Kenneth Cornetta

Indiana University-Purdue University Indianapolis, Indianapolis, Indiana, United States

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Publications (170)909.34 Total impact

  • 06/2014; 2(2):195-210. DOI:10.3390/biomedicines2020195
  • Annual Conference of the British-Society-for-Gene-and-Cell-Therapy; 05/2014
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    ABSTRACT: It has been demonstrated that large numbers of tumor-specific T cells for adoptive cell transfer (ACT) can be manufactured by retroviral genetic engineering of autologous peripheral blood lymphocytes and expanding them over several weeks. In mouse models, this therapy is optimized when administered with dendritic cell (DC) vaccination. We developed a short one-week manufacture protocol to determine the feasibility, safety and antitumor efficacy of this double cell therapy. A clinical trial (NCT00910650) adoptively transferring MART-1 T cell receptor (TCR) transgenic lymphocytes together with MART-1 peptide pulsed DC vaccination in HLA-A2.1 patients with metastatic melanoma. Autologous TCR transgenic cells were manufactured in 6 to 7 days using retroviral vector gene transfer, and re-infused with (n = 10) or without (n = 3) prior cryopreservation. 14 patients with metastatic melanoma were enrolled and nine out of 13 treated patients (69%) showed evidence of tumor regression. Peripheral blood reconstitution with MART-1-specific T cells peaked within two weeks of ACT indicating rapid in vivo expansion. Administration of freshly manufactured TCR transgenic T cells resulted in a higher persistence of MART-1-specific T cells in the blood as compared to cryopreserved. Evidence that DC vaccination could cause further in vivo expansion was only observed with ACT using non-cryopreserved T cells. Double cell therapy with ACT of TCR engineered T cells with a very short ex vivo manipulation and DC vaccines is feasible and results in antitumor activity, but improvements are needed to maintain tumor responses.
    Clinical Cancer Research 03/2014; 20(9). DOI:10.1158/1078-0432.CCR-13-3017 · 8.72 Impact Factor
  • Aaron Shaw · Kenneth Cornetta
    03/2014; 2(1):14-35. DOI:10.3390/biomedicines2010014
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    ABSTRACT: Gene transfer has therapeutic potential for treating HIV-1 infection by generating cells that are resistant to the virus. We have engineered a novel self-inactivating lentiviral vector, LVsh5/C46, using two viral-entry inhibitors to block early steps of HIV-1 cycle. The LVsh5/C46 vector encodes a short hairpin RNA (shRNA) for downregulation of CCR5, in combination with the HIV-1 fusion inhibitor, C46. We demonstrate here the effective delivery of LVsh5/C46 to human T cell lines, peripheral blood mononuclear cells, primary CD4(+) T lymphocytes, and CD34(+) hematopoietic stem/progenitor cells (HSPC). CCR5-targeted shRNA (sh5) and C46 peptide were stably expressed in the target cells and were able to effectively protect gene-modified cells against infection with CCR5- and CXCR4-tropic strains of HIV-1. LVsh5/C46 treatment was nontoxic as assessed by cell growth and viability, was noninflammatory, and had no adverse effect on HSPC differentiation. LVsh5/C46 could be produced at a scale sufficient for clinical development and resulted in active viral particles with very low mutagenic potential and the absence of replication-competent lentivirus. Based on these in vitro results, plus additional in vivo safety and efficacy data, LVsh5/C46 is now being tested in a phase 1/2 clinical trial for the treatment of HIV-1 disease.
    02/2014; 1:11. DOI:10.1038/mtm.2013.11
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    ABSTRACT: Gene transfer into autologous hematopoietic stem cells by γ-retroviral vectors (gRV) is an effective treatment for adenosine deaminase (ADA) deficient-SCID. However, current gRV have significant potential for insertional mutagenesis as reported in clinical trials for other primary immunodeficiencies. To improve the efficacy and safety of ADA-SCID gene therapy, we generated a self-inactivating lentiviral vector (LV) with a codon-optimized human cADA gene under the control of the short form elongation factor-1α promoter (LV-EFS-ADA). In ADA-/- mice, LV-EFS-ADA displayed high efficiency gene transfer and sufficient ADA expression to rescue ADA-/- mice from their lethal phenotype with good thymic and peripheral T and B cell reconstitution. Human ADA-deficient CD34+ cells transduced with 1-5x10(7) TU/ml had 1-3 vector copies/cell and expressed 1-2x of normal endogenous levels of ADA, as assayed in vitro and by transplantation into immune-deficient mice. Importantly, in vitro immortalization assays demonstrated that LV-EFS-ADA had significantly less transformation potential compared to gRV vectors, and vector integration-site analysis by nrLAM-PCR of transduced human cells grown in immune-deficient mice showed no evidence of clonal skewing. These data demonstrated that the LV-EFS-ADA vector can effectively transfer the human ADA cDNA and promote immune and metabolic recovery, whilst reducing the potential for vector mediated insertional mutagenesis.Molecular Therapy (2013); doi:10.1038/mt.2013.265.
    Molecular Therapy 11/2013; 22(3). DOI:10.1038/mt.2013.265 · 6.23 Impact Factor
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    ABSTRACT: It is essential to improve therapies for controlling excessive bleeding in patients with haemorrhagic disorders. As activated blood platelets mediate the primary response to vascular injury, we hypothesize that storage of coagulation Factor VIII within platelets may provide a locally inducible treatment to maintain haemostasis for haemophilia A. Here we show that haematopoietic stem cell gene therapy can prevent the occurrence of severe bleeding episodes in dogs with haemophilia A for at least 2.5 years after transplantation. We employ a clinically relevant strategy based on a lentiviral vector encoding the ITGA2B gene promoter, which drives platelet-specific expression of human FVIII permitting storage and release of FVIII from activated platelets. One animal receives a hybrid molecule of FVIII fused to the von Willebrand Factor propeptide-D2 domain that traffics FVIII more effectively into α-granules. The absence of inhibitory antibodies to platelet-derived FVIII indicates that this approach may have benefit in patients who reject FVIII replacement therapies. Thus, platelet FVIII may provide effective long-term control of bleeding in patients with haemophilia A.
    Nature Communications 11/2013; 4:2773. DOI:10.1038/ncomms3773 · 11.47 Impact Factor
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    ABSTRACT: Biomedical research enterprises require a large number of core facilities and resources to supply the infrastructure necessary for translational research. Maintaining the financial viability and promoting efficiency in an academic environment can be particularly challenging for medical schools and universities. The Indiana Clinical and Translational Sciences Institute sought to improve core and service programs through a partnership with the Indiana University Kelley School of Business. The program paired teams of Masters of Business Administration students with cores and programs that self-identified the need for assistance in project management, financial management, marketing, or resource efficiency. The projects were developed by CTSI project managers and business school faculty using service-learning principles to ensure learning for students who also received course credit for their participation. With three years of experience, the program demonstrates a successful partnership that improves clinical research infrastructure by promoting business best practices and providing a valued learning experience for business students.
    Clinical and Translational Science 08/2013; 6(4):297-302. DOI:10.1111/cts.12059 · 1.43 Impact Factor
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    ABSTRACT: Gene therapy has shown clinical efficacy for several rare diseases, using different approaches and vectors. This workshop, sponsored by the National Institutes of Health Office of Biotechnology Activities and Office of Rare Diseases Research, brought together investigators from different disciplines to discuss the challenges and opportunities for advancing the field including means for enhancing data sharing for preclinical and clinical studies, development and utilization of available NIH resources, and interactions with the Food and Drug Administration (FDA).
    Human gene therapy 03/2013; 24(4). DOI:10.1089/hum.2013.064 · 3.76 Impact Factor
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    ABSTRACT: Abstract Translational research is a lengthy, complex, and necessary endeavor in order to bring basic science discoveries to clinical fruition. The NIH offers several programs to support translational research including an important resource established specifically for gene therapy researchers-the National Heart, Lung, and Blood Institute (NHLBI) Gene Therapy Resource Program (GTRP). This paper reviews the core components of the GTRP and describes how the GTRP provides researchers with resources that are critical to advancing investigational gene therapy products into clinical testing.
    Human gene therapy. Clinical development 03/2013; 24(1):5-10. DOI:10.1089/humc.2013.036
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    ABSTRACT: mt is a cross-disciplinary biomedical journal devoted to publishing the most exciting advances in pharmacology and therapeutics, as they pertain to advances in translational and clinical medicine. It is recognized as one of the most prestigious journals in the field. With an impact factor of 6.825*, mt ranks in the top 4.2% of scientific journals in the latest Science Citation Index. Published monthly online and in print.
    Molecular Therapy 02/2013; 21(2):266-268. DOI:10.1038/mt.2013.4 · 6.23 Impact Factor
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    ABSTRACT: Generating gene and cell therapy products under Good Manufacturing Practices is a complex process. Determining the cost of these products must consider the large number of supplies used for manufacturing and the personnel and facility costs to generate vector and maintain a cleanroom facility. To facilitate cost estimates, the Indiana University Vector Production Facility teamed with the Indiana University Kelley School of Business to develop a costing tool which in turn informs pricing. The tool is designed in Microsoft Excel and is customizable to meet the needs of other core facilities. It is available from the National Gene Vector Biorepository. The tool allows cost determinations using three different costing methods and was developed in an effort to meet the A21 circular requirements for US core facilities performing work for federally funded projects. The costing tool analysis reveals that the cost of vector production does not have a linear relationship with batch size. For example, increasing the production from 9 to18 liters of a retroviral vector product increases total costs a modest 1.2 fold increase rather than a doubling in total cost. The analysis discussed in this paper will help core facilities and investigators plan a cost-effective strategy for gene and cell therapy production.
    Human Gene Therapy Methods 01/2013; 24(1). DOI:10.1089/hgtb.2012.213 · 2.44 Impact Factor
  • Kenneth Cornetta · Candy Gunther Brown
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    ABSTRACT: The current description of personalized medicine by the National Institutes of Health is "the science of individualized prevention and therapy." Although physicians are just beginning to see the promise of genetic medicine coming to fruition, the rapid pace of sequencing technology, informatics, and computer science predict a true revolution in the ability to care for patients in the near future. The enthusiasm expressed by researchers is well founded, but the expectations voiced by the public do not center on advancing technology. Rather, patients are asking for personalized care: a holistic approach that considers an individual's physical, mental, and spiritual well-being. This perspective considers psychological, religious, and ethical challenges that may arise as the precision of preventive medicine improves. Psychological studies already highlight the barriers to single gene testing and suggest significant barriers to the predictive testing envisioned by personalized medicine. Certain religious groups will likely mount opposition if they believe personalized medicine encourages embryo selection. If the technology prompts cost-containment discussions, those concerned about the sanctity of life may raise ethical objections. Consequently, the availability of new scientific developments does not guarantee advances in treatment because patients may prove unwilling to receive and act on personalized genetic information. This perspective highlights current efforts to incorporate personalized medicine and personalized care into the medical curriculum, genetic counseling, and other aspects of clinical practice. Because these efforts are generally independent, the authors offer recommendations for physicians and educators so that personalized medicine can be implemented in a manner that meets patient expectations for personalized care.
    Academic medicine: journal of the Association of American Medical Colleges 01/2013; 88(3). DOI:10.1097/ACM.0b013e3182806345 · 2.93 Impact Factor
  • Sunyong Tang · Kenneth Cornetta
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    ABSTRACT: The ability to introduce genetic material into target cells has tremendous potential as a novel means for disease treatment and correction. While gene therapy is still in clinical trials, the past 20 years has seen the development of a large armamentarium of plasmid and viral vectors for human use. Initial trials focused on the correction of genetic diseases, but vectors are now available to deliver pharmacologic agents, reengineer cells, or express ribozyme and inhibitory RNAs that downregulate gene expression. Currently the majority of clinical trials have been in cancer. Approaches directed at malignancies include reengineering of autologous T cells to recognize tumor antigens and eliminate cancer cells, introduction of DNA repair genes into hematopoietic cells to protect them from chemotherapy and foster dose escalation, and introduction of immune stimulatory molecules to foster cancer cell recognition by the immune system. This chapter provides an introduction to gene therapy by illustrating the technology and discussing current clinical applications.
    Molecular Genetic Pathology, 01/2013: pages 399-412; , ISBN: 978-1-4614-4799-3
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    ABSTRACT: Delayed engraftment is a significant limitation of UCB transplantation due to low stem cell numbers. Inhibition of dipeptidylpeptidase (DPP)-4 enhanced engraftment in murine transplants. We evaluated the feasibility of systemic DPP-4 inhibition using sitagliptin to enhance engraftment of single-unit UCB grafts in adults with hematological malignancies. Twenty-four patients (21-58 years) received myeloablative conditioning, followed by sitagliptin 600mg PO days -1 to +2, and single UCB grafts day 0. Seventeen receiving red cell-depleted (RCD) grafts, matched at 4 (n=10) or 5 (n=7) of 6 HLA loci with median nucleated cell dose 3.6 (2.5-5.2) x107/kg, engrafted at median of 21 (range, 13-50) days with cumulative incidence of 94% (95% CI, 84-100%) at 50 days. Plasma DDP-4 activity was reduced to 23±7% within two hours. Area under DPP-4 activity-time curve (AUCA) correlated with engraftment; 9 of 11 with AUCA <6000 activity*h engrafted within ≤21 days, while all 6 with higher AUCA engrafted later (P=0.002). Seven patients receiving red cell replete grafts had ten-fold lower CFUs after thawing compared with RCD grafts, with poor engraftment. Systemic DPP-4 inhibition was well-tolerated and may enhance engraftment. Optimizing sitagliptin dosing to achieve more sustained DPP-4 inhibition may further improve outcome.
    Stem cells and development 12/2012; 22(7). DOI:10.1089/scd.2012.0636 · 3.73 Impact Factor
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    ABSTRACT: The safety of HIV-1 based vectors was evaluated during the production of transgenic sheep. Vectors were introduced into the perivitelline space of in vivo derived one-cell sheep embryos by microinjection then transferred into the oviducts of recipient females. At 60-70 days of gestation, a portion of the recipients were euthanized and tissues collected from both surrogates and fetuses. Other ewes were allowed to carry lambs to term. Inadvertent transfer of vector from offspring to surrogates was evaluated in 330 blood and tissue samples collected from 57 ewes that served as embryo recipients. Excluding uterine contents, none of the samples tested positive for vector, indicating that that the vector did not cross the fetal maternal interface and infect surrogate ewes. Evaluating ewes, fetuses and lambs for replication competent lentivirus (RCL); 84 serum samples analyzed for HIV-1 capsid by ELISA and over 600 blood and tissue samples analyzed by quantitative PCR for the VSV-G envelopes revealed no evidence of RCL. Results of these experiments provide further evidence as to the safety of HIV-1 based vectors in animal and human applications.
    Transgenic Research 11/2012; 22(4). DOI:10.1007/s11248-012-9674-3 · 2.32 Impact Factor
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    ABSTRACT: Human ex vivo gene therapy protocols have been used successfully to treat a variety of genetic disorders, infectious diseases, and cancer. Murine oncoretroviruses (specifically, gammaretroviruses) have served as the primary gene delivery vehicles for these trials. However, in some cases, such vectors have been associated with insertional mutagenesis. As a result, alternative vector platforms such as lentiviral vectors (LVVs) are being developed. LVVs may provide advantages compared with gammaretroviral vectors, including the ability to transduce large numbers of nondividing cells, resistance to gene silencing, and a potentially safer integration profile. The aim of this study was to develop a simplified process for the rapid production of clinical-grade LVVs. To that end, we used a self-inactivating bicistronic LVV encoding an MART (melanoma antigen recognized by T cells)-1-reactive T cell receptor containing oPRE, an optimized and truncated version of woodchuck hepatitis virus posttranslational regulatory element (wPRE). Using our simplified clinical production process, 293T cells were transiently transfected in roller bottles. The LVV supernatant was collected, treated with Benzonase, and clarified by modified step filtration. LVV produced in this manner exhibited titers and a biosafety profile similar to those of cGMP (current Good Manufacturing Practices) LVVs previously manufactured at the Indiana University Vector Production Facility in support of a phase I/II clinical trial. We describe a simple, efficient, and low-cost method for the production of clinical-grade LVV for ex vivo gene therapy protocols.
    Human Gene Therapy Methods 04/2012; 23(2):73-83. DOI:10.1089/hgtb.2011.199 · 2.44 Impact Factor
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    ABSTRACT: Although novel retroviral vectors for use in gene-therapy products are reducing the potential for formation of replication-competent retrovirus (RCR), it remains crucial to screen products for RCR for both research and clinical purposes. For clinical-grade gammaretrovirus-based vectors, RCR screening is achieved by an extended S(+)L(-) or marker-rescue assay, whereas standard methods for replication-competent lentivirus detection are still in development. In this report, we describe a rapid and sensitive method for replication-competent gammaretrovirus detection. We used this assay to detect three members of the gammaretrovirus family and compared the sensitivity of our assay with well-established methods for retrovirus detection, including the extended S(+)L(-) assay. Results presented here demonstrate that this assay should be useful for gene-therapy product testing.Gene Therapy advance online publication, 8 March 2012; doi:10.1038/gt.2012.18.
    Gene therapy 03/2012; 20(2). DOI:10.1038/gt.2012.18 · 3.10 Impact Factor
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    ABSTRACT: In the production of lentiviral vector for clinical studies the purity of the final product is of vital importance. To remove plasmid and producer cell line DNA, investigators have incubated the vector product with Benzonase, a bacterially derived DNase. As an alternative we investigated the use of Pulmozyme, a U.S. Food and Drug Administration-approved human DNase for the treatment of cystic fibrosis, by comparing the efficiency of DNA removal from lentiviral vector preparations. A green fluorescent protein-expressing lentiviral vector was prepared by transient calcium phosphate transfection of HEK 293T cells and DNA removal was compared when treating vector after harvest or immediately after transfection. The effectiveness of DNase treatment was measured by quantitative PCR using primers for vesicular stomatitis virus glycoprotein G viral envelope plasmid. When treating the final product, 1-hr incubations (37°C) with Pulmozyme at 20 U/ml reduced plasmid DNA to undetectable levels. Longer incubations (up to 4 hr) did not improve DNA removal at lower concentrations and the effectiveness was equivalent to or better than Benzonase at 50 U/ml. Attempting to use Pulmozyme immediately after transfection, but before final medium change, as a means to decrease Pulmozyme concentration in the final product provided a 2-log reduction in DNA but was inferior to treatment at the end of production. Pulmozyme, at concentrations up to 100 U/ml, had no measurable effect on infectious titer of the final vector product. The use of Pulmozyme is likely to increase the cost of DNase treatment when preparing vector product and should be considered when generating clinical-grade vector products.
    Human Gene Therapy Methods 02/2012; 23(1):65-71. DOI:10.1089/hgtb.2011.204 · 2.44 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: mt is a cross-disciplinary biomedical journal devoted to publishing the most exciting advances in pharmacology and therapeutics, as they pertain to advances in translational and clinical medicine. It is recognized as one of the most prestigious journals in the field. With an impact factor of 6.825*, mt ranks in the top 4.2% of scientific journals in the latest Science Citation Index. Published monthly online and in print.
    Molecular Therapy 02/2012; 20(2):246-9. DOI:10.1038/mt.2011.288 · 6.23 Impact Factor

Publication Stats

5k Citations
909.34 Total Impact Points


  • 1991–2014
    • Indiana University-Purdue University Indianapolis
      • • Department of Medical and Molecular Genetics
      • • Department of Microbiology and Immunology
      • • Department of Medicine
      • • Division of Hematology/Oncology
      Indianapolis, Indiana, United States
  • 1996–2012
    • Indiana University-Purdue University School of Medicine
      • • Medical and Molecular Genetics
      • • Division of Hematology/Oncology
      Indianapolis, Indiana, United States
  • 2004
    • Purdue University
      West Lafayette, Indiana, United States
  • 1998
    • Institut Paoli Calmettes
      Marsiglia, Provence-Alpes-Côte d'Azur, France
    • Indiana Blood and Marrow Transplantation
      Indianapolis, Indiana, United States
  • 1997
    • Michiana Hematology Oncology
      Индиана, Pennsylvania, United States
  • 1991–1997
    • National Institutes of Health
      • Branch of Metabolism
      Maryland, United States
  • 1990
    • University of Rochester
      Rochester, New York, United States
    • University of Wisconsin–Madison
      • Department of Medicine
      Madison, Wisconsin, United States
  • 1989–1990
    • National Heart, Lung, and Blood Institute
      • Hematology Branch
      베서스다, Maryland, United States