The invasion and colonization of oral cavity mucosal tissues by microflora may contribute to the pathophysiology of ulcerative oral mucositis (UOM). Iseganan is an analog of protegrin-1, a naturally ...occurring peptide with broad-spectrum microbicidal activity. A randomized, double-blind, placebo-controlled study was conducted to evaluate the efficacy and safety of iseganan in preventing UOM after stomatotoxic therapy.
Patients received an oral rinse, consisting of iseganan 9
mg or placebo, to be swished/swallowed six times daily, starting with stomatotoxic therapy and continuing up to 21 days. Patients were assessed for stomatitis and UOM, and administered a questionnaire evaluating mouth pain and difficulty swallowing thrice weekly. The primary study efficacy endpoint was the proportion of patients who did not have peak stomatitis NCI-CTC grade ≥2.
Between November 2001 and June 2002, 502 patients were randomized to receive iseganan (251) or placebo (251). Equivalent numbers of patients in both cohorts received bone marrow or peripheral blood allogeneic or autologous stem cell transplantation (SCT). Forty-three percent and 37% of iseganan and placebo patients, respectively, did not have peak stomatitis grade =2 (
P=0.182). There was no significant difference between the cohorts in stomatitis severity, incidence of UOM, peak mouth pain, peak difficulty swallowing, amount of opiate analgesics used, or adverse event type or incidence.
A major impact of Iseganan on reducing stomatitis, UOM, or its clinical sequelae in patients receiving stomatotoxic therapy was not detected on this study.
Microfloral invasion and colonization of oral cavity mucosal tissues contribute to the pathophysiology of ulcerative oral mucositis (UOM). Iseganan is an analog of Protegrin-1, a naturally occurring ...peptide with broad-spectrum microbicidal activity. A randomized, double-blind, placebo-controlled study was conducted to evaluate iseganan in preventing UOM after stomatotoxic therapy. Patients received an oral rinse of iseganan 9 mg or placebo, swished/swallowed 6 times daily, starting with stomatotoxic therapy and continuing for 21-28 days. One hundred sixty three and 160 patients, respectively, were randomized to receive iseganan or placebo. One hundred and two patients (32%) were affected by a drug dispensing error, caused by a flawed computerized allocation system. Among all 323 patients, analyzed according to randomization assignment, 43% and 33% of iseganan and placebo patients, respectively, did not develop UOM (P=0.067). On an 11-point scale, iseganan patients experienced less mouth pain (3.0 and 3.8 {P=0.041}), throat pain (3.8 and 4.6 {P=0.048}), and difficulty swallowing (3.9 and 4.7 {P=0.074}), compared to placebo patients. On the 5-point NCI CTC scale, iseganan patients experienced lower stomatitis scores (1.6 and 2.0 {P=0.013}). Iseganan was well tolerated; no systemic absorption was detected. Iseganan is safe and may be effective in reducing UOM and its clinical sequelae.
Background. Cytomegalovirus (CMV) is a major cause of morbidity in transplant recipients. An immunologic predictor of protection against CMV reactivation or disease is highly desirable. Methods. ...Thirty-eight allogeneic hematopoietic stem cell transplant recipients at risk of CMV disease were prospectively monitored using whole blood CMV-DNA polymerase chain reaction assay, lymphocyte proliferation assay (LPA), interferon γ enzyme-linked immunospot assay (ELISPOT), and flow cytometric enumeration of CMV-specific CD69+interferon (IFN)γ+CD4, CD8, natural killer cells, and γδ T cells. Results. Twenty-one subjects developed ⩾1 episode of CMV viremia and 4 developed disease during 360 days of follow-up. Among CMV-seropositive recipients, positive CMV-LPA before transplantation correlated with higher risk of developing viremia after transplantation (P=.02). In contrast, after transplantation, reconstitution of CMV-LPA was significantly associated with absence of CMV viremia over 360 days of follow-up (P=.04) and with faster clearance of viremia during individual episodes of CMV reactivation (P=.03). Reconstitution of CMV-specific natural killer cells was also associated with absence of CMV viremia over 360 days of study (P=.04) but not with faster clearance of viremia. CMV-specific CD4, CD8, γδ T cells, and ELISPOT values were not significantly different in viremic subjects, compared with the corresponding values in nonviremic subjects, at any time point. Conclusions. To our knowledge, this is the first study to prospectively compare multiple measures of innate and adaptive immune responses in hematopoietic stem cell transplant recipients with CMV viremia. The strongest immune correlates with protection against CMV viremia in hematopoietic stem cell transplant recipients are reconstitution of CMV-specific T cell memory responses (LPA) and recovery of natural killer cell function. In contrast, positive CMV-LPA before transplantation may be a marker of high risk of CMV reactivation after transplantation.
We tested the hypothesis that oral beclomethasone dipropionate (BDP) would control gastrointestinal graft-versus-host disease (GVHD) in patients with anorexia, vomiting, and diarrhea. Patients were ...randomized to prednisone for 10 days and either oral BDP 8 mg/d (n = 62) or placebo (n = 67) tablets for 50 days. At study day 10, prednisone was rapidly tapered while continuing study drug. On an intent-to-treat basis, the risk of GVHD-treatment failure was reduced for the BDP group at study day 50 (hazard ratio HR 0.63, 95% confidence interval CI 0.35-1.13) and at 30 days follow-up (HR 0.55, 95% CI 0.32-0.93). Among patients eligible for prednisone taper at study day 10, the risk of GVHD-treatment failure was significantly reduced at both study days 50 and 80 (HR 0.39 and 0.38, respectively). By day 200 after transplantation, 5 patients randomized to BDP had died compared with 16 deaths on placebo, a 67% reduction in the hazard of mortality (HR 0.33, P = .03). In 47 recipients of unrelated and HLA-mismatched stem cells, mortality at transplantation day 200 was reduced by 91% in the BDP group compared with placebo (HR 0.09, P = .02). The survival benefit was durable to 1 year after randomization. Oral BDP prevents relapses of gastrointestinal GVHD following tapering of prednisone; survival is statistically significantly better among patients receiving BDP.
Abstract PRO131921 is a third-generation, humanized anti-CD20 monoclonal antibody with increased antibody-dependent cytotoxicity and complement-dependent cytotoxicity compared to rituximab. In this ...phase I study, PRO131921 was administered as a single agent to patients with CD20 +, relapsed or refractory, indolent non-Hodgkin lymphoma (NHL) who had been treated with a prior rituximab-containing regimen. The primary aim of this study was safety and tolerability of PRO131921. The secondary aim of the study, and focus of this report, was to determine the pharmacokinetics (PK) profile of PRO131921 and establish a correlation between drug exposure and clinical efficacy. Patients were treated with PRO131921 by intravenous infusion weekly for 4 weeks and the dose was escalated based on safety in a 3 + 3 design. Twenty-four patients were treated with PRO131921 at doses from 25 mg/m2 to 800 mg/m2 . Analysis of PK data demonstrated a correlation between higher normalized drug exposure (normalized AUC) and tumor shrinkage (p = .0035). Also, normalized AUC levels were higher among responders and subjects displaying tumor shrinkage versus subjects progressing or showing no regression (p = 0.030). In conclusion, PRO131921 demonstrated clinical activity in rituximab-relapsed and refractory indolent NHL patients. The observation that higher normalized AUC may be associated with improved clinical responses has potential implications in future trials of monoclonal antibody-based therapies, and emphasizes the importance of early PK studies to optimize antibody efficacy.
A conditional block to transcriptional elongation is an important mechanism for regulating c-myc gene expression. This elongation block within the first c-myc exon was defined originally in mammalian ...cells by nuclear run-on transcription analyses. Subsequent oocyte injection and in vitro transcription analyses suggested that sequences near the end of the first c-myc exon are sites of attenuation and/or premature termination. We report here that the mapping of single stranded DNA in vivo with potassium permanganate (KMnO4) and nuclear run-on transcription assays reveal that polymerase is paused near position +30 relative to the major c-myc transcription initiation site. Deletion of 350 bp, including the sites of 3'-end formation and intrinsic termination defined in oocyte injection and in vitro transcription assays does not affect-the pausing of polymerase in the promoter-proximal region. In addition, sequences upstream of +47 are sufficient to confer the promoter-proximal pausing of polymerases and to generate the polarity of transcription farther downstream. Thus, the promoter-proximal pausing of RNA polymerase II complexes accounts for the block to elongation within the c-myc gene in mammalian cells. We speculate that modification of polymerase complexes at the promoter-proximal pause site may determine whether polymerases can read through intrinsic sites of termination farther downstream.
The repetitive activation of T cells (priming) enhances the expression of many cytokines, such as IL-4, but not others, such as IL-2. Molecular mechanisms underlying selective expression of cytokines ...by T cells remain poorly understood. Here we show that priming of CD4 T cells selectively enhances IL-4 expression relative to IL-2 expression by a transcriptional mechanism involving nuclear factor of activated T cells (NFAT) proteins. As detected by in vivo footprinting, priming markedly increases the activation-dependent engagement of the P0 and P1 NFAT-binding elements of the IL-4 promoter. Moreover, each proximal P element is essential for optimal IL-4 promoter activity. Activated primed CD4 T cells contain more NFAT1 and support greater NFAT-directed transcription than unprimed CD4 T cells, while activator protein 1 binding and activator protein 1-mediated transcription by both cell types is similar. Increased expression of wild-type NFAT1 substantially increases IL-4 promoter activity in unprimed CD4 T cells, suggesting NFAT1 may be limiting for IL-4 gene expression in this cell type. Furthermore, a truncated form of NFAT1 acts as a dominant-negative, reducing IL-4 promoter activity in primed CD4 T cells and confirming the importance of endogenous NFAT to increased IL-4 gene expression by effector T cells. NFAT1 appears to be the major NFAT family member responsible for the initial increased expression of IL-4 by primed CD4 T cells.
The specificity of T lymphocyte activation is determined by engagement of the T cell receptor (TCR) by peptide/major histocompatibility complexes expressed on the antigen-presenting cell (APC). ...Lacking costimulation by accessory molecules on the APC, T cell proliferation does not occur and unresponsiveness to subsequent antigenic stimulus is induced. The B7/BB1 receptor on APCs binds CD28 and CTLA-4 on T cells, and provides a costimulus for T cell proliferation. Here, we show that prolonged, specific T cell hyporesponsiveness to antigenic restimulation is achieved by blocking the interaction between CD28 and B7/BB1 in human mixed leukocyte culture (MLC). Secondary T cell proliferative responses to specific alloantigen were inhibited by addition to the primary culture of monovalent Fab fragments of anti-CD28 monoclonal antibody (mAb) 9.3, which block interaction of CD28 with B7/BB1 without activating T cells. Hypo-responsiveness was also induced in MLC by CTLA4Ig, a chimeric immunoglobulin fusion protein incorporating the extracellular domain of CTLA-4 with high binding avidity for B7/BB1. Cells previously primed could also be made hyporesponsive, if exposed to alloantigen in the presence of CTLA4Ig. Maximal hyporesponsiveness was achieved in MLC after 2 d of incubation with CTLA4Ig, and was maintained for at least 27 d after removal of CTLA4Ig. Accumulation of interleukin 2 (IL-2) and interferon gamma but not IL-4 mRNA was blocked by CTLA4Ig in T cells stimulated by alloantigen. Antigen-specific responses could be restored by addition of exogenous IL-2 at the time of the secondary stimulation. Addition to primary cultures of the intact bivalent anti-CD28 mAb 9.3, or B7/BB1+ transfected CHO cells or exogenous IL-2, abrogated induction of hyporesponsiveness by CTLA4Ig. These data indicate that interaction of CD28 with B7/BB1 during TCR engagement with antigen is required to maintain T cell competence and that blocking such interaction can result in a state of T cell hyporesponsiveness.
Abstract 3742
Poster Board III-678
PRO131921 is a third-generation, humanized anti-CD20 monoclonal antibody engineered to have significantly increased antibody-dependent cytotoxicity and ...complement-dependent cytotoxicity compared to rituximab as shown in in vitro models. In preclinical in vivo lymphoma models, PRO131921 has superior anti-tumor efficacy compared to rituximab. In this Phase I study, PRO131921 was administered as a single agent to patients (pts) with CD20+, relapsed or refractory indolent non-Hodgkin's lymphoma (NHL) who had been treated with a prior rituximab-containing regimen. The aim of the study was to determine the safety and tolerability of PRO131921, the maximum tolerated dose (MTD), its pharmacokinetics (PK), and to establish a Phase II dose. Pts were treated with PRO131921 by intravenous infusion (premedication with acetaminophen and anti-histamine) weekly for 4 weeks on days 1, 8, 15 and 22. The dose of the first infusion was approximately 50% that of subsequent infusions. The dose was escalated based on safety in a 3+3 design. PK samples were obtained pre- and post-infusion on days 1, 8, 15, and 22, and once each on days 2, 23, 29, 50, and 78 (and at later time points for up to a year).
Twenty-four pts were treated with PRO131921 at doses from 25 mg/m2 to 800 mg/m2. Median age was 58 yrs (38-78). Histologies were follicular NHL (n=20), small lymphocytic lymphoma (n=3) or marginal zone NHL (n=1). Pts had received a median of 2 (range 1-6) prior regimens. PRO131921 was generally well-tolerated and no MTD was reached in the study. The most common adverse events were Grade 1 or 2 (CTCAE V3.0) chills, flushing, itching, fatigue, fever, nausea, dizziness, diarrhea, and hypotension, most of which were part of infusion-related reactions limited in general to the first infusion. These responded well to slowing or interruption of the infusion, and symptomatic treatment (including steroids). Grade 3 AEs (related and unrelated to study drug) included 3 episodes each of transient neutropenia and hypoxia, and single episodes of throat tightness, bronchospasm, syncope, fatigue, periarthritis, pneumonia, and deep venous thrombosis. There was 1 unrelated Grade 4 pulmonary embolism. Two pts did not receive all 4 doses of therapy due to DLTs. One dose limiting toxicity (DLT) was observed in the 200/400 mg/m2 dose cohort due to a significant infusion reaction, and a second was observed at the 300/800 mg/m2 dose cohort due to Grade 3 joint pain and fatigue after 2 infusions. Detailed PK studies of PRO131921 in all patients were broadly similar to rituximab with a dose-dependent increase in exposure, but with significant inter- and intra-patient variability. Analysis of PK data demonstrated a correlation between higher normalized drug exposure (normalized AUC) and both tumor shrinkage (p=0.049) and clinical response (p=0.034), consistent with the hypothesis that rapid drug clearance (e.g. by tumor in excess of drug) may result in decreased clinical efficacy. Best investigator-assessed responses to treatment in the 22 evaluable pts by day 78 or later were 6 PR, 13 SD, and 3 PD; 5/10 pts in the two highest dose cohorts responded.
In conclusion, PRO131921 has shown clinical activity in rituximab-relapsed and refractory indolent NHL pts. The observation that higher normalized AUC may be associated with improved clinical responses has potential implications in future trials of monoclonal antibody-based therapies, and emphasizes the importance of early PK studies to optimize antibody efficacy.
Friedberg:Genentech, Inc.: Honoraria, Research Funding. Vose:Genentech, Inc.: Consultancy, Research Funding. Kahl:Genentech, Inc.: Consultancy, Research Funding. Brunvand:Genentech, Inc.: Speakers Bureau. Goy:Genentech/Biogen IDEC: Consultancy, Speakers Bureau. Kasamon:Genentech/Biogen IDEC: Research Funding. Burington:Genentech, Inc.: Employment. Li:Genentech, Inc.: Employment. Ho:Genentech, Inc.: Employment. Cheson:Genentech, Inc.: Consultancy, Speakers Bureau.
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