Kenneth I Weinberg

Stanford Medicine, Stanford, California, United States

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Publications (139)920.96 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Blood and Marrow Transplantation (BMT) is a standard curative therapy for patients with non-malignant genetic diseases. Myeloablative conditioning has been associated with significant regimen related toxicity (RRT), while reduced intensity conditioning regimens have been associated with graft failure. In this prospective pilot trial conducted at two-centers between 2006 and 2013, we report the outcome of patients with non-malignant genetic diseases (n=22) who were conditioned with a novel reduced toxicity regimen: intravenous busulfan (16mg/kg), alemtuzumab (52mg/m2), fludarabine (140mg/m2) and cyclophosphamide (105mg/kg). The median age of the study population was 3.5 years (5 months to 26 years). There were no reported cases of sinusoidal obstruction syndrome (SOS), severe or chronic graft-versus-host-disease (GVHD) or primary graft failure. Median (range) time to neutrophil engraftment (>500 cells/μL) and platelet engraftment (>20K cells/microliter) were 19 (12-50) and 23.5 (14-134) days respectively. The median (range) length of follow-up was 3 (0.2- 6.3) years. Overall survival (OS) was 95% at 100 days (95% confidence interval (CI): 0.72-0.99) and 90% (95% CI: 0.68-0.98) at 6 years. RRT and chronic GVHD are significant barriers to BMT for patients with non-malignant genetic diseases. This alemtuzumab-based reduced toxicity regimen appears promising with durable engraftment, effective cure of clinical disease, low rates of regimen related toxicity and no observed chronic GVHD.
    Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 11/2014;
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    ABSTRACT: Outcomes have improved for pediatric patients undergoing autologous bone marrow transplantation for refractory or relapsed Hodgkin Lymphoma.•Cyclophosphamide, Carmustine (BCNU), and etoposide (VP-16) is an appropriate therapy for patients <21 years old with relapsed or refractory Hodgkin Lymphoma.•Post-transplantation consolidative radiation therapy may improve outcomes following autologous bone marrow transplantation for relapsed or refractory Hodgkin Lymphoma.•Improved outcomes may be due to factors other than improvements in transplant conditioning regimen.
    Biology of Blood and Marrow Transplantation. 10/2014;
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    ABSTRACT: Allogeneic hematopoietic stem cell transplantation (HSCT) for patients with a hemoglobinopathy can be curative but is limited by donor availability. While positive results are frequently observed in those with a HLA matched sibling donor, the use of unrelated donors has been complicated by poor engraftment, excessive regimen-related toxicity and graft-versus-host disease (GVHD). As a potential strategy to address these obstacles, a pilot study was designed that incorporated both a reduced intensity conditioning (RIC) and mesenchymal stromal cells (MSCs). Six patients were enrolled including four with high risk Sickle Cell Disease (SCD) and two with transfusion dependent thalassemia major. Conditioning consisted of Fludarabine (150mg/m2), Melphalan (140mg/m2), and Alemtuzumab (60mg for patients weighing >30kg and 0.9mg/kg for patients weighing <30kg). Two patients received a HLA 7/8 allele matched bone marrow and four received 4-5/6 HLA matched umbilical cord blood (UCB) as the source of HSCs. MSCs were of bone marrow origin and derived from a parent in one patient and unrelated third party donor in the remaining five patients. GVHD prophylaxis consisted of cyclosporine A (CSA) and mycophenolate mofetil (MMF). One patient had neutropenic graft failure, two had autologous hematopoietic recovery and three had hematopoietic recovery with complete chimerism. The two SCD patients with autologous hematopoietic recovery are alive. The remaining four died either from opportunistic infection, GVHD, or intracranial hemorrhage. While there was no infusion-related toxicity, the co-transplantation of MSCs was not sufficient for reliable engraftment in patients with advanced hemoglobinopathy. While poor engraftment has been observed in nearly all such trials to date in this patient population, there was no evidence to suggest that MSC had any positive impact on engraftment. Due to lack of improved engraftment and unacceptably high transplant-related mortality, the study was prematurely terminated. Further investigations into understanding the mechanisms of graft resistance and development of strategies to overcome this barrier are needed to move this field forward.
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 12/2013; · 3.15 Impact Factor
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    ABSTRACT: The Primary Immune Deficiency Treatment Consortium (PIDTC) is a network of 33 centers in North America that study the treatment of rare and severe primary immunodeficiency diseases. Current protocols address the natural history of patients treated for severe combined immunodeficiency (SCID), Wiskott-Aldrich syndrome, and chronic granulomatous disease through retrospective, prospective, and cross-sectional studies. The PIDTC additionally seeks to encourage training of junior investigators, establish partnerships with European and other International colleagues, work with patient advocacy groups to promote community awareness, and conduct pilot demonstration projects. Future goals include the conduct of prospective treatment studies to determine optimal therapies for primary immunodeficiency diseases. To date, the PIDTC has funded 2 pilot projects: newborn screening for SCID in Navajo Native Americans and B-cell reconstitution in patients with SCID after hematopoietic stem cell transplantation. Ten junior investigators have received grant awards. The PIDTC Annual Scientific Workshop has brought together consortium members, outside speakers, patient advocacy groups, and young investigators and trainees to report progress of the protocols and discuss common interests and goals, including new scientific developments and future directions of clinical research. Here we report the progress of the PIDTC to date, highlights of the first 2 PIDTC workshops, and consideration of future consortium objectives.
    The Journal of allergy and clinical immunology 10/2013; · 12.05 Impact Factor
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    ABSTRACT: Multi-center evaluations of pediatric patients with juvenile systemic sclerosis (jSSc) have suggested that the pathogenesis of jSSc may differ from that of systemic sclerosis (SSc) in adult patients. Therefore, we undertook to identify abnormalities in the T lymphocytes of jSSc patients and to determine if they differed from the abnormalities reported in the T lymphocytes of adult SSc patients. We identified decreases in the frequency of resting regulatory T lymphocytes and an increased frequency of CD45RA expressing effector memory (EMRA) CD4 T lymphocytes, which were characterized by an increased frequency of CCR7 protein expressing cells. Neither the increases in the EMRA subpopulation nor the increased CCR7 protein expression have been reported in adult SSc patients. The decrease in resting regulatory T lymphocytes in jSSc patients may permit the expansion of the disease initiating CD4 T lymphocytes present in the CCR7 expressing EMRA CD4 T lymphocyte subpopulation.
    Clinical Immunology 08/2013; 149(1):146-155. · 3.77 Impact Factor
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    ABSTRACT: Besides its cooperating effects on stem cell proliferation and survival, Kit ligand (KL) is a potent chemotactic protein. While transwell assays permit studies of the frequency of migrating cells, the lack of direct visualization precludes dynamic chemotaxis studies. In response, we utilize microfluidic chambers that enable direct observation of murine bone marrow-derived mast cells (BMMC) within stable KL gradients. Using this system, individual Kit+ BMMC were quantitatively analyzed for migration speed and directionality during KL-induced chemotaxis. Our results indicated a minimum activating threshold of ∼3 ng ml(-1) for chemoattraction. Analysis of cells at KL concentrations below 3 ng ml(-1) revealed a paradoxical chemorepulsion, which has not been described previously. Unlike chemoattraction, which occurred continuously after an initial time lag, chemorepulsion occurred only during the first 90 minutes of observation. Both chemoattraction and chemorepulsion required the action of G-protein coupled receptors (GPCR), as treatment with pertussis toxin abrogated directed migration. These results differ from previous studies of GPCR-mediated chemotaxis, where chemorepulsion occurred at high ligand concentrations. These data indicate that Kit-mediated chemotaxis is more complex than previously understood, with the involvement of GPCRs in addition to the Kit receptor tyrosine kinase and the presence of both chemoattractive and chemorepellent phases.
    Integrative Biology 07/2013; · 4.32 Impact Factor
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    ABSTRACT: Thymic involution during aging is a major cause of decreased production of T cells and reduced immunity. Here we show that inactivation of Rb family genes in young mice prevents thymic involution and results in an enlarged thymus competent for increased production of naive T cells. This phenotype originates from the expansion of functional thymic epithelial cells (TECs). In RB family mutant TECs, increased activity of E2F transcription factors drives increased expression of Foxn1, a central regulator of the thymic epithelium. Increased Foxn1 expression is required for the thymic expansion observed in Rb family mutant mice. Thus, the RB family promotes thymic involution and controls T cell production via a bone marrow-independent mechanism, identifying a novel pathway to target to increase thymic function in patients.
    Journal of Experimental Medicine 05/2013; · 13.21 Impact Factor
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    ABSTRACT: We conducted a gene therapy trial in 10 patients with adenosine deaminase-deficient severe combined immunodeficiency (ADA-deficient SCID) using two slightly different retroviral vectors for the transduction of patients' bone marrow CD34+ cells. Four subjects were treated without pre-transplant cytoreduction and remained on ADA enzyme replacement therapy (ERT) throughout the procedure. Only transient (months), low level (<0.01%) gene marking was seen in peripheral blood mononuclear cells (PBMC) of two older subjects (15 and 20 years old), whereas some gene marking of PBMC has persisted for the past nine years in two younger subjects (4 and 6 years). Six additional subjects were treated using the same gene transfer protocol, but after withdrawal of ERT and administration of low-dose busulfan (65-90 mg/m(2)). Three of these remain well, off ERT (5, 4, and 3 years post-procedure), with gene marking in PBMC of 1-10%, and ADA enzyme expression in PBMC near or in the normal range. Two subjects were restarted on ERT due to poor gene marking and immune recovery and one had a subsequent allogeneic hematopoietic stem cell transplant. These studies directly demonstrate the importance of providing non-myeloablative pre-transplant conditioning to achieve therapeutic benefits with gene therapy for ADA-deficient SCID.
    Blood 09/2012; · 9.78 Impact Factor
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    ABSTRACT: The primary cause of poor outcome following allogeneic hematopoietic cell transplantation (HCT) for chronic lymphocytic leukemia (CLL) is disease recurrence. Detection of increasing minimal residual disease (MRD) following HCT may permit early intervention to prevent clinical relapse; however, MRD quantification remains an uncommon diagnostic test because of logistical and financial barriers to widespread use. Here we describe a method for quantifying CLL MRD using widely available consensus primers for amplification of all Ig heavy chain (IGH) genes in a mixture of peripheral blood mononuclear cells, followed by high-throughput sequencing (HTS) for disease-specific IGH sequence quantification. To achieve accurate MRD quantification, we developed a systematic bioinformatic methodology to aggregate cancer clone sequence variants arising from systematic and random artifacts occurring during IGH-HTS. We then compared the sensitivity of IGH-HTS, flow cytometry, and allele-specific oligonucleotide PCR for MRD quantification in 28 samples collected from 6 CLL patients following allogeneic HCT. Using amplimer libraries generated with consensus primers from patient blood samples, we demonstrate the sensitivity of IGH-HTS with 454 pyrosequencing to be 10(-5), with a high correlation between quantification by allele-specific oligonucleotide PCR and IGH-HTS (r = 0.85). From the same dataset used to quantify MRD, IGH-HTS also allowed us to profile IGH repertoire reconstitution after HCT-information not provided by the other MRD methods. IGH-HTS using consensus primers will broaden the availability of MRD quantification in CLL and other B cell malignancies, and this approach has potential for quantitative evaluation of immune diversification following transplant and nontransplant therapies.
    Proceedings of the National Academy of Sciences 12/2011; 108(52):21194-9. · 9.81 Impact Factor
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    ABSTRACT: Autologous hematopoietic stem cell transplantation (HSCT) has been used for the treatment of both adult and pediatric autoimmune diseases. However, HSCT has significant side effects (neutropenia, thrombocytopenia, infertility, cardiotoxicity) and costs (HSC collection/harvesting, blood product support). In an attempt to avoid the toxicities and costs associated with HSCT, we investigated whether immune ablation similar to that achieved following myeloablative HSCT could be achieved by the intensive administration of an anti-CD52 antibody (Campath-1H antibody). The first patient treated with the treatment regime, who had refractory juvenile polymyositis, achieved immune ablation (the elimination of pre-therapy antigen-specific T lymphocyte immunity) and has had stable clinical improvement for more than 6 years.
    Journal of Clinical Immunology 05/2011; 31(4):615-22. · 3.38 Impact Factor
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    ABSTRACT: The decreased ability of the thymus to generate T cells after bone marrow transplantation (BMT) is a clinically significant problem. Interleukin (IL)-7 and stem cell factor (SCF) induce proliferation, differentiation, and survival of thymocytes. Although previous studies have shown that administration of recombinant human IL-7 (rhIL-7) after murine and human BMT improves thymopoiesis and immune function, whether administration of SCF exerts similar effects is unclear. To evaluate independent or combinatorial effects of IL-7 and SCF in post-BMT thymopoiesis, bone marrow (BM)-derived mesenchymal stem cells transduced ex vivo with the rhIL-7 or murine SCF (mSCF) genes were cotransplanted with T cell-depleted BM cells into lethally irradiated mice. Although rhIL-7 and mSCF each improved immune reconstitution, the combination treatment had a significantly greater effect than either cytokine alone. Moreover, the combination treatment significantly increased donor-derived common lymphoid progenitors (CLPs) in BM, suggesting that transplanted CLPs expand more rapidly in response to IL-7 and SCF and may promote immune reconstitution. Our findings demonstrate that IL-7 and SCF might be therapeutically useful for enhancing de novo T cell development. Furthermore, combination therapy may allow the administration of lower doses of IL-7, thereby decreasing the likelihood of IL-7-mediated expansion of mature T cells.
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 01/2011; 17(1):48-60. · 3.15 Impact Factor
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    ABSTRACT: Although the mammalian immune system is generally thought to develop in a linear fashion, findings in avian and murine species argue instead for the developmentally ordered appearance (or "layering") of distinct hematopoietic stem cells (HSCs) that give rise to distinct lymphocyte lineages at different stages of development. Here we provide evidence of an analogous layered immune system in humans. Our results suggest that fetal and adult T cells are distinct populations that arise from different populations of HSCs that are present at different stages of development. We also provide evidence that the fetal T cell lineage is biased toward immune tolerance. These observations offer a mechanistic explanation for the tolerogenic properties of the developing fetus and for variable degrees of immune responsiveness at birth.
    Science 12/2010; 330(6011):1695-9. · 31.20 Impact Factor
  • Journal of Reproductive Immunology - J REPROD IMMUNOL. 01/2010; 86(1):21-21.
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    ABSTRACT: Following hematopoietic stem cell transplantation (HSCT), thymic reconstitution of peripheral T lymphocytes is essential to avoid a chronically immunodeficient state and disease recurrence. The purpose of this study was to determine if children and adolescents with treatment refractory SSc, awaiting HSCT, have sufficient thymic function to reconstitute T lymphocyte function after transplantation. Thirteen children with systemic scleroderma were enrolled and assessed by physical exam, chest MRI, measurement of autoantibodies, B and T cell immuno-phenotyping, and quantization of T cell receptor rearrangement excision circles (TREC) as a marker of thymopoiesis. MRI detected thymic tissue in 9/13 children. TREC levels were detectable in all but one child but were significantly reduced (p<0.001) when compared to a control population. SSc patients also had a reduced percentage of naïve (CD45RA+CD31+) CD4+ T lymphocytes, further indicating diminished thymopoiesis. Our data suggest that thymic function in children with SSc might be insufficient for an adequate immunoreconstitution following transplantation in some patients. A thorough evaluation of immune and thymic functions to identify those patients prior to HSCT is recommended.
    Clinical Immunology 09/2009; 133(3):295-302. · 3.77 Impact Factor
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    ABSTRACT: The pleiotropic receptor tyrosine kinase Kit can provide cytoskeletal signals that define cell shape, positioning, and migration, but the underlying mechanisms are less well understood. In this study, we provide evidence that Kit signals through Wiskott-Aldrich syndrome protein (WASP), the central hematopoietic actin nucleation-promoting factor and regulator of the cytoskeleton. Kit ligand (KL) stimulation resulted in transient tyrosine phosphorylation of WASP, as well as interacting proteins WASP-interacting protein and Arp2/3. KL-induced filopodia in bone marrow-derived mast cells (BMMCs) were significantly decreased in number and size in the absence of WASP. KL-dependent regulation of intracellular Ca(2+) levels was aberrant in WASP-deficient BMMCs. When BMMCs were derived from WASP-heterozygous female mice using KL as a growth factor, the cultures eventually developed from a mixture of WASP-positive and -negative populations into a homogenous WASP-positive culture derived from the WASP-positive progenitors. Thus, WASP expression conferred a selective advantage to the development of Kit-dependent hematopoiesis consistent with the selective advantage of WASP-positive hematopoietic cells observed in WAS-heterozygous female humans. Finally, KL-mediated gene expression in wild-type and WASP-deficient BMMCs was compared and revealed that approximately 30% of all Kit-induced changes were WASP dependent. The results indicate that Kit signaling through WASP is necessary for normal Kit-mediated filopodia formation, cell survival, and gene expression, and provide new insight into the mechanism in which WASP exerts a strong selective pressure in hematopoiesis.
    Blood 08/2009; 114(14):2900-8. · 9.78 Impact Factor
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    Bone marrow transplantation 04/2009; 44(7):449-50. · 3.00 Impact Factor
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    ABSTRACT: Allogeneic hematopoietic stem cell transplantation (HSCT) is a standard treatment for a variety of hematologic conditions. However, very young children may experience different complications of HSCT compared to older patients. The authors retrospectively analyzed the results of 51 transplants performed on children less than 3 years of age between June 1987 and October 2005. Donors were matched-related (n = 21), partially mismatched related (n = 3), and unrelated (n = 27). The majority of patients had one or more grade III organ toxicities, but all nonrelapse deaths were attributable to infection. Perineal dermatitis was found in a large number (73%) of recipients of cyclophosphamide-based conditioning regimens. The 1-year transplant-related mortality (TRM) was 14%, but significantly declined in the more modern period. Grades II-IV acute graft-versus-host-disease (GvHD) was seen in 22% of patients, while chronic extensive GvHD developed in only 7% of patients. Relapse was seen in 40% of transplants performed for a malignant condition, most commonly in those patients not in remission at time of HSCT. The 5-year event-free survival (EFS) and overall survival (OS) were 53 and 64%, respectively. Recipients of fractionated total body irradiation (fTBI) were more likely to have at least one long-term sequelae than patients who received chemotherapy-based regimens (p = .014). These data demonstrate that HSCT can be performed safely in very young children, especially as supportive-care techniques improve. Cyclophosphamide-related perineal dermatitis is a unique complication in very young children. Finally, the incidence of acute and chronic GvHD in this population is low.
    Pediatric Hematology and Oncology 01/2009; 25(8):705-22. · 0.90 Impact Factor
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    ABSTRACT: Hemophagocytic lymphohistiocytosis (HLH) is a rare autosomal recessive disorder of infancy and childhood that is invariably fatal if not treated. We report on the first patient to receive post-natal HSCT for HLH after receiving in utero chemotherapy for disease stabilization.
    Pediatric Blood & Cancer 10/2008; 52(1):139-42. · 2.35 Impact Factor
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    ABSTRACT: Alveolar rhabdomyosarcomas (ARMS) are highly malignant soft-tissue sarcomas that arise in children, adolescents, and young adults. Although formation and expression of the PAX-FKHR fusion genes is thought to be the initiating event in this cancer, the role of PAX-FKHR in the neoplastic process remains largely unknown in a progenitor cell that is undefined. We hypothesize that PAX-FKHR determine the ARMS progenitor to the skeletal muscle lineage, which when coupled to the inactivation and/or activation of critical cell signaling pathways leads to the formation of ARMS. Because a number of studies have proposed that mesenchymal stem cells (MSC) are the progenitor for several of the sarcomas, we tested this hypothesis in MSCs. We show that PAX-FKHR induce skeletal myogenesis in MSCs by transactivating MyoD and myogenin. Despite exhibiting enhanced growth in vitro, the PAX-FKHR-expressing populations do not form colonies in soft agar or tumors in mice. Expression of dominant-negative p53, or the SV40 early region, elicits tumor formation in some of the PAX-FKHR-expressing populations. Additional activation of the Ras signaling pathway leads to highly malignant tumor formation for all of the populations. The PAX-FKHR-expressing tumors were shown to have histologic, immunohistochemical, and gene expression profiles similar to human ARMS. Our results show the critical role played by PAX-FKHR in determining the molecular, myogenic, and histologic phenotype of ARMS. More importantly, we identify MSCs as a progenitor that can give rise to ARMS.
    Cancer Research 09/2008; 68(16):6587-97. · 9.28 Impact Factor
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    ABSTRACT: This study was undertaken to investigate possible immune mechanisms in fatal herpes simplex virus type 1 (HSV-1) encephalitis (HSE) after HSV-1 corneal inoculation. Susceptible 129S6 (129) but not resistant C57BL/6 (B6) mice developed intense focal inflammatory brain stem lesions of primarily F4/80(+) macrophages and Gr-1(+) neutrophils detectable by magnetic resonance imaging as early as day 6 postinfection (p.i.). Depletion of macrophages and neutrophils significantly enhanced the survival of infected 129 mice. Immunodeficient B6 (IL-7R(-/-) Kit(w41/w41)) mice lacking adaptive cells (B6-E mice) and transplanted with 129 bone marrow showed significantly accelerated fatal HSE compared to B6-E mice transplanted with B6 marrow or control nontransplanted B6-E mice. In contrast, there was no difference in ocular viral shedding in B6-E mice transplanted with 129 or B6 bone marrow. Acyclovir treatment of 129 mice beginning on day 4 p.i. (24 h after HSV-1 first reaches the brain stem) reduced nervous system viral titers to undetectable levels but did not alter brain stem inflammation or mortality. We conclude that fatal HSE in 129 mice results from widespread damage in the brain stem caused by destructive inflammatory responses initiated early in infection by massive infiltration of innate cells.
    Journal of Virology 08/2008; 82(14):7078-88. · 5.08 Impact Factor

Publication Stats

5k Citations
920.96 Total Impact Points


  • 2008–2014
    • Stanford Medicine
      • Department of Pediatrics
      Stanford, California, United States
    • Childrens Hospital of Pittsburgh
      • Department of Pediatrics
      Pittsburgh, PA, United States
  • 1990–2013
    • Children's Hospital Los Angeles
      • • Division of Rheumatology
      • • Department of Pediatrics
      • • Division of Bone Marrow Transplant/Research Immunology
      • • Division of Hematology-Oncology
      Los Angeles, California, United States
  • 2012
    • National Human Genome Research Institute
      Maryland, United States
  • 2007–2011
    • Stanford University
      • • Division of Blood and Marrow Transplantation
      • • Department of Pediatrics
      Stanford, CA, United States
    • Baylor College of Medicine
      Houston, Texas, United States
    • The EMMES Corporation
      Maryland, United States
    • University of California, Davis
      • School of Veterinary Medicine
      Davis, CA, United States
  • 1990–2007
    • University of California, Los Angeles
      • Department of Pediatrics
      Los Angeles, CA, United States
  • 2002–2006
    • University of Pennsylvania
      • • Department of Pathobiology
      • • School of Veterinary Medicine
      Philadelphia, PA, United States
    • Boston Children's Hospital
      • Division of Genetics
      Boston, MA, United States
  • 2004
    • Duke University
      Durham, North Carolina, United States
  • 1989–2003
    • University of Southern California
      • • Department of Molecular Microbiology and Immunology
      • • Department of Biochemistry and Molecular Biology
      • • Division of Hematology
      • • Department of Medicine
      Los Angeles, California, United States
  • 1990–2002
    • Wolfson Childrens Hospital
      Jacksonville, Florida, United States