Ronald D Alvarez

Oklahoma City University, Oklahoma City, Oklahoma, United States

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Publications (272)1140.14 Total impact

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    ABSTRACT: To investigate whether tumor cells could be detected in the vagina of women with serous ovarian cancer through TP53 analysis of DNA samples collected by placement of a vaginal tampon. Women undergoing surgery for a pelvic mass were identified in the gynecologic oncology clinic. They placed a vaginal tampon before surgery, which was removed in the operating room. Cells were isolated and DNA was extracted from both the cells trapped within the tampon and the primary tumor. In patients with serous carcinoma, the DNA was interrogated for the presence of TP53 mutations using a method capable of detecting rare mutant alleles in a mixture of mutant and wild-type DNA. Thirty-three patients were enrolled. Eight patients with advanced serous ovarian cancer were included for analysis. Three had a prior tubal ligation. TP53 mutations were identified in all eight tumor samples. Analysis of the DNA from the tampons revealed mutations in three of the five patients with intact tubes (sensitivity 60%) and in none of the three patients with tubal ligation. In all three participants with mutation detected in the tampon specimen, the tumor and the vaginal DNA harbored the exact same TP53 mutation. The fraction of DNA derived from exfoliated tumor cells ranged from 0.01% to 0.07%. In this pilot study, DNA derived from tumor was detected in the vaginas of 60% of patients with ovarian cancer with intact fallopian tubes. With further development, this approach may hold promise for the early detection of this deadly disease. : III.
    Obstetrics and gynecology. 11/2014; 124(5):881-5.
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    ABSTRACT: AbstractA significant limiting factor to the human clinical application of conditionally replicative adenovirus (CRAd)-based virotherapy is the inability to noninvasively monitor these agents and their potential persistence. To address this issue, we proposed a novel imaging approach that combines transient expression of the human somatostatin receptor (SSTR) subtype 2 reporter gene with genetic labeling of the viral capsid with mCherry fluorescent protein. To test this dual modality system, we constructed the Ad5/3Δ24pIXcherry/SSTR CRAd and validated its capacity to generate fluorescent and nuclear signals in vitro and following intratumoral injection. Analysis of 64Cu-CB-TE2A-Y3-TATE biodistribution in mice revealed reduced uptake in tumors injected with the imaging CRAd relative to the replication-incompetent, Ad-expressing SSTR2 but significantly greater uptake compared to the negative CRAd control. Optical imaging demonstrated relative correlation of fluorescent signal with virus replication as determined by viral genome quantification in tumors. Positron emission tomography/computed tomography studies demonstrated that we can visualize radioactive uptake in tumors injected with imaging CRAd and the trend for greater uptake by standardized uptake value analysis compared to control CRAd. In the aggregate, the plasticity of our dual imaging approach should provide the technical basis for monitoring CRAd biodistribution and persistence in preclinical studies while offering potential utility for a range of clinical applications.
    Molecular imaging. 09/2014; 13:1-19.
  • Ronald D. Alvarez
    Gynecologic Oncology. 09/2014; 134(3):445–446.
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    ABSTRACT: We previously reported that a higher degree of methylation of CpG sites in the promoter (positions 31, 37, 43, 52 and 58) and enhancer site 7862 of HPV 16 was associated with a lower likelihood of being diagnosed with HPV 16-associated CIN 2+. The purpose of the current study was to replicate our previous findings and in addition to evaluate the influence of plasma concentrations of folate and vitamin B12 on the degree of HPV 16 methylation (HPV 16m). The study included 315 HPV 16 positive women diagnosed with either CIN 2+ or ≤ CIN 1. Pyrosequencing technology was used to quantify the degree of HPV 16m. We reproduced the previously reported inverse association between HPV 16m and risk of being diagnosed with CIN 2+. In addition, we observed that women with higher plasma folate and higher HPV 16m or those with higher plasma vitamin B12 and higher HPV 16m were 75% (P<0.01) and 60% (P=0.02) less likely to be diagnosed with CIN 2+, respectively. With a tertile increase in the plasma folate or vitamin B12, there was a 50% (P=0.03) and 40% (P=0.07) increase in the odds of having a higher degree of HPV 16m, respectively. The present study provides initial evidence that methyl donor micronutrients, folate and vitamin B12, may play an important role in maintaining a desirably high degree of methylation at specific CpG sites in the HPV E6 promoter and enhancer that are associated with the likelihood of being diagnosed with CIN 2+.
    Cancer prevention research (Philadelphia, Pa.). 08/2014;
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    ABSTRACT: A cornerstone of preclinical cancer research has been the use of clonal cell lines. However, this resource has underperformed in its ability to effectively identify novel therapeutics and evaluate the heterogeneity in a patient's tumor. The patient-derived xenograft (PDX) model retains the heterogeneity of patient tumors, allowing a means to not only examine efficacy of a therapy, but also basic tenets of cancer biology in response to treatment. Herein we describe the development and characterization of an ovarian-PDX model in order to study the development of chemoresistance. We demonstrate that PDX tumors are not simply composed of tumor-initiating cells, but recapitulate the original tumor's heterogeneity, oncogene expression profiles, and clinical response to chemotherapy. Combined carboplatin/paclitaxel treatment of PDX tumors enriches the cancer stem cell populations, but persistent tumors are not entirely composed of these populations. RNA-Seq analysis of six pair of treated PDX tumors compared to untreated tumors demonstrates a consistently contrasting genetic profile after therapy, suggesting similar, but few, pathways are mediating chemoresistance. Pathways and genes identified by this methodology represent novel approaches to targeting the chemoresistant population in ovarian cancer.
    Oncotarget 08/2014; · 6.64 Impact Factor
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    ABSTRACT: The Wnt/β-catenin pathway is known to regulate cellular proliferation and plays a role in chemoresistance. Niclosamide, an FDA approved salicyclamide derivative used for the treatment of tapeworm infections, targets the Wnt/β-catenin pathway. Therefore, the objective of this study was to investigate niclosamide as a potential therapeutic agent for ovarian cancer. Tumor cells isolated from 34 patients' ascites with primary ovarian cancer were treated with niclosamide (0.1 to 5μM)±carboplatin (5 to 150μM). Cell viability was assessed using the ATP-lite assay. LRP6, Axin 2, Cyclin D1, survivin and cytosolic free β-catenin levels were determined using Western blot analysis. Tumorspheres were treated, and Wnt transcriptional activity was measured by the TOPflash reporter assay. ALDH and CD133 were analyzed by Flow cytometry and IHC. ALDH1A1 and LRP6 were analyzed by IHC in solid tumor and in ascites before and after treatment with niclosamide. Combination treatment produced increased cytotoxicity compared to single agent treatment in 32/34 patient samples. Western blot analysis showed a decrease in Wnt/ß-catenin pathway proteins and the expression of target genes. A significant reduction of Wnt/β-catenin signaling was confirmed by TOPflash assay. There was increased staining of ALDH1A1 and LRP6 in ascites compared to solid tumor which decreased after treatment. This study demonstrates that niclosamide is a potent Wnt/β-catenin inhibitor. Targeting the Wnt/ß-catenin pathway led to decreased cellular proliferation and increased cell death. These findings warrant further research of this drug and other niclosamide analogs as a treatment option for ovarian cancer.
    Gynecologic Oncology 04/2014; · 3.93 Impact Factor
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    ABSTRACT: The purpose of this phase II trial was to evaluate the toxicity and antitumor activity of EGEN-001 in platinum resistant recurrent ovarian cancer. Eligible patients had weekly IP infusion of EGEN-001 at a dose of 24mg/m(2). Toxicity and antitumor activity were evaluated using CTCAE and RESIST criteria, respectively. Co-primary endpoints were tumor response and survival without progression (PFS) for at least 6months. Survival without progression before going onto a subsequent therapy (EFS) for at least six months was also considered. A total of 58 EGEN-001cycles were administered to 20/ 22 enrolled patients (median 2cycles, range 1-9). The most frequently associated adverse events related specifically to EGEN-001 treatment were grade 1/2 fatigue, fever, chills, abdominal pain, nausea, vomiting, anemia, thrombocytopenia, and leukopenia. Three of 20 EGEN-001 treated patients evaluable for toxicity elected to withdraw from the study motivated in part by grade 1 treatment related toxicities. There were no patients with partial or complete response (0%; 90% CI 0~10.9%). Seven (35%) of 16 patients evaluable for response had stable disease, and 9 (45%) had progressive disease. Six (30%) patients had a PFS of greater than six months, although three had gone off study and onto other therapies before six months. The estimated six-month EFS was 15%. The median PFS and OS was 2.89 and 9.17months, respectively. EGEN-001 at the dose and schedule evaluated was associated with some but limited activity and was seemingly less tolerated in platinum resistant recurrent ovarian cancer patients.
    Gynecologic Oncology 04/2014; · 3.93 Impact Factor
  • Ronald D. Alvarez
    Gynecologic Oncology 04/2014; 133(1):98–99. · 3.93 Impact Factor
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    ABSTRACT: Human papillomavirus (HPV) infections are particularly problematic for HIV + and solid organ transplant patients with compromised CD4+ T cell-dependent immunity as they produce more severe and progressive disease compared to healthy individuals. There are no specific treatments for chronic HPV infection, resulting in an urgent unmet need for a modality that is safe and effective for both immunocompromised and otherwise normal patients with recalcitrant disease. DNA vaccination is attractive because it avoids the risks of administration of live vectors to immunocompromised patients, and can induce potent HPV-specific cytotoxic T cell responses. We have developed a DNA vaccine (pNGVL4a-hCRTE6E7L2) encoding calreticulin (CRT) fused to E6, E7 and L2 proteins of HPV-16, the genotype associated with approximately 90% vaginal, vulvar, anal, penile and oropharyngeal HPV-associated cancers and the majority of cervical cancers. Administration of the DNA vaccine by intramuscular (IM) injection followed by electroporation induced significantly greater HPV-specific immune responses compared to IM injection alone or mixed with alum. Furthermore, pNGVL4a-hCRTE6E7L2 DNA vaccination via electroporation of mice carrying an intravaginal HPV-16 E6/E7-expressing syngeneic tumor demonstrated more potent therapeutic effects than IM vaccination alone. Of note, administration of the DNA vaccine by IM injection followed by electroporation elicited potent E6 and E7-specific CD8+ T cell responses and antitumor effects despite CD4+ T cell-depletion, although no antibody response was detected. While CD4+ T cell-depletion did reduce the E6 and E7-specific CD8+ T cell response, it remained sufficient to prevent subcutaneous tumor growth and to eliminate circulating tumor cells in a model of metastatic HPV-16+ cancer. Thus, the antibody response was CD4-dependent, whereas CD4+ T cell help enhanced the E6/E7-specific CD8+ T cell immunity, but was not required. Taken together, our data suggest that pNGVL4a-hCRTE6E7L2 DNA vaccination via electroporation warrants testing in otherwise healthy patients and those with compromised CD4+ T cell immunity to treat HPV-16-associated anogenital disease and cancer.
    Cell & bioscience. 03/2014; 4(1):11.
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    ABSTRACT: Objective To explore and facilitate the multifaceted process of drug development and regulatory approval in ovarian cancer. Methods The Society of Gynecologic Oncology (SGO) recently sought and received input from multiple stakeholders including the National Cancer Institute’s (NCI) Clinical Therapy Evaluation Program (CTEP), the Food and Drug Administration (FDA), pharmaceutical industry, and patient advocates. This whitepaper is the work product and opinion solely of the SGO. Results This document summarizes the SGO’s interpretation of these meetings and the current regulatory environment where there has been a paucity of recent approvals in the United States. It provides guidance in clinical trial design with the express purpose of encouraging novel drug development in ovarian cancer. Points of emphasis include: ovarian cancer heterogeneity (histologic subtypes and molecular genetic alterations), clinical trial design elements, surrogate as well as composite endpoints, and the four principles of clinical drug development (unmet medical need, discovery, safety, and efficacy). Conclusions There has been an evolution in the acceptance of surrogate endpoints depending upon the clinical setting in ovarian cancer. While overall survival (OS) remains the most objective clinical trial endpoint, there is now realization that demanding OS as the primary endpoint has many obstacles. Ovarian cancer is a heterogeneous disease that is now divided by histologic subtypes. Future registration strategies will need to address disease heterogeneity. Exploration of currently acceptable clinical trial endpoints and alternative regulatory strategies will hopefully stimulate interest in novel drug development for patients with ovarian cancer.
    Gynecologic Oncology. 01/2014;
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    ABSTRACT: Objective BRCA-positive ovarian cancer patients derive benefit PARP inhibitors. Approximately 50% of ovarian cancer tumors have homologous recombination (HR) deficiencies and are therefore “BRCA-like,” possibly rendering them sensitive to PARP inhibition. However, no predictive assay exists to identify these patients. We sought to determine if irradiation-induced Rad51 foci formation, a known marker of HR, correlated to PARP inhibitor response in an ovarian cancer model. Methods Ovarian cancer cell lines were exposed to PARP-inhibitor ABT-888 to determine effect on growth. Rad51 protein expression prior to irradiation was determined via Western blot. Cultured cells and patient-derived xenograft tumors (PDX) were irradiated and probed for Rad51 foci. In vivo PDX tumors were treated with ABT-888 and carboplatin; these results were correlated with the ex vivo ionizing radiation assay. Results Three of seven cell lines were sensitive to ABT-888. Sensitive lines had the lowest Rad51 foci formation rate after irradiation, indicating functional HR deficiency. Approximately 50% of the PDX samples had decreased Rad51 foci formation. Total Rad51 protein levels were consistently low, suggesting DNA damage induction is required to characterize HR status. The ex vivo IR assay accurately predicted which PDX models were sensitive to PARP inhibition in vitro and in vivo. ABT-888 alone reduced orthotopic tumor growth by 51% in A2780ip2 cell line, predicted to respond by the ex vivo assay. Three PDX models’ response also correlated with the assay. Conclusions The ex vivo IR assay correlates with response to PARP inhibition. Analysis of total Rad51 protein is not a reliable substitute.
    Gynecologic Oncology. 01/2014;
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    ABSTRACT: Abstract Purpose: Study distribution, pharmacokinetics, and safety of intraperitoneal (IP) (212)Pb-TCMC-trastuzumab in patients with HER-2-expressing malignancy. Experimental Design: IP (212)Pb-TCMC-trastuzumab was delivered, after 4 mg/kg intravenous (IV) trastuzumab, to 3 patients with HER-2-expressing cancer who had failed standard therapies. Patients were monitored for toxicity and pharmacokinetics/dosimetry parameters. Results: Imaging studies after 0.2 mCi/m(2) (7.4 MBq/m(2)) show little redistribution out of the peritoneal cavity and no significant uptake in major organs. Peak blood level of the radiolabeled antibody, determined by decay corrected counts, was <23% injected dose at 63 hours; maximum blood radioactivity concentration was 6.3nCi/mL at 18 hours. Cumulative urinary excretion was ≤6% in 2.3 half-lives. The maximum external exposure rate immediately post-infusion at skin contact over the abdomen averaged 7.67 mR/h and dropped to 0.67 mR/h by 24 hours. The exposure rates at the other positions monitored (axilla, chest, and femur) decreased as a function of distance from the abdomen. The data points correlate closely with (212)Pb physical decay (T1/2=10.6 hours). Follow-up >6 months showed no evidence of agent-related toxicity. Conclusions: Pharmacokinetics and imaging after 0.2 mCi/m(2) IP (212)Pb-TCMC-trastuzumab in patients with HER-2-expressing malignancy showed minimal distribution outside the peritoneal cavity, ≤6% urinary excretion, and good tolerance.
    Cancer Biotherapy & Radiopharmaceuticals 12/2013; 29(1):12. · 1.44 Impact Factor
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    ABSTRACT: Radiation therapy (RT) kills cancer cells by causing DNA damage, and stimulates a systemic antitumor immune response by releasing tumor antigen and endogenous adjuvant within the tumor microenvironment. However, RT also induces the recruitment of immunosuppressive myeloid cells, which can interfere with the antitumor immune responses elicited by apoptotic tumor cells. We hypothesized that local delivery of vaccine following RT will lead to the priming of antigen-specific cytotoxic T lymphocyte (CTL) immune responses and render immunosuppressive myeloid cells susceptible to killing by the activated CTLs. Using several antigenic systems, we tested whether intratumoral injection of antigenic peptide/protein in irradiated tumors would be able to prime CTLs as well as load myeloid cells with antigen, rendering them susceptible to antigen-specific CTL killing. We show that by combining RT and targeted antigenic peptide delivery to the tumor, the adjuvant effect generated by RT itself was sufficient to elicit the priming and expansion of antigen-specific CTLs, through the type I interferon dependent pathway, leading to synergistic therapeutic antitumor effects compared to either treatment alone. In addition, using two different types of transgenic mice, we demonstrated that CTL-mediated killing of stromal cells in tumors by our approach is important for tumor control. Finally, we confirmed the efficacy of this approach in our preclinical model using two clinically tested therapeutic HPV vaccines. These data serve as an important foundation for the future clinical translation of RT combined with a clinically tested therapeutic HPV vaccine for the control of HPV-associated cancers.
    Clinical Cancer Research 12/2013; · 7.84 Impact Factor
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    ABSTRACT: Clinical trial endpoints have profound effects on late phase clinical trial design, results interpretation, drug development, and regulatory approval of therapeutics. Selection of the optimal clinical trial endpoint is particularly provocative in ovarian cancer where long overall survival (OS) is observed even for those who present with advanced disease stages. The lack of new regulatory approvals and the lack of harmony between regulatory bodies globally for ovarian cancer therapeutics are of concern. The advantages and disadvantages of the numerous endpoints available are herein discussed within the unique context of ovarian cancer where both crossover and post-progression therapies potentially uncouple the surrogacy between progression-free survival (PFS) and OS, the two most widely supported and utilized endpoints. The roles of patient reported outcomes (PRO) and health related quality of life (HRQoL) are discussed, but even these widely supported parameters are affected by the unique characteristics of ovarian cancer where a significant percentage of patients may be asymptomatic. Original data regarding the endpoint preferences of ovarian cancer advocates is presented. Endpoint selection in ovarian cancer clinical trials should reflect the impact on disease burden and unique characteristics of the treatment cohort while reflecting true patient benefit. Both OS and PFS have led to regulatory approvals and are clinically important. However, current regulatory approval guidance by the FDA indicates that surrogates for overall survival, while acceptable, must be clinically meaningful. OS remains the most objective and accepted endpoint because it is least vulnerable to bias; however, the feasibility of OS in ovarian cancer is compromised by the requirement for large trial size, prolonged time-line for final analysis, and potential for unintended loss of treatment effect from active post-progression therapies. A large magnitude of effect in PFS improvement should establish benefit, and further communication with regulatory authorities to clarify acceptable endpoints should be undertaken.
    Gynecologic Oncology 11/2013; · 3.93 Impact Factor
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    ABSTRACT: These NCCN Guidelines Insights focus on the major updates to the 2013 NCCN Guidelines for Ovarian Cancer. Four updates were selected based on recent important updates in the guidelines and on debate among panel members about recent clinical trials. The topics include 1) intraperitoneal chemotherapy, 2) CA-125 monitoring for ovarian cancer recurrence, 3) surveillance recommendations for less common ovarian histopathologies, and 4) recent changes in therapy for recurrent epithelial ovarian cancer. These NCCN Guidelines Insights also discuss why some recommendations were not made.
    Journal of the National Comprehensive Cancer Network: JNCCN 10/2013; 11(10):1199-209. · 5.11 Impact Factor
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    ABSTRACT: The primary objective of this study was to evaluate the safety and tolerability of a formulated IL-12 plasmid administered intraperitoneally (IP) in conjunction with intravenous (IV) carboplatin/docetaxel in platinum-sensitive ovarian cancer patients. Escalating doses of IL-12 plasmid (phIL-12) formulated with the lipopolymer PEG-PEI-Cholesterol (PPC) were administered IP every 10-11 days for a total of four treatments and the highest dose was expanded to eight treatments. Patients also received IV carboplatin (AUC 5) and docetaxel (75 mg/m(2)) every 21 days. Patients were followed for safety, biological activity and antitumor activity after phIL-12/PPC treatment. All 13 patients enrolled in the study received both phIL-12/PPC and chemotherapy treatment. There were 49 plasmid-associated adverse events (AEs). The most common AEs were abdominal pain, transient hypotension, low grade fever, catheter site pain, chills, dysgeusia, infusion related reaction, and nausea. These AEs appeared to be plasmid dose related. Grade 3 AEs included manageable abdominal pain and cytokine release syndrome. There were no dose limiting toxicities and the plasmid treatment did not augment the chemotherapy-associated adverse events. The best overall antitumor response (17% CR, 33% PR, 42% SD and 8% PD) was typical of the patient population enrolled for the study. Translational studies showed rise in IFN-γ and TNF-α concentrations in a dose dependent manner. The escalating doses and cycles of intraperitoneal phIL-12/PPC when combined with carboplatin/docetaxel chemotherapy in recurrent ovarian cancer patients were well tolerated and did not appear to exacerbate the side effects or attenuate the efficacy of the chemotherapy treatment.
    Gynecologic Oncology 07/2013; · 3.93 Impact Factor
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    ABSTRACT: The goal of this report is to review the activity of promising antifolate and folate receptor agents being developed for ovarian cancer including thymidylate synthetase inhibitors, antifolate receptor antibodies, and folate-chemotherapy conjugates. A literature search was performed over the last 5 years using the terms "folate receptor" and "ovarian cancer" and those that specifically addressed the MOA were included. Abstracts presented within the last 3 years were also searched and included in this review where appropriate. Thymidylate synthetase inhibitors are a promising avenue for ovarian cancer treatment. Phase II trials have shown pemetrexed to have activity in patients with platinum resistant ovarian cancer. Several other thymidylate synthetase inhibitors are in the early phase of development including BGC 945 and ZD-9331. Monoclonal antibodies that target the folate receptor have also shown great potential in the development of ovarian cancer therapies. Farletuzumab is one of these antibodies. A recent phase III trial found that farletuzumab in combination with carboplatin and a taxane did not meet the study's primary endpoint of progression-free survival (PFS). The post hoc exploratory analysis showed, however, a trend toward improved PFS in some patient subsets and further analysis is ongoing. The folate receptor is also utilized through folate conjugates. Vintafolide is one such agent which is currently in phase III development. Encouraging data from phase II trials showed an improvement in PFS from 2.7mo to 5mo. Folate can also be conjugated to radioisotopes for both therapeutic and imaging purposes, and early studies have shown correlation with amount of disease to therapy response. Folate targeted agents continue to show promising antitumor activity in ovarian malignancy and initial clinical experience has demonstrated favorable toxicity profiles. Further development and resources targeted towards these therapies appear to be warranted.
    Gynecologic Oncology 07/2013; · 3.93 Impact Factor
  • R. Coleman, R. Alvarez, T. Herzog
    Gynecologic Oncology. 07/2013; 130(1):e13.
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    ABSTRACT: OBJECTIVE: The conditionally replicative adenovirus Ad5/3-Δ24 has a type-3 knob incorporated into the type-5 fiber that facilitates enhanced ovarian cancer infectivity. Preclinical studies have shown that Ad5/3-Δ24 achieves significant oncolysis and anti-tumor activity in ovarian cancer models. The purpose of this study was to evaluate in a Phase I trial the feasibility and safety of intraperitoneal (IP) Ad5/3-Δ24 in recurrent ovarian cancer patients. METHODS: Eligible patients were treated with IP Ad5/3-Δ24 for 3 consecutive days in one of three dose cohorts ranging 1 x 10(10)-1 x 10(12) vp. Toxicity was assessed utilizing CTC grading and efficacy with RECIST. Ascites, serum, and other samples were obtained to evaluate gene transfer, generation of wildtype virus, viral shedding, and antibody response. RESULTS: Nine of 10 patients completed treatment per protocol. A total of 15 vector-related adverse events were experienced in 5 patients. These events included fever or chills, nausea, fatigue, and myalgia. All were grade 1-2 in nature, transient, and medically managed. Of the 8 treated patients evaluable for response, six patients had stable disease and 2 patients had progressive disease. Three patients had decreased CA-125 from pretreatment levels one month after treatment. Ancillary biologic studies indicated Ad5/3-Δ24 replication in patients in the higher dose cohorts. All patients experienced an anti-adenoviral neutralizing antibody effect. CONCLUSIONS: This study suggests the feasibility and safety of a serotype chimeric infectivity-enhanced CRAd, Ad5/3-Δ24, as a potential therapeutic option for recurrent ovarian cancer patients.
    Gynecologic Oncology 06/2013; · 3.93 Impact Factor
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    ABSTRACT: We have previously created a potent DNA vaccine encoding calreticulin linked to the human papillomavirus (HPV) oncogenic protein E7 (CRT/E7). While treatment with the CRT/E7 DNA vaccine generates significant tumor-specific immune responses in vaccinated mice, the potency with the DNA vaccine could potentially be improved by co-administration of a histone deacetylase inhibitor (HDACi) as HDACi has been shown to increase the expression of MHC class I and II molecules. Thus, we aimed to determine whether co-administration of a novel HDACi, AR-42, with therapeutic HPV DNA vaccines could improve the activation of HPV antigen-specific CD8(+) T cells, resulting in potent therapeutic antitumor effects. To do so, HPV-16 E7-expressing murine TC-1 tumor-bearing mice were treated orally with AR-42 and/or CRT/E7 DNA vaccine via gene gun. Mice were monitored for E7-specific CD8(+) T cell immune responses and antitumor effects. TC-1 tumor-bearing mice treated with AR-42 and CRT/E7 DNA vaccine experienced longer survival, decreased tumor growth, and enhanced E7-specific immune response compared to mice treated with AR-42 or CRT/E7 DNA vaccine alone. Additionally, treatment of TC-1 cells with AR-42 increased the surface expression of MHC class I molecules and increased the susceptibility of tumor cells to the cytotoxicity of E7-specific T cells. This study indicates the ability of AR-42 to significantly enhance the potency of the CRT/E7 DNA vaccine by improving tumor-specific immune responses and antitumor effects. Both AR-42 and CRT/E7 DNA vaccines have been used in independent clinical trials; the current study serves as foundation for future clinical trials combining both treatments in cervical cancer therapy. KEY MESSAGE: AR-42, a novel HDAC inhibitor, enhances potency of therapeutic HPV DNA vaccines AR-42 treatment leads to strong E7-specific CD8+ T cell immune responses AR-42 improves tumor-specific immunity and antitumor effects elicited by HPV DNA vaccine AR-42 is more potent than clinically available HDACi in combination with HPV DNA vaccine.
    Journal of Molecular Medicine 05/2013; · 4.77 Impact Factor

Publication Stats

6k Citations
1,140.14 Total Impact Points

Institutions

  • 2014
    • Oklahoma City University
      Oklahoma City, Oklahoma, United States
  • 1987–2014
    • University of Alabama at Birmingham
      • • Division of Gynecologic Oncology
      • • Department of Obstetrics and Gynecology
      • • Department of Medicine
      • • Department of Pathology
      Birmingham, Alabama, United States
  • 2013
    • University of Alabama in Huntsville
      Huntsville, Alabama, United States
  • 2008–2013
    • Johns Hopkins Medicine
      • Department of Pathology
      Baltimore, MD, United States
    • Johns Hopkins University
      • Department of Pathology
      Baltimore, MD, United States
    • University of South Alabama
      • Department of Obstetrics and Gynecology
      Mobile, AL, United States
  • 2004–2013
    • Columbia University
      • College of Physicians and Surgeons
      New York City, New York, United States
  • 2009
    • Alpert Medical School - Brown University
      Providence, Rhode Island, United States
  • 2007
    • Southern Research Institute
      Birmingham, Alabama, United States
  • 2003–2006
    • National Cancer Institute (USA)
      • • Division of Cancer Treatment and Diagnosis
      • • Cancer Therapy Evaluation Program
      Bethesda, MD, United States
  • 2002
    • Arizona Research Center
      Phoenix, Arizona, United States
  • 2001
    • Cornell University
      • Department of Obstetrics and Gynecology
      Ithaca, NY, United States
  • 1994
    • Carolinas Medical Center University
      Charlotte, North Carolina, United States
  • 1989
    • Mayo Clinic - Rochester
      • Department of Obstetrics & Gynecology
      Rochester, Minnesota, United States