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Immunomodulation in Gene Therapeutics
Published in Thomas F. Kresina, Immune Modulating Agents, 2020
Andreas Block, Susan S. Rich, Shu-Hsia Chen, Savio L. C. Woo
The efficacy of an adenoviral combination gene therapy approach with a suicide gene and the interleukin 2 gene was investigated in our lab by using a murine metastatic colon cancer model [93]. Metastatic colon carcinoma was generated in the liver by intrahepatic implantation of MCA-26 tumor cells. These colon cancer cells were chemically induced in Balb/c mice, poorly differentiated and highly tumorigenic in the syngeneic host [94,95]. Injection of 3 × 105 cells into the left lateral tip resulted in tumors measuring 5 to 7 mm in diameter after 7 days. These tumors were then treated by intratumoral injection of various combinations of recombinant, replication-deficient adenoviruses, expressing the herpes simplex virus thymidine kinase suicide gene Ad.RSV-TK, mouse interleukin 2 Ad.RSV-IL-2, and β-galactosidase Ad.RSV-βGal.
Genetic therapy for ocular tumors
Published in A Peyman MD Gholam, A Meffert MD Stephen, D Conway MD FACS Mandi, Chiasson Trisha, Vitreoretinal Surgical Techniques, 2019
Onken Michael D, Harbour J William
An ingenious application of gene transfer technology was the introduction of genes into cancer cells that make them more sensitive than normal cells to a specific treatment. A good example of this ‘suicide gene therapy’ is the introduction of a herpesvirus thymidine kinase into cancer cells followed by treatment with ganciclovir.19 Ganciclovir is a nucleoside analog of guanosine that is converted in vivo to ganciclovir triphosphate, which inhibits viral DNA polymerases and hence DNA synthesis.20 The viral thymidine kinase catalyzes the conversion of ganciclovir to its triphosphate, whereas normal human cells do not contain a kinase that efficiently phosphorylates ganciclovir. Consequently, human cells infected with herpesvirus are highly sensitive to ganciclovir, whereas surrounding normal cells are relatively unaffected. The therapeutic potential of viral thymidine kinase was first demonstrated by Evans and co-workers,19 who showed that ganciclovir could induce the regression of lymphoma cells expressing the herpes simplex virus thymidine kinase (HSV-TK).
Molecular-Genetic Imaging
Published in Martin G. Pomper, Juri G. Gelovani, Benjamin Tsui, Kathleen Gabrielson, Richard Wahl, S. Sam Gambhir, Jeff Bulte, Raymond Gibson, William C. Eckelman, Molecular Imaging in Oncology, 2008
Yannic Waerzeggers, Alexandra Winkeler, Andreas H. Jacobs
Another problem of current gene therapy approaches is specific vector targeting. In an ideal gene therapy protocol, transgene expression must be strictly limited to the tissue of interest, mostly cancer cells, and spare surrounding normal cells. Numerous strategies have been developed to compensate this lack of specific targeting. By the use of inducible promoters or introduction of a suicide gene as “death switch” transgene expression can be controlled temporally and turned off when not desired any more. However, specific vector targeting can be realized by the use of tumor cell–specific promoters (122,123,216,217) or tumor cell–specific translation (218).
Gene Therapy for High Grade Glioma: The Clinical Experience
Published in Expert Opinion on Biological Therapy, 2023
Maria Luisa Varela, Andrea Comba, Syed M Faisal, Anna Argento, Andrea Franson, Marcus N Barissi, Sean Sachdev, Maria G Castro, Pedro R Lowenstein
Gene therapy is a versatile and promising technique to be employed in neuro-oncology. Viral vectors used for gene therapy can be administered locally during initial surgery and reach infiltrating cells that cannot be resected, therefore overcoming therapeutic resistance and reducing recurrence. The high infection efficiency of viral vectors has made them widely popular for gene therapy in HGG clinical trials. Furthermore, several different vectors employing a variety of genome editing strategies have been proven to be safe. Histopathological analyses of pre- and post-treatment tissue have demonstrated not only virus activity in vivo but also lysis of tumor cells and an increase in immune cell infiltration and activation. Despite these promising data, several Phase III clinical trials have been conducted with suicide gene therapy, targeted therapy, and immunotherapy without achieving an increase in survival for patients suffering from HGG.
T-cell acute lymphoblastic leukemia: promising experimental drugs in clinical development
Published in Expert Opinion on Investigational Drugs, 2023
First studies using CD7CAR T cells showed an incomplete downregulation of CD7 on transduced CAR T cells leading to fratricide [131]. Abrogating CD7 expression was then proposed by various specific techniques, such as blockade of CD7 protein trafficking [132], and CRISPR/Cas9 gene editing [133]. Consequently, a robust anti-tumor activity was observed in both preclinical and clinical studies against CD7+ T-ALL. Another risk with CD7CAR T cells is T-cell depletion and immunodeficiency. Activation of an inducible suicide gene was proposed to avoid such side effects [134]. Fratricide-resistant anti-CD7 CAR T cells have also been developed from healthy donors [133]. These allogeneic CAR T cells have the advantage to be immediately available but also to eliminate the risk of graft-versus-host disease (GvHD). Several studies using CD7CAR T cells, involving overall more than 40 T-ALL patients, have already been published [135–139]. ORR and CR ranged from 63% to 100%. CRS was observed in all cases.
Mechanism of Action of Mesenchymal Stem Cells (MSCs): impact of delivery method
Published in Expert Opinion on Biological Therapy, 2022
Luiza L. Bagno, Alessandro G. Salerno, Wayne Balkan, Joshua M. Hare
The utilization of MSCs as delivery vehicles for different types of anticancer therapy has been an emerging concept pursued by several research groups [108,109]. Briefly, the ‘suicide gene’ strategy foresees the insertion of a gene that enables selective targeting of the transfected cells by the subsequent administration of an otherwise nontoxic drug. When this drug is administered after MSCs home to a tumor, the conversion/uptake of the then toxic drug, kills not only MSCs but also the surrounding tumor and stromal cells [110]. These suicide genes can encode either an enzyme by Gene-directed enzyme-producing therapy (GDEPT) or the sodium/iodide symporter, NIS. The next challenge is to understand better the interactions between MSCs and cancer cells in order to improve the clinical safety of these MSC-based therapeutic approaches.