where we infuse virus-specific T cells derived from cord blood into cord blood transplant recipients. Using TCR sequencing, we are trying to determine whether the T cells that we give to the patients persist in vivo and correlate with protection or resolution of viral infections.