Browsing by Author "Duffy, Lisa"

Now showing 1 - 4 of 4
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    Absence of Replication-Competent Lentivirus in the Clinic: Analysis of Infused T Cell Products
    (Elsevier, 2017) Cornetta, Kenneth; Duffy, Lisa; Turtle, Cameron J.; Jensen, Michael; Forman, Stephen; Binder-Scholl, Gwendolyn; Fry, Terry; Chew, Anne; Maloney, David G.; June, Carl H.; Medical and Molecular Genetics, School of Medicine
    Exposure to replication-competent lentivirus (RCL) is a theoretical safety concern for individuals treated with lentiviral gene therapy. For certain ex vivo gene therapy applications, including cancer immunotherapy trials, RCL detection assays are used to screen the vector product as well as the vector-transduced cells. In this study, we reviewed T cell products screened for RCL using methodology developed in the National Gene Vector Biorepository. All trials utilized third-generation lentiviral vectors produced by transient transfection. Samples from 26 clinical trials totaling 460 transduced cell products from 375 subjects were evaluated. All cell products were negative for RCL. A total of 296 of the clinical trial participants were screened for RCL at least 1 month after infusion of the cell product. No research subject has shown evidence of RCL infection. These findings provide further evidence attesting to the safety of third-generation lentiviral vectors and that testing T cell products for RCL does not provide added value to screening the lentiviral vector product.
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    The National Gene Vector Biorepository: Eleven Years of Providing Resources to the Gene Therapy Community
    (Mary Ann Liebert, Inc., 2020-02) Cornetta, Kenneth; Matheson, Lorraine; Long, Ryan; Duffy, Lisa; Medical and Molecular Genetics, School of Medicine
    The National Gene Vector Biorepository (NGVB) program has been highly accessed by gene therapy investigators. The reagent repository has distributed over 1,000 reagents to 397 investigators. The Pharmacology/Toxicology Archive contains over 36,000 specimens from a variety of adeno-associated virus (AAV), adenoviral, and other pharmacology/toxicology studies. NGVB also maintains a searchable database of gene therapy pharmacology/toxicology studies to promote data sharing. NGVB has provided Food and Drug Administration (FDA)-mandated replication-competent virus testing for over 70 clinical trials. From 2008 to 2018, there have been 114 publications acknowledging the NGVB. It is unlikely that any other National Institutes of Health (NIH)-funded program has served as many gene therapy investigators as the NGVB.
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    Replication competent retrovirus testing (RCR) in the National Gene Vector Biorepository: No evidence of RCR in 1,595 post-treatment peripheral blood samples obtained from 60 clinical trials
    (Elsevier, 2023) Cornetta, Kenneth; Yao, Jing; House, Kimberley; Duffy, Lisa; Adusumilli, Prasad S.; Beyer, Rachel; Booth, Claire; Brenner, Malcolm; Curran, Kevin; Grilley, Bambi; Heslop, Helen; Hinrichs, Christian S.; Kaplan, Rosandra N.; Kiem, Hans-Peter; Kochenderfer, James; Kohn, Donald B.; Mailankody, Sham; Norberg, Scott M.; O’Cearbhaill, Roisin E.; Pappas, Jennifer; Park, Jae; Ramos, Carlos; Ribas, Antonio; Rivière, Isabelle; Rosenberg, Steven A.; Sauter, Craig; Shah, Nirali N.; Slovin, Susan F.; Thrasher, Adrian; Williams, David A.; Lin, Tsai-Yu; Medical and Molecular Genetics, School of Medicine
    The clinical impact of any therapy requires the product be safe and effective. Gammaretroviral vectors pose several unique risks, including inadvertent exposure to replication competent retrovirus (RCR) that can arise during vector manufacture. The US FDA has required patient monitoring for RCR, and the National Gene Vector Biorepository is an NIH resource that has assisted eligible investigators in meeting this requirement. To date, we have found no evidence of RCR in 338 pre-treatment and 1,595 post-treatment blood samples from 737 patients associated with 60 clinical trials. Most samples (75%) were obtained within 1 year of treatment, and samples as far out as 9 years after treatment were analyzed. The majority of trials (93%) were cancer immunotherapy, and 90% of the trials used vector products produced with the PG13 packaging cell line. The data presented here provide further evidence that current manufacturing methods generate RCR-free products and support the overall safety profile of retroviral gene therapy.
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    Screening Clinical Cell Products for Replication Competent Retrovirus: The National Gene Vector Biorepository Experience
    (Elsevier, 2018-09-21) Cornetta, Kenneth; Duffy, Lisa; Feldman, Steven A.; Mackall, Crystal L.; Davila, Marco L.; Curran, Kevin J.; Junghans, Richard P.; Tang, Jean Yuh; Kochenderfer, James N.; O'Cearbhaill, Roisin; Archer, Gary; Kiem, Hans-Peter; Shah, Nirali N.; Delbrook, Cindy; Kaplan, Rosie; Brentjens, Renier J.; Rivière, Isabelle; Sadelain, Michel; Rosenberg, Steven A.; Medical and Molecular Genetics, School of Medicine
    Replication-competent retrovirus (RCR) is a safety concern for individuals treated with retroviral gene therapy. RCR detection assays are used to detect RCR in manufactured vector, transduced cell products infused into research subjects, and in the research subjects after treatment. In this study, we reviewed 286 control (n = 4) and transduced cell products (n = 282) screened for RCR in the National Gene Vector Biorepository. The transduced cell samples were submitted from 14 clinical trials. All vector products were previously shown to be negative for RCR prior to use in cell transduction. After transduction, all 282 transduced cell products were negative for RCR. In addition, 241 of the clinical trial participants were also screened for RCR by analyzing peripheral blood at least 1 month after infusion, all of which were also negative for evidence of RCR infection. The majority of vector products used in the clinical trials were generated in the PG13 packaging cell line. The findings suggest that screening of the retroviral vector product generated in PG13 cell line may be sufficient and that further screening of transduced cells does not provide added value.