Bio

Bio

Kara Davis, D.O. is an Assistant Professor of Pediatrics in the Division of Hematology and Oncology. Dr. Davis obtained her B.A. from Pennsylvania State University and her D.O. from the Philadelphia College of Osteopathic Medicine. Clinically, she completed her training in Pediatrics at Thomas Jefferson University/A.I. DuPont Children?s Hospital and her Heme/Onc fellowship at Lucile Packard Children?s Hospital at Stanford. During her fellowship training, Kara worked in the laboratory of Garry Nolan, Ph.D. where she utilized single-cell, high-dimensional analysis platforms to study healthy human B cell development and B cell leukemia. Her research focuses on using single-cell analysis to organize tumor heterogeneity in pediatric cancers, especially blood cancers, as means to determine cell populations associated with clinical risks such as relapse. Clinically, Dr. Davis sees patients with leukemia and is involved with the Cancer Cellular Therapies program with experience in treating children with chimeric antigen receptor (CAR) T-cells and other immunotherapies including checkpoint inhibitors.

Clinical Focus

  • Pediatric Hematology-Oncology

Academic Appointments

Administrative Appointments

  • Vice Chair, COG Study ADVL1412, Children's Oncology Group (2016 - Present)

Professional Education

  • Fellowship: Stanford University Pediatric Hematology Oncology Fellowship (2010) CA
  • Residency: AI Dupont Hospital for Children (2007) DE
  • Medical Education: Philadelphia College of Osteopathic Medicine Office of the Registrar (2004) PA
  • Board Certification: American Board of Pediatrics, Pediatric Hematology-Oncology (2011)
  • Board Certification: American Board of Pediatrics, Pediatrics (2007)

Contact

  • Alyssa Ray Research Administrator
  • Pediatric Hematology and Oncology 1000 Welch Rd Ste 300 MC 5798 Palo Alto, CA 94304
    • Tel: (650) 723-5535
    Fax: (650) 723-5231

Links

Research & Scholarship

Current Research and Scholarly Interests

To address the intrinsic heterogeneity of primary cancers, we have taken a single-cell approach to the study of cancer, particularly childhood leukemia. To organize the tremendous data generated from single-cell studies, we also seek to understand the healthy structure of the tissue of origin.

Using single-cell, high-parameter analysis platforms, especially mass cytometry, to examine primary patient samples, we seek to identify how childhood cancers diverge from their healthy tissue of origin and how cancer cells may exploit developmental states for their benefit. Further, what populations or features of tumor cells are associated with clinical outcomes of interest, such as site of disease, relapse, or drug resistance? Using this knowledge, we can further investigate new approaches to treatment for children with cancer and mechanisms of drug resistance, and with a particular interest in how this relates to immunotherapeutic approaches to cancer treatment.

Clinical Trials

  • Nivolumab With or Without Ipilimumab in Treating Younger Patients With Recurrent or Refractory Solid Tumors or Sarcomas Recruiting

    This phase I/II trial studies the side effects and best dose of nivolumab when given with or without ipilimumab to see how well they work in treating younger patients with solid tumors or sarcomas that have come back (recurrent) or do not respond to treatment (refractory). Immunotherapy with monoclonal antibodies, such as nivolumab and ipilimumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. It is not yet known whether nivolumab works better alone or with ipilimumab in treating patients with recurrent or refractory solid tumors or sarcomas.

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  • Phase I Dose Escalation Study of CD19/CD22 Chimeric Antigen Receptor (CAR) T Cells in Children and Young Adults With Recurrent or Refractory B Cell Malignancies Recruiting

    This phase I trial studies the best dose and side effects of CD19/CD22 chimeric antigen receptor (CAR) T cells when given together with chemotherapy, and to see how well they work in treating children or young adults with CD19 positive B acute lymphoblastic leukemia that has come back or does not respond to treatment. A CAR is a genetically-engineered receptor made so that immune cells (T cells) can attack cancer cells by recognizing and responding to the CD19/CD22 proteins. These proteins are commonly found on B acute lymphoblastic leukemia. Drugs used in chemotherapy, such as fludarabine phosphate and cyclophosphamide, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving CD19/CD22-CAR T cells and chemotherapy may work better in treating children or young adults with B acute lymphoblastic leukemia.

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  • Determine Efficacy and Safety of CTL019 in Pediatric Patients With Relapsed and Refractory B-cell ALL and High Risk B-cell ALL at First Relapse. Determine Feasibility and Safety of CTL019 Therapy in Pediatric Patients With High Risk B-cell ALL That Relapsed < 6 Months Post All-HSCT. Not Recruiting

    This is a single arm, open-label, multi-center, phase II study to determine the efficacy and safety of CTL019 in pediatric patients with r/r B-cell ALL and high risk B-cell ALL at first relapse. Determine feasibility and safety of CTL019 therapy in pediatric patients with high risk B-cell ALL that relapsed < 6 months post allo-HSCT.

    Stanford is currently not accepting patients for this trial. For more information, please contact Christina Baggott, 650-497-7659.

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  • Genome, Proteome and Tissue Microarray in Childhood Acute Leukemia Not Recruiting

    We will study gene and protein expression in leukemia cells of children diagnosed with acute leukemia. We hope to identify genes or proteins which can help us grade leukemia at diagnosis in order to: (a) develop better means of diagnosis and (b) more accurately choose the best therapy for each patient.

    Stanford is currently not accepting patients for this trial. For more information, please contact Norman J Lacayo, 650-723-5535.

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  • Open Label, Phase II Study to Evaluate Efficacy and Safety of Oral Nilotinib in Philadelphia Positive (Ph+) Chronic Myelogenous Leukemia (CML) Pediatric Patients. Not Recruiting

    To evaluate the safety, efficacy and pharmacokinetics of nilotinib over time in the Ph+ chronic myelogenous leukemia (CML) in pediatric patients (from 1 to <18 years).

    Stanford is currently not accepting patients for this trial. For more information, please contact Contact, 650-723-5117.

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  • Study of Efficacy and Safety of CTL019 in Pediatric ALL Patients Not Recruiting

    This was a single arm, open-label, multi-center, phase II study to determine the efficacy and safety of an experimental therapy called CTL019 T-cells in pediatric patients with B-cell acute lymphoblastic leukemia, who were refractory to standard chemotherapy regimen or relapsed after allogeneic stem cell transplant.

    Stanford is currently not accepting patients for this trial.

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Teaching

2020-21 Courses

Stanford Advisees

Publications

All Publications

  • A novel platform for isotype-specific testing of autoantibodies. PloS one Carter, K. L., Treurnicht, A., Davis, K. L., Kumar, R. B., Feldman, B. J. 2019; 14 (2): e0211596

    Abstract

    The objective of this study was to test if a novel platform could be used for isotype-specific autoantibody testing in humans. Further, we evaluated if testing with this novel platform enables earlier detection of insulin autoantibodies in individuals that have first-degree relatives with type-1 diabetes than currently used approaches. Longitudinal serum samples from participants were collected before and after they converted to become positive for insulin autoantibodies by the current standardly used assays. Using a novel plasmonic gold chip platform, we tested these samples for IgM isotype-specific autoantibodies. Serial serum samples from individuals without diabetes were also tested as a comparison control cohort. Our results demonstrate proof-of-concept that a plasmonic gold chip can specifically detect the IgM insulin autoantibody. Five out of the six individuals that converted to being positive for insulin autoantibodies by standard testing had significant IgM autoantibodies on the plasmonic chip platform. The plasmonic chip platform detected IgM autoantibodies earlier than standard testing by up to 4 years. Our results indicate that the plasmonic gold platform can specifically detect the IgM isotype autoantibodies and suggest that combining isotype-specific testing with currently used approaches enables earlier detection of insulin autoantibodies in individuals that have first-degree relatives with type 1 diabetes.

    View details for DOI 10.1371/journal.pone.0211596

    View details for PubMedID 30730939

  • False-positive results with select HIV-1 NAT methods following lentivirus-based tisagenlecleucel therapy BLOOD Laetsch, T. W., Maude, S. L., Milone, M. C., Davis, K. L., Krueger, J., Cardenas, A., Eldjerou, L. K., Keir, C. H., Wood, P. A., Grupp, S. A. 2018; 131 (23): 2596?98

    View details for PubMedID 29669777

  • SRC/ABL inhibition disrupts CRLF2-driven signaling to induce cell death in B-cell acute lymphoblastic leukemia. Oncotarget Sarno, J., Savino, A. M., Buracchi, C., Palmi, C., Pinto, S., Bugarin, C., Jager, A., Bresolin, S., Barber, R. C., Silvestri, D., Israeli, S., Dyer, M. J., Cazzaniga, G., Nolan, G. P., Biondi, A., Davis, K. L., Gaipa, G. 2018; 9 (33): 22872?85

    Abstract

    Children with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) overexpressing the CRLF2 gene (hiCRLF2) have poor prognosis. CRLF2 protein overexpression leads to activated JAK/STAT signaling and trials are underway using JAK inhibitors to overcome treatment failure. Pre-clinical studies indicated limited efficacy of single JAK inhibitors, thus additional pathways must be targeted in hiCRLF2 cells. To identify additional activated networks, we used single-cell mass cytometry to examine 15 BCP-ALL primary patient samples. We uncovered a coordinated signaling network downstream of CRLF2 characterized by co-activation of JAK/STAT, PI3K, and CREB pathways. This CRLF2-driven network could be more effectively disrupted by SRC/ABL inhibition than single-agent JAK or PI3K inhibition, and this could be demonstrated even in primary minimal residual disease (MRD) cells. Our study suggests SCR/ABL inhibition as effective in disrupting the cooperative functional networks present in hiCRLF2 BCP-ALL patients, supporting further investigation of this strategy in pre-clinical studies.

    View details for PubMedID 29796158

  • Single-cell developmental classification of B cell precursor acute lymphoblastic leukemia at diagnosis reveals predictors of relapse. Nature medicine Good, Z., Sarno, J., Jager, A., Samusik, N., Aghaeepour, N., Simonds, E. F., White, L., Lacayo, N. J., Fantl, W. J., Fazio, G., Gaipa, G., Biondi, A., Tibshirani, R., Bendall, S. C., Nolan, G. P., Davis, K. L. 2018; 24 (4): 474?83

    Abstract

    Insight into the cancer cell populations that are responsible for relapsed disease is needed to improve outcomes. Here we report a single-cell-based study of B cell precursor acute lymphoblastic leukemia at diagnosis that reveals hidden developmentally dependent cell signaling states that are uniquely associated with relapse. By using mass cytometry we simultaneously quantified 35 proteins involved in B cell development in 60 primary diagnostic samples. Each leukemia cell was then matched to its nearest healthy B cell population by a developmental classifier that operated at the single-cell level. Machine learning identified six features of expanded leukemic populations that were sufficient to predict patient relapse at diagnosis. These features implicated the pro-BII subpopulation of B cells with activated mTOR signaling, and the pre-BI subpopulation of B cells with activated and unresponsive pre-B cell receptor signaling, to be associated with relapse. This model, termed 'developmentally dependent predictor of relapse' (DDPR), significantly improves currently established risk stratification methods. DDPR features exist at diagnosis and persist at relapse. By leveraging a data-driven approach, we demonstrate the predictive value of single-cell 'omics' for patient stratification in a translational setting and provide a framework for its application to human cancer.

    View details for PubMedID 29505032

  • Publisher Correction: High-resolution myogenic lineage mapping by single-cell mass cytometry. Nature cell biology Porpiglia, E., Samusik, N., Van Ho, A. T., Cosgrove, B. D., Mai, T., Davis, K. L., Jager, A., Nolan, G. P., Bendall, S. C., Fantl, W. J., Blau, H. M. 2018

    Abstract

    In the version of this Article originally published, the name of author Andrew Tri Van Ho was coded wrongly, resulting in it being incorrect when exported to citation databases. This has been corrected, though no visible changes will be apparent.

    View details for PubMedID 29507406

  • Tisagenlecleucel in Children and Young Adults with B-Cell Lymphoblastic Leukemia NEW ENGLAND JOURNAL OF MEDICINE Maude, S. L., Laetsch, T. W., Buechner, J., Rives, S., Boyer, M., Bittencourt, H., Bader, P., Verneris, M. R., Stefanski, H. E., Myers, G. D., Qayed, M., De Moerloose, B., Hiramatsu, H., Schlis, K., Davis, K. L., Martin, P. L., Nemecek, E. R., Yanik, G. A., Peters, C., Baruchel, A., Boissel, N., Mechinaud, F., Balduzzi, A., Krueger, J., June, C. H., Levine, B. L., Wood, P., Taran, T., Leung, M., Mueller, K. T., Zhang, Y., Sen, K., Lebwohl, D., Pulsipher, M. A., Grupp, S. A. 2018; 378 (5): 439?48

    Abstract

    In a single-center phase 1-2a study, the anti-CD19 chimeric antigen receptor (CAR) T-cell therapy tisagenlecleucel produced high rates of complete remission and was associated with serious but mainly reversible toxic effects in children and young adults with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL).We conducted a phase 2, single-cohort, 25-center, global study of tisagenlecleucel in pediatric and young adult patients with CD19+ relapsed or refractory B-cell ALL. The primary end point was the overall remission rate (the rate of complete remission or complete remission with incomplete hematologic recovery) within 3 months.For this planned analysis, 75 patients received an infusion of tisagenlecleucel and could be evaluated for efficacy. The overall remission rate within 3 months was 81%, with all patients who had a response to treatment found to be negative for minimal residual disease, as assessed by means of flow cytometry. The rates of event-free survival and overall survival were 73% (95% confidence interval [CI], 60 to 82) and 90% (95% CI, 81 to 95), respectively, at 6 months and 50% (95% CI, 35 to 64) and 76% (95% CI, 63 to 86) at 12 months. The median duration of remission was not reached. Persistence of tisagenlecleucel in the blood was observed for as long as 20 months. Grade 3 or 4 adverse events that were suspected to be related to tisagenlecleucel occurred in 73% of patients. The cytokine release syndrome occurred in 77% of patients, 48% of whom received tocilizumab. Neurologic events occurred in 40% of patients and were managed with supportive care, and no cerebral edema was reported.In this global study of CAR T-cell therapy, a single infusion of tisagenlecleucel provided durable remission with long-term persistence in pediatric and young adult patients with relapsed or refractory B-cell ALL, with transient high-grade toxic effects. (Funded by Novartis Pharmaceuticals; ClinicalTrials.gov number, NCT02435849 .).

    View details for PubMedID 29385370

  • Niclosamide suppresses acute myeloid leukemia cell proliferation through inhibition of CREB-dependent signaling pathways ONCOTARGET Chae, H., Cox, N., Dahl, G. V., Lacayo, N. J., Davis, K. L., Capolicchio, S., Smith, M., Sakamoto, K. M. 2018; 9 (4): 4301?17

    Abstract

    CREB (cAMP Response Element Binding protein) is a transcription factor that is overexpressed in primary acute myeloid leukemia (AML) cells and associated with a decreased event-free survival and increased risk of relapse. We recently reported a small molecule inhibitor of CREB, XX-650-23, which inhibits CREB activity in AML cells. Structure-activity relationship analysis for chemical compounds with structures similar to XX-650-23 led to the identification of the anthelminthic drug niclosamide as a potent anti-leukemic agent that suppresses cell viability of AML cell lines and primary AML cells without a significant decrease in colony forming activity of normal bone marrow cells. Niclosamide significantly inhibited CREB function and CREB-mediated gene expression in cells, leading to apoptosis and G1/S cell cycle arrest with reduced phosphorylated CREB levels. CREB knockdown protected cells from niclosamide treatment-mediated cytotoxic effects. Furthermore, treatment with a combination of niclosamide and CREB inhibitor XX-650-23 showed an additive anti-proliferative effect, consistent with the hypothesis that niclosamide and XX-650-23 regulate the same targets or pathways to inhibit proliferation and survival of AML cells. Niclosamide significantly inhibited the progression of disease in AML patient-derived xenograft (PDX) mice, and prolonged survival of PDX mice. Niclosamide also showed synergistic effects with chemotherapy drugs to inhibit AML cell proliferation. While chemotherapy antagonized the cytotoxic potential of niclosamide, pretreatment with niclosamide sensitized cells to chemotherapeutic drugs, cytarabine, daunorubicin, and vincristine. Therefore, our results demonstrate niclosamide as a potential drug to treat AML by inducing apoptosis and cell cycle arrest through inhibition of CREB-dependent pathways in AML cells.

    View details for PubMedID 29435104

  • DRUG-NEM: Optimizing drug combinations using single-cell perturbation response to account for intratumoral heterogeneity. Proceedings of the National Academy of Sciences of the United States of America Anchang, B., Davis, K. L., Fienberg, H. G., Williamson, B. D., Bendall, S. C., Karacosta, L. G., Tibshirani, R., Nolan, G. P., Plevritis, S. K. 2018; 115 (18): E4294?E4303

    Abstract

    An individual malignant tumor is composed of a heterogeneous collection of single cells with distinct molecular and phenotypic features, a phenomenon termed intratumoral heterogeneity. Intratumoral heterogeneity poses challenges for cancer treatment, motivating the need for combination therapies. Single-cell technologies are now available to guide effective drug combinations by accounting for intratumoral heterogeneity through the analysis of the signaling perturbations of an individual tumor sample screened by a drug panel. In particular, Mass Cytometry Time-of-Flight (CyTOF) is a high-throughput single-cell technology that enables the simultaneous measurements of multiple ([Formula: see text]40) intracellular and surface markers at the level of single cells for hundreds of thousands of cells in a sample. We developed a computational framework, entitled Drug Nested Effects Models (DRUG-NEM), to analyze CyTOF single-drug perturbation data for the purpose of individualizing drug combinations. DRUG-NEM optimizes drug combinations by choosing the minimum number of drugs that produce the maximal desired intracellular effects based on nested effects modeling. We demonstrate the performance of DRUG-NEM using single-cell drug perturbation data from tumor cell lines and primary leukemia samples.

    View details for PubMedID 29654148

  • Single-cell mass cytometry and machine learning predict relapse in childhood leukemia. Molecular & cellular oncology Sarno, J., Davis, K. L. 2018; 5 (5): e1472057

    Abstract

    Improved insight into cancer cell populations responsible for treatment failure will lead to better outcomes for patients. We herein highlight a single-cell study of B-cell precursor acute lymphoblastic leukemia (BCP-ALL) at diagnosis that revealed hidden developmentally dependent cell signaling states uniquely associated with relapse.

    View details for PubMedID 30263942

  • Cost-Effectiveness of Chimeric Antigen Receptor T-Cell Therapy in Relapsed or Refractory Pediatric B-Cell Acute Lymphoblastic Leukemia Journal of Clinical Oncology Lin, J., Lerman, B. J., Barnes, J., Boursiquot, B., Tan, Y., Robinson, A., Davis, K., Owens, D., Goldhaber-Fiebert, J. 2018

    View details for DOI 10.1200/JCO.2018.79.0642

  • Identity and Diversity of Human Peripheral Th and T Regulatory Cells Defined by Single-Cell Mass Cytometry JOURNAL OF IMMUNOLOGY Kunicki, M. A., Hernandez, L., Davis, K. L., Bacchetta, R., Roncarolo, M. 2018; 200 (1): 336?46

    Abstract

    Human CD3+CD4+ Th cells, FOXP3+ T regulatory (Treg) cells, and T regulatory type 1 (Tr1) cells are essential for ensuring peripheral immune response and tolerance, but the diversity of Th, Treg, and Tr1 cell subsets has not been fully characterized. Independent functional characterization of human Th1, Th2, Th17, T follicular helper (Tfh), Treg, and Tr1 cells has helped to define unique surface molecules, transcription factors, and signaling profiles for each subset. However, the adequacy of these markers to recapitulate the whole CD3+CD4+ T cell compartment remains questionable. In this study, we examined CD3+CD4+ T cell populations by single-cell mass cytometry. We characterize the CD3+CD4+ Th, Treg, and Tr1 cell populations simultaneously across 23 memory T cell-associated surface and intracellular molecules. High-dimensional analysis identified several new subsets, in addition to the already defined CD3+CD4+ Th, Treg, and Tr1 cell populations, for a total of 11 Th cell, 4 Treg, and 1 Tr1 cell subsets. Some of these subsets share markers previously thought to be selective for Treg, Th1, Th2, Th17, and Tfh cells, including CD194 (CCR4)+FOXP3+ Treg and CD183 (CXCR3)+T-bet+ Th17 cell subsets. Unsupervised clustering displayed a phenotypic organization of CD3+CD4+ T cells that confirmed their diversity but showed interrelation between the different subsets, including similarity between Th1-Th2-Tfh cell populations and Th17 cells, as well as similarity of Th2 cells with Treg cells. In conclusion, the use of single-cell mass cytometry provides a systems-level characterization of CD3+CD4+ T cells in healthy human blood, which represents an important baseline reference to investigate abnormalities of different subsets in immune-mediated pathologies.

    View details for PubMedID 29180490

  • High-resolution myogenic lineage mapping by single-cell mass cytometry NATURE CELL BIOLOGY Porpiglia, E., Samusik, N., Van Ho, A. T., Cosgrove, B. D., Mai, T., Davis, K. L., Jager, A., Nolan, G. P., Bendall, S. C., Fantl, W. J., Blau, H. M. 2017; 19 (5): 558-?

    Abstract

    Muscle regeneration is a dynamic process during which cell state and identity change over time. A major roadblock has been a lack of tools to resolve a myogenic progression in vivo. Here we capitalize on a transformative technology, single-cell mass cytometry (CyTOF), to identify in vivo skeletal muscle stem cell and previously unrecognized progenitor populations that precede differentiation. We discovered two cell surface markers, CD9 and CD104, whose combined expression enabled in vivo identification and prospective isolation of stem and progenitor cells. Data analysis using the X-shift algorithm paired with single-cell force-directed layout visualization defined a molecular signature of the activated stem cell state (CD44(+)/CD98(+)/MyoD(+)) and delineated a myogenic trajectory during recovery from acute muscle injury. Our studies uncover the dynamics of skeletal muscle regeneration in vivo and pave the way for the elucidation of the regulatory networks that underlie cell-state transitions in muscle diseases and ageing.

    View details for DOI 10.1038/ncb3507

    View details for Web of Science ID 000400376100019

    View details for PubMedID 28414312

  • New developments in immunotherapy for pediatric solid tumors. Current opinion in pediatrics Schultz, L. M., Majzner, R., Davis, K. L., Mackall, C. 2017

    Abstract

    Building upon preclinical advances, we are uncovering immunotherapy strategies that are translating into improved outcomes in tumor subsets. Advanced pediatric solid tumors carry poor prognoses and resultant robust efforts to apply immunotherapy advances to pediatric solid tumors are in progress. Here, we discuss recent developments in the field using mAb and mAb-based therapies including checkpoint blockade and chimeric antigen receptors (CARs).The pediatric solid tumor mAb experience targeting the diganglioside, GD2, for patients with neuroblastoma has been the most compelling to date. GD2 and alternative antigen-specific mAbs are now being incorporated into antibody-drug conjugates, bispecific antibodies and CARs for treatment of solid tumors. CARs in pediatric solid tumors have not yet achieved comparative responses to the hematologic CAR experience; however, novel strategies such as bispecific targeting, intratumoral administration and improved understanding of T-cell biology may yield enhanced CAR-efficacy. Therapeutic effect using single-agent checkpoint blocking antibodies in pediatric solid tumors also remains limited to date. Combinatorial strategies continue to hold promise and the clinical effect in tumor subsets with high antigenic burden is being explored.Pediatric immunotherapy remains at early stages of translation, yet we anticipate that with advanced technology, we will achieve widespread, efficacious use of immunotherapy for pediatric solid tumors.

    View details for DOI 10.1097/MOP.0000000000000564

    View details for PubMedID 29189429

  • Checkpoint inhibition in pediatric hematologic malignancies PEDIATRIC HEMATOLOGY AND ONCOLOGY Davis, K. L., Agarwal, A. M., Verma, A. R. 2017; 34 (6-7): 379?94

    Abstract

    Immune surveillance comprising of adaptive and innate immune systems is naturally designed to eliminate cancer development; overexpression of inhibitory receptors and their ligands prevent this check and lead to evasion and hence cancer progression and metastasis. The use of tumor-specific monoclonal antibodies (MAbs) targeting these checkpoint regulators is promising and has led to this novel field of cancer immunotherapy. The first antibody directed against cytotoxic T-lymphocyte associated protein 4 (CTLA-4), ipilimumab, showed promising results in clinical trials and was approved by the US Food and Drug Administration (FDA) for the treatment of metastatic melanoma in 2011. Since then, various other immune checkpoint inhibitors are being studied in preclinical and clinical trial phases, targeting programmed-death-1 (PD-1) and its ligand programmed death ligand 1 (PD-L1), T cell lymphocyte activation gene-3 (LAG-3), and others. Results from clinical trials are promising, and currently this approach has proven effective and safe in patients with solid tumors and some hematological malignancies in adults. In general, CTLA-4 and PD-1 inhibitors are well tolerated; however, the augmented immune response enabled by this class of agents is associated with a unique group of side effects called immune-related adverse events (irAEs). Experience in pediatrics using immune checkpoint inhibitors for hematological malignancies is limited to Hodgkin's disease and non-Hodgkin's lymphoma as in the ongoing Children's Oncology Group (COG) protocol ADVL1412. Therapeutic advances in childhood leukemia and lymphoma (TACL) consortium will initiate an early phase clinical trial with PD-1 inhibitor nivolumab in relapsed/refractory acute myeloid leukemia (AML) in the next few months.

    View details for PubMedID 29190182

  • Data-Driven Phenotypic Dissection of AML Reveals Progenitor-like Cells that Correlate with Prognosis CELL Levine, J. H., Simonds, E. F., Bendall, S. C., Davis, K. L., Amir, E. D., Tadmor, M. D., Litvin, O., Fienberg, H. G., Jager, A., Zunder, E. R., Finck, R., Gedman, A. L., Radtke, I., Downing, J. R., Pe'er, D., Nolan, G. P. 2015; 162 (1): 184-197

    Abstract

    Acute myeloid leukemia (AML) manifests as phenotypically and functionally diverse cells, often within the same patient. Intratumor phenotypic and functional heterogeneity have been linked primarily by physical sorting experiments, which assume that functionally distinct subpopulations can be prospectively isolated by surface phenotypes. This assumption has proven problematic, and we therefore developed a data-driven approach. Using mass cytometry, we profiled surface and intracellular signaling proteins simultaneously in millions of healthy and leukemic cells. We developed PhenoGraph, which algorithmically defines phenotypes in high-dimensional single-cell data. PhenoGraph revealed that the surface phenotypes of leukemic blasts do not necessarily reflect their intracellular state. Using hematopoietic progenitors, we defined a signaling-based measure of cellular phenotype, which led to isolation of a gene expression signature that was predictive of survival in independent cohorts. This study presents new methods for large-scale analysis of single-cell heterogeneity and demonstrates their utility, yielding insights into AML pathophysiology.

    View details for DOI 10.1016/j.cell.2015.05.047

    View details for Web of Science ID 000357542300019

    View details for PubMedID 26095251

    View details for PubMedCentralID PMC4508757

  • Single-Cell Trajectory Detection Uncovers Progression and Regulatory Coordination in Human B Cell Development CELL Bendall, S. C., Davis, K. L., Amir, E. D., Tadmor, M. D., Simonds, E. F., Chen, T. J., Shenfeld, D. K., Nolan, G. P., Pe'er, D. 2014; 157 (3): 714-725

    Abstract

    Tissue regeneration is an orchestrated progression of cells from an immature state to a mature one, conventionally represented as distinctive cell subsets. A continuum of transitional cell states exists between these discrete stages. We combine the depth of single-cell mass cytometry and an algorithm developed to leverage this continuum by aligning single cells of a given lineage onto a unified trajectory that accurately predicts the developmental path de novo. Applied to human B cell lymphopoiesis, the algorithm (termed Wanderlust) constructed trajectories spanning from hematopoietic stem cells through to naive B cells. This trajectory revealed nascent fractions of B cell progenitors and aligned them with developmentally cued regulatory signaling including IL-7/STAT5 and cellular events such as immunoglobulin rearrangement, highlighting checkpoints across which regulatory signals are rewired paralleling changes in cellular state. This study provides a comprehensive analysis of human B lymphopoiesis, laying a foundation to apply this approach to other tissues and "corrupted" developmental processes including cancer.

    View details for DOI 10.1016/j.cell.2014.04.005

    View details for Web of Science ID 000335392100019

    View details for PubMedID 24766814

    View details for PubMedCentralID PMC4045247

  • viSNE enables visualization of high dimensional single-cell data and reveals phenotypic heterogeneity of leukemia. Nature biotechnology Amir, E. D., Davis, K. L., Tadmor, M. D., Simonds, E. F., Levine, J. H., Bendall, S. C., Shenfeld, D. K., Krishnaswamy, S., Nolan, G. P., Pe'er, D. 2013; 31 (6): 545-552

    Abstract

    New high-dimensional, single-cell technologies offer unprecedented resolution in the analysis of heterogeneous tissues. However, because these technologies can measure dozens of parameters simultaneously in individual cells, data interpretation can be challenging. Here we present viSNE, a tool that allows one to map high-dimensional cytometry data onto two dimensions, yet conserve the high-dimensional structure of the data. viSNE plots individual cells in a visual similar to a scatter plot, while using all pairwise distances in high dimension to determine each cell's location in the plot. We integrated mass cytometry with viSNE to map healthy and cancerous bone marrow samples. Healthy bone marrow automatically maps into a consistent shape, whereas leukemia samples map into malformed shapes that are distinct from healthy bone marrow and from each other. We also use viSNE and mass cytometry to compare leukemia diagnosis and relapse samples, and to identify a rare leukemia population reminiscent of minimal residual disease. viSNE can be applied to any multi-dimensional single-cell technology.

    View details for DOI 10.1038/nbt.2594

    View details for PubMedID 23685480

  • Pediatric Acute Myeloid Leukemia as Classified Using 2008 WHO Criteria: A Single-Center Experience. American journal of clinical pathology Davis, K. L., Marina, N., Arber, D. A., Ma, L., Cherry, A., Dahl, G. V., Heerema-McKenney, A. 2013; 139 (6): 818-825

    Abstract

    The classification of acute myeloid leukemia (AML) has evolved to the most recent World Health Organization (WHO) schema, which integrates genetic, morphologic, and prognostic data into a single system. However, this system was devised using adult data and how this system applies to a pediatric cohort is unknown. Performing a retrospective chart review, we examined our single-center experience with AML in 115 children and classified their leukemia using the WHO 2008 schema. We examined patient samples for mutations of FLT3, NPM1, and CEBPA. Overall survival was calculated within categories. In our pediatric population, most cases of AML had recurrent genetic abnormalities of favorable prognosis. More than 10% of patients in our series were categorized as AML, with myelodysplasia-related changes, an entity not well-described in pediatric patients. In addition, a large proportion of patients were categorized with secondary, therapy-related AML. To our knowledge, this is the first application of the WHO 2008 classification to a pediatric cohort. In comparison to adult studies, AML in the pediatric population shows a distinct distribution within the WHO 2008 classification.

    View details for DOI 10.1309/AJCP59WKRZVNHETN

    View details for PubMedID 23690127

  • Ikaros: master of hematopoiesis, agent of leukemia. Therapeutic advances in hematology Davis, K. L. 2011; 2 (6): 359-368

    Abstract

    Ikaros is the founding member of a family of zinc finger transcription factors whose function during early hematopoietic development is required for differentiation into the three major hematopoietic lineages. Ikaros deletions have been described in human malignancies, particularly precursor B-cell leukemia. Deletions of this transcription factor appear to mediate leukemogenesis, although the exact mechanism is unclear. This article reviews the structure and function of Ikaros proteins in chromatin remodeling and gene expression as well as the current knowledge of Ikaros deletions in human malignancies. A new proteomic platform, mass cytometry, is introduced which allows measurements of greater than 30 parameters at the single-cell level and should thus provide a greater level of detail to unravel the mechanistic consequences of Ikaros dysfunction in leukemia.

    View details for DOI 10.1177/2040620711412419

    View details for PubMedID 23556102

  • Speeding the Flow Toward Personalized Therapy in Childhood Acute Leukemia PEDIATRIC BLOOD & CANCER Simonds, E. F., Davis, K. L., Lacayo, N. J. 2009; 53 (4): 525-526

    View details for DOI 10.1002/pbc.22180

    View details for Web of Science ID 000269295500001

    View details for PubMedID 19642213

  • Why Are Young Infants Tested for Herpes Simplex Virus? PEDIATRIC EMERGENCY CARE Davis, K. L., Shah, S. S., Frank, G., Eppes, S. C. 2008; 24 (10): 673-678

    Abstract

    The polymerase chain reaction (PCR)-based test to detect herpes simplex virus (HSV) genome in cerebrospinal fluid (CSF) has become the test of choice for diagnosing this infection. The utility of this test in young infants undergoing sepsis evaluations is unknown.We sought to identify the factors that prompted physicians to include HSV PCR in their evaluation of young infants undergoing lumbar puncture. In addition, the impact of ordering this test on patient management was assessed.This case-control study included infants 0 to 60 days who were evaluated by lumbar puncture at the Alfred I. duPont Hospital for Children over a 5-year period. Case patients had CSF HSV PCR ordered as part of their evaluation and control patients did not.Eighty-eight case patients and 83 control patients were identified. The median patient age was 12 days and most patients (55%) were male. Both groups were similar in demographics. Herpes simplex virus infection was diagnosed by PCR in 3.4% of cases. The occurrence of a seizure (adjusted odds ratio [OR], 8.3; 95% confidence interval [CI], 1.7-41.0), the performance of CSF enteroviral PCR testing (adjusted OR, 4.7; 95% CI, 1.4-15.8), and the decision to obtain hepatic transaminases (adjusted OR, 5.6; 95% CI, 2.7-11.8) were associated with the decision to perform CSF HSV PCR testing. Use of health care resources associated with PCR testing was considerable.The occurrence of a seizure, the performance of CSF enteroviral PCR testing, and the decision to obtain hepatic transaminases were independently associated with the decision to perform CSF HSV PCR testing. Features traditionally associated with neonatal HSV infection, such as elevated numbers of CSF white blood cells or red blood cells, did not appear to influence the decision to perform CSF HSV PCR testing. The yield of testing in this population was low. Clinicians should weigh the benefits of early diagnosis in a few patients against the consequences of excessive testing in this population.

    View details for Web of Science ID 000260157500006

    View details for PubMedID 19242136

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