Holbrook E Kohrt

Stanford University, Palo Alto, California, United States

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Publications (79)511.73 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: We have designed a novel therapeutic approach for lymphoma that combines targeted kinase inhibition with in situ vaccination. Intratumoral injection of an unmethylated CG-enriched oligodeoxynucleotide (CpG), an agonist for the toll like receptor 9 (TLR9), induces the activation of NK cells, macrophages and antigen presenting cells that control tumor growth at the local site. Ibrutinib, an irreversible inhibitor of Bruton's tyrosine kinase (BTK), a key enzyme in the signaling pathway downstream of B Cell receptor (BCR), is an effective treatment against many types of B cell lymphomas. The combination of intratumoral injection of CpG with systemic treatment by ibrutinib resulted in eradication of the tumors not only in the injected site but also at distant sites. Surprisingly, this combinatorial antitumor effect required an intact T cell immune system since it did not occur in nude, scid or T cell depleted mice. Moreover, T cells from animals treated with intratumoral CpG and ibrutinib prevented the outgrowth of newly injected tumors. This result suggests that ibrutinib can induce immunogenic cell death of lymphoma cells and that concomitant stimulation of antigen-presenting cells in the tumor microenvironment by TLR ligands can lead to a powerful systemic antitumor immune response. Copyright © 2015 American Society of Hematology.
    Blood 02/2015; DOI:10.1182/blood-2014-08-593137 · 9.78 Impact Factor
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    ABSTRACT: An expanding panel of monoclonal antibodies (mAbs) that specifically target malignant cells or intercept trophic factors delivered by the tumor stroma is now available for cancer therapy. These mAbs can exert direct antiproliferative/cytotoxic effects as they inhibit pro-survival signal transduction cascades or activate lethal receptors at the plasma membrane of cancer cells, they can opsonize neoplastic cells to initiate a tumor-targeting immune response, or they can be harnessed to specifically deliver toxins or radionuclides to transformed cells. As an indication of the success of this immunotherapeutic paradigm, international regulatory agencies approve new tumor-targeting mAbs for use in cancer patients every year. Moreover, the list of indications for previously licensed molecules is frequently expanded to other neoplastic disorders as the results of large, randomized clinical trials become available. Here, we discuss recent advances in the preclinical and clinical development of tumor-targeting mAbs for oncological indications.
    OncoImmunology 01/2015; 4(1):e985940. DOI:10.4161/2162402X.2014.985940 · 6.28 Impact Factor
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    ABSTRACT: Cancer immunotherapy is a rapidly evolving field that offers a novel paradigm for cancer treatment: therapies focus on enhancing the immune system's innate and adaptive anti-tumor response. Early immunotherapeutics have achieved impressive clinical outcomes and monoclonal antibodies are now integral to therapeutic strategies in a variety of cancers. However, only recently have antibodies targeting innate immune cells entered clinical development. Innate immune effector cells play important roles in generating and maintaining antitumor immunity. Antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) are important innate immune mechanisms for tumor eradication. These cytolytic processes are initiated by the detection of a tumor-targeting antibody and can be augmented by activating co-stimulatory pathways or blocking inhibitory signals on innate immune cells. The combination of FDA-approved monoclonal antibodies with innate effector-targeting antibodies has demonstrated potent preclinical therapeutic synergy and early-phase combinatorial clinical trials are ongoing. Copyright © 2015 Elsevier Ltd. All rights reserved.
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    ABSTRACT: Preclinical evidence of successful combinations of ionizing radiation with immunotherapy has inspired testing the translation of these results to the clinic. Interestingly, the preclinical work has consistently predicted the responses encountered in clinical trials. The first example came from a proof-of-principle trial started in 2001 that tested the concept that growth factors acting on antigen-presenting cells improve presentation of tumor antigens released by radiation and induce an abscopal effect. Granulocyte-macrophage colony-stimulating factor was administered during radiotherapy to a metastatic site in patients with metastatic solid tumors to translate evidence obtained in a murine model of syngeneic mammary carcinoma treated with cytokine FLT-3L and radiation. Subsequent clinical availability of vaccines and immune checkpoint inhibitors has triggered a wave of enthusiasm for testing them in combination with radiotherapy. Examples of ongoing clinical trials are described in this report. Importantly, most of these trials include careful immune monitoring of the patients enrolled and will generate important data about the proimmunogenic effects of radiation in combination with a variety of immune modulators, in different disease settings. Results of these studies are building a platform of evidence for radiotherapy as an adjuvant to immunotherapy and encourage the growth of this novel field of radiation oncology. Copyright © 2015 Elsevier Inc. All rights reserved.
    Seminars in radiation oncology 01/2015; 25(1):54-64. DOI:10.1016/j.semradonc.2014.07.003 · 3.77 Impact Factor
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    ABSTRACT: Despite advances in combinatorial chemotherapy regimens and the advent of intraperitoneal chemotherapy administration, current therapeutic options for ovarian cancer patients are inadequate. Immunotherapy offers a novel and promising therapeutic strategy for treating ovarian tumors. Following the demonstration of the immunogenicity of ovarian tumors, multiple immunotherapeutic modalities have been developed. Antibody-based therapies, immune checkpoint blockade, cancer vaccines, and chimeric antigen receptor-modified T cells have demonstrated preclinical success and entered clinical testing. In this review, we discuss these promising immunotherapeutic approaches and emphasize the importance of combinatorial treatment strategies and biomarker discovery.
    01/2015; 3:7. DOI:10.1186/s40425-015-0051-7
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    ABSTRACT: The clinical successes of CTLA4 and PD-1 immune checkpoint blockade in aggressive malignancies such as metastatic melanoma and non-small cell lung carcinoma inaugurate a new era in oncology. Indeed, as opposed to tumor-targeted therapies, it is now clear that immune-targeted therapies designed to enhance the antitumor immune response are a relevant strategy to obtain long-term tumor responses. Interestingly, the study of tumor cell death biology has recently revealed that part of radiotherapy efficacy relies on its ability to trigger an immune response against tumor cells. This "immunogenic cell death" partly relies on the generation of damage-associated molecular patterns, which can stimulate immune sensors such as toll-like receptors. Tumor radiation therapy can therefore be envisioned as a strategy to perform an in situ immunization because it can initiate the release of tumor-associated antigens, deplete immune suppressors, and stimulate antigen-presenting cells via endogenous release of toll-like receptor agonists. Moreover, combinations of radiotherapy with immune checkpoint antibodies are synergistic in preclinical models. The translation of these observations in the clinic is ongoing in early phase I/II trials. Copyright © 2015 Elsevier Inc. All rights reserved.
    Seminars in radiation oncology 01/2015; 25(1):34-39. DOI:10.1016/j.semradonc.2014.07.006 · 3.77 Impact Factor
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    ABSTRACT: Blockade of the immune checkpoint programmed death receptor ligand-1 (PD-L1)/PD-1 pathway has well-established clinical activity across many tumor types. PD-L1 protein expression by immunohistochemistry (IHC) is emerging as a predictive biomarker of response to these therapies. Here, we examine PD-L1 expression in a thymic epithelial tumor (TET) tissue microarray (TMA). The TMA contained 69 TETs and 17 thymic controls, with each case represented by triplicate cores. The TMA was stained with rabbit monoclonal antibody (clone 15, Sino Biological) to human PD-L1. PD-L1 staining was scored based on intensity as follows: 0=none, 1=equivocal/uninterpretable, 2=weak, and 3=intermediate-strong. Those cases with all cores scoring 3 in the epithelial component were categorized as PD-L1 and the remaining as PD-L1. D-L1 scores were more frequent in TETs than controls (68.1% vs. 17.6%, p=0.0036). PD-L1 scores and histology were significantly correlated, with higher intensity staining in WHO B2/B3/C TETs. Only 14.8% of TETs had PD-L1 staining of associated lymphocytes. In an adjusted analysis (age/gender), PD-L1 TETs had a significantly worse overall survival (HR 5.40, 95% CI 1.13-25.89, p=0.035) and a trend for worse event-free survival (HR 2.94, 95% CI 0.94-9.24, p=0.064). PD-L1 expression was present in all cases of TETs within the epithelial component but only in a minority in the lymphocytic component. TETs stained more intensely for PD-L1 than controls, and PD-L1 TETs were associated with more aggressive histology and worse prognosis. This study lends rationale to a clinical trial with anti-PD1/PD-L1 therapy in this rare tumor type.
    Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 11/2014; DOI:10.1097/JTO.0000000000000429 · 4.55 Impact Factor
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    ABSTRACT: The goal of this study was to determine whether a combination of local tumor irradiation and autologous T-cell transplantation can effectively treat metastatic 4T1 breast cancer in mice. BALB/c mice were injected subcutaneously with luciferase-labeled 4T1 breast tumor cells and allowed to grow for 21 days, at which time metastases appeared in the lungs. Primary tumors were treated at that time with 3 daily fractions of 20 Gy of radiation each. Although this approach could eradicate primary tumors, tumors in the lungs grew progressively. We attempted to improve efficacy of the radiation by adding autologous T-cell infusions. Accordingly, T cells were purified from the spleens of tumor-bearing mice after completion of irradiation and cryopreserved. Cyclophosphamide was administered thereafter to induce lymphodepletion, followed by T-cell infusion. Although the addition of cyclophosphamide to irradiation did not improve survival or reduce tumor progression, the combination of radiation, cyclophosphamide and autologous T-cell infusion induced durable remissions and markedly improved survival. We conclude that the combination of radiation and autologous T-cell infusion is an effective treatment for metastatic 4T1 breast cancer.
    Radiation Research 07/2014; 182(2). DOI:10.1667/RR13471.1 · 2.45 Impact Factor
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    ABSTRACT: The inflammatory marker, C reactive protein has been proposed to also be a biomarker for adaptive immune responses in cancer patients with a possible application in time based chemotherapy. Fluxes in serum CRP levels were suggested to be indicative of a cyclical process in which, immune activation is followed by auto-regulating immune suppression. The applicability of CRP as a biomarker for regulatory or effector T cells was therefore investigated in a cohort of patients with gynaecological malignancies.
    Journal of Translational Medicine 06/2014; 12(1):179. DOI:10.1186/1479-5876-12-179 · 3.99 Impact Factor
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    ABSTRACT: IntroductionHypothalamic-pituitary-adrenal (HPA) axis activity is related to childhood disruptive behavior disorders and to exposure to abuse and neglect. This study explores the relationship of diurnal salivary cortisol levels with oppositional defiant disorder (ODD) and caregiver attitudes toward physical punishment among boys in Mongolia.Methods Salivary cortisol was collected in the home or institution 4 times daily for 4 days from 46 boys, aged 4-10 years, in Ulaanbaatar, Mongolia. Caregivers rated child disruptive behavior symptoms, attitudes toward physical punishment, and community violence exposures. Mixed effects models were used to estimate the association of psychopathology and caregiver attitudes with salivary cortisol levels.ResultsBoys meeting criteria for ODD displayed consistently lower diurnal salivary cortisol levels compared to boys without ODD diagnoses. Controlling for ODD diagnosis, boys with depression showed higher cortisol levels throughout the day. No other diagnosis was associated with cortisol levels. Psychiatric diagnosis accounted for 17% of between individual variations in cortisol levels unexplained by the covariates. In a separate model, caregivers’ beliefs regarding physical punishment accounted for 11% of between individual differences: boys with caregivers who stated physical punishment was necessary for discipline displayed hypocortisolism. Institutionalization did not associate with cortisol levels.DiscussionSalivary cortisol data from a non-Western naturalistic setting support an association of reduced basal HPA activity with disruptive behavior disorders and caregiver attitudes toward discipline. These findings suggest HPA functioning may be a reflection of or mediate disruptive behavior disorders in children across ethnic and cultural settings.
    Asia-Pacific Psychiatry 06/2014; 7(1). DOI:10.1111/appy.12141 · 0.47 Impact Factor
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    ABSTRACT: Treatment with cetuximab, an EGFR-targeting IgG1 mAb, results in beneficial, yet limited, clinical improvement for patients with head and neck (HN) cancer as well as colorectal cancer (CRC) patients with WT KRAS tumors. Antibody-dependent cell-mediated cytotoxicity (ADCC) by NK cells contributes to the efficacy of cetuximab. The costimulatory molecule CD137 (4-1BB) is expressed following NK and memory T cell activation. We found that isolated human NK cells substantially increased expression of CD137 when exposed to cetuximab-coated, EGFR-expressing HN and CRC cell lines. Furthermore, activation of CD137 with an agonistic mAb enhanced NK cell degranulation and cytotoxicity. In multiple murine xenograft models, including EGFR-expressing cancer cells, HN cells, and KRAS-WT and KRAS-mutant CRC, combined cetuximab and anti-CD137 mAb administration was synergistic and led to complete tumor resolution and prolonged survival, which was dependent on the presence of NK cells. In patients receiving cetuximab, the level of CD137 on circulating and intratumoral NK cells was dependent on postcetuximab time and host FcyRIIIa polymorphism. Interestingly, the increase in CD137-expressing NK cells directly correlated to an increase in EGFR-specific CD8+ T cells. These results support development of a sequential antibody approach against EGFR-expressing malignancies that first targets the tumor and then the host immune system.
    Journal of Clinical Investigation 05/2014; 124(6). DOI:10.1172/JCI73014 · 13.77 Impact Factor
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    ABSTRACT: Immune cell infiltration in the tumor microenvironment is of prognostic and therapeutic import. These immune cell subsets can be heterogeneous and are composed of mature antigen-presenting cells, helper and effector cytotoxic T cells, toleragenic dendritic cells, tumor-associated macrophages, and regulatory T cells, among other cell types. With the development of novel drugs that target the immune system rather than the cancer cells, the tumor immune microenvironment is not only prognostic for overall patient outcome, but also predictive for likelihood of response to these immune-targeted therapies. Such therapies aim to reverse the cancer immunotolerance and trigger an effective antitumor immune response. Two major families of immunostimulatory drugs are currently in clinical development: pattern recognition receptor agonists (PRRago) and immunostimulatory monoclonal antibodies (ISmAb). Despite their immune-targeted design, these agents have so far been developed clinically as if they were typical anticancer drugs. Here, we review the limitations of this conventional approach, specifically addressing the shortcomings of the usual schedules of intravenous infusions every 2 or 3 weeks. If the new modalities of immunotherapy target specific immune cells within the tumor microenvironment, it might be preferable to deliver them locally into the tumor rather than systemically. There is preclinical and clinical evidence that a therapeutic systemic antitumor immune response can be generated upon intratumoral immunomodulation. Moreover, preclinical results have shown that therapeutic synergy can be obtained by combining PRRagos and ISmAbs to the local tumor site. Clin Cancer Res; 20(7); 1747-56. ©2014 AACR.
    Clinical Cancer Research 04/2014; 20(7):1747-56. DOI:10.1158/1078-0432.CCR-13-2116 · 8.19 Impact Factor
  • Blood 03/2014; 123(12):1957-60. DOI:10.1182/blood-2014-01-547869 · 9.78 Impact Factor
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    ABSTRACT: Allogeneic hematopoietic cell transplantation (allo HCT) is the only curative therapy for the Myelodysplastic Syndromes (MDS) and Myeloproliferative Neoplasms (MPN), but treatment related toxicity has been a barrier to its more widespread use. The non-myeloablative regimen of Total Lymphoid Irradiation (TLI) and Anti-Thymocyte Globulin (ATG) permits the establishment of donor hematopoiesis necessary for the graft versus malignancy (GVM) effect and is protective against acute Graft versus Host Disease (aGVHD) but has minimal direct cytotoxicity against myeloid diseases. We explored the use of TLI-ATG conditioning to treat 61 patients with allo HCT for MDS (n= 32), therapy-related myeloid neoplasms (n=15), MPN (n=9) and CMML (n=5). The median age of all patients was 63 years (range 50-73). The cumulative incidence of aGVHD Grades II-IV was 14% (95% CI 4-23%) and Grades III-IV 4% (0-9%) and did not differ between patients that received allografts from related or unrelated donors. The cumulative incidence of non-relapse mortality (NRM) at 100 days, 12 months, and 36 months was 0%, 7%, and 11%. Overall survival (OS) and progression-free survival (PFS) were 41% (29-53%) and 35% (23-48%) respectively. The safety and tolerability of TLI-ATG, as exemplified by its low non-relapse mortality, provides a foundation for further risk-adapted or prophylactic interventions to prevent disease progression.
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 03/2014; DOI:10.1016/j.bbmt.2014.02.023 · 3.15 Impact Factor
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    ABSTRACT: Total lymphoid irradiation (TLI) with anti-thymocyte globulin (ATG) is a unique regimen that prepares recipients for allogeneic hematopoietic cell transplantation (HCT) by targeting lymph nodes, while sparing large areas of the bone marrow (BM). TLI is reported to increase the frequency of regulatory CD4(+)CD25(+)FoxP3(+) T cells (Treg) relative to conventional T cells. Here, barriers to hematopoietic stem cell (HSC) engraftment following this non-myeloablative conditioning were evaluated. TLI/ATG resulted in profound lymphoablation but endogenous host HSC remained. Initial donor HSC engraftment occurred only in radiation exposed marrow sites, but gradually distributed to BM outside the radiation field. Sustained donor engraftment required host lymphoid cells since lymphocyte deficient Rag2γc(-/-) recipients had unstable engraftment compared to wild-type. TLI/ATG treated wild-type recipients had increased proportions of Treg which was associated with increased HSC frequency and proliferation. In contrast, Rag2γc(-/-) recipients that lack Treg did not. Adoptive transfer of Treg into Rag2γc(-/-) recipients resulted in increased cell cycling of endogenous HSC. Thus, we hypothesize that Treg influence donor engraftment post-TLI/ATG by increasing HSC cell cycling, thereby promoting exit of host HSC from the marrow niche. Our study highlights the unique dynamics of donor hematopoiesis following TLI/ATG, and the effect of Treg on HSC activity.
    Blood 03/2014; DOI:10.1182/blood-2013-10-530212 · 9.78 Impact Factor
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    ABSTRACT: Natural killer (NK) cells mediate anti-lymphoma activity by spontaneous cytotoxicity and antibody-dependent cell-mediated cytotoxicity (ADCC) when triggered by rituximab, an anti-CD20 monoclonal antibody (mAb) used to treat patients with B cell lymphomas. The balance of inhibitory and activating signals determines the magnitude of NK cell's efficacy by spontaneous cytoxicity. Here, using a killer cell immunoglobulin-like receptor (KIR) transgenic murine model, we show that blockade of the interface of inhibitory KIRs with MHC class I antigens on lymphoma by anti-KIR antibodies prevents a tolerogenic interaction and augments NK cell spontaneous cytotoxicity. In combination with anti-CD20 mAbs, anti-KIR treatment induces enhanced NK cell-mediated, rituximab-dependent cytotoxicity against lymphoma in vitro and in vivo in KIR transgenic and syngeneic murine lymphoma models. These results support a therapeutic strategy of combination, rituximab and KIR blockade through lirilumab, illustrating the potential efficacy of combining a tumor targeting therapy with an NK cell agonist thus stimulating the post-rituximab anti-lymphoma immune response.
    Blood 12/2013; 123(5). DOI:10.1182/blood-2013-08-519199 · 9.78 Impact Factor
  • Ronald Levy, Aurélien Marabelle, Holbrook E Kohrt
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    ABSTRACT: Systemic administration of the checkpoint blockade antibody anti-CTLA4 results in severe auto-immune toxicity, limiting its clinical efficacy. Fransen and colleagues show here that peri-tumoral delivery of low doses of this immunomodulatory drug can trigger a systemic anti-tumor immune response while preventing the toxicity against other organs.
    Clinical Cancer Research 08/2013; 19(19). DOI:10.1158/1078-0432.CCR-13-1923 · 8.19 Impact Factor
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    ABSTRACT: The aryl hydrocarbon receptor (AhR) has become increasingly recognized for its role in the differentiation and activity of immune cell subsets; however, its role in regulating the activity of natural killer (NK) cells has not been described. Here, we show that AhR expression is induced in murine NK cells upon cytokine stimulation. We show that in the absence of AhR, NK cells have reduced cytolytic activity and reduced capacity to control RMA-S tumor formation in vivo, despite having normal development and maturation markers. Although AhR was first identified to bind the xenobiotic compound dioxin, AhR is now known to bind a variety of natural exogenous (e.g., dietary) and endogenous ligands. We show that activation of AhR with an endogenous tryptophan derivative, 6-formylindolo[3,2-b]carbazole, potentiates NK cell IFN-γ production and cytolytic activity. Further, administration of 6-formylindolo[3,2-b]carbazole in vivo enhances NK cell control of tumors in an NK cell- and AhR-dependent manner. Finally, similar effects on NK cell potency occur with AhR dietary ligands, potentially explaining the numerous associations that have been observed in the past between diet and NK cell function. Our studies introduce AhR as another regulator of NK cell activity in vivo.
    Proceedings of the National Academy of Sciences 07/2013; 110(30). DOI:10.1073/pnas.1302856110 · 9.81 Impact Factor
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    ABSTRACT: Activation of TLR9 by direct injection of unmethylated CpG nucleotides into a tumor can induce a therapeutic immune response; however, Tregs eventually inhibit the antitumor immune response and thereby limit the power of cancer immunotherapies. In tumor-bearing mice, we found that Tregs within the tumor preferentially express the cell surface markers CTLA-4 and OX40. We show that intratumoral coinjection of anti–CTLA-4 and anti-OX40 together with CpG depleted tumor-infiltrating Tregs. This in situ immunomodulation, which was performed with low doses of antibodies in a single tumor, generated a systemic antitumor immune response that eradicated disseminated disease in mice. Further, this treatment modality was effective against established CNS lymphoma with leptomeningeal metastases, sites that are usually considered to be tumor cell sanctuaries in the context of conventional systemic therapy. These results demonstrate that antitumor immune effectors elicited by local immunomodulation can eradicate tumor cells at distant sites. We propose that, rather than using mAbs to target cancer cells systemically, mAbs could be used to target the tumor infiltrative immune cells locally, thereby eliciting a systemic immune response.
    Journal of Clinical Investigation 05/2013; In Press(6). DOI:10.1172/JCI64859 · 13.77 Impact Factor
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    ABSTRACT: Chronic graft-versus-host disease (GVHD) results in significant morbidity and mortality, limiting the benefit of allogeneic hematopoietic cell transplantation (HCT). Peripheral blood gene expression profiling of the donor immune repertoire following HCT may provide associated genes and pathways thereby improving the pathophysiologic understanding of chronic GVHD. We profiled 70 patients and identified candidate genes that provided mechanistic insight in the biologic pathways that underlie chronic GVHD. Our data revealed that the dominant gene signature in patients with chronic GVHD represented compensatory responses that control inflammation and included the interleukin-1 decoy receptor, IL-1 receptor type II, and genes that were profibrotic and associated with the IL-4, IL-6 and IL-10 signaling pathways. In addition, we identified three genes that were important regulators of extracellular matrix. Validation of this discovery phase study will determine if the identified genes have diagnostic, prognostic or therapeutic implications.
    Clinical Immunology 05/2013; 148(1):124-135. DOI:10.1016/j.clim.2013.04.013 · 3.77 Impact Factor

Publication Stats

1k Citations
511.73 Total Impact Points


  • 2005–2015
    • Stanford University
      • • Division of Oncology
      • • Division of Hematology
      Palo Alto, California, United States
  • 2004–2013
    • Stanford Medicine
      • • Department of Medicine
      • • Division of Oncology
      • • Division of Hematology
      Stanford, California, United States
  • 2012
    • Icahn School of Medicine at Mount Sinai
      Borough of Manhattan, New York, United States
    • Université de Rennes 1
      Roazhon, Brittany, France
  • 2009
    • Indiana Blood and Marrow Transplantation
      Indianapolis, Indiana, United States