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Gene Therapy for Cancer Treatment
Published in Yashwant V. Pathak, Gene Delivery Systems, 2022
Manish P. Patel, Mansi S. Shah, Mansi N. Athalye, Jayvadan K. Patel
Some pharmaceutical companies have developed several medications, such as Novartis-LBH589, cIAP1 and cIAP2, which inhibit the Bcl-2 protein, thus promoting apoptosis and tumor regression, prevent or delay tumor resistance and prolong remission following gene therapy [Amer 2014]. Notably, clinical trials for the treatment of cervical dysplasia (high-grade squamous intraepithelial lesions) caused by human papilloma virus with the DNA vaccine VGX-3100 are in advanced stages (phase III, NCT03185013) [Ginn et al. 2017]. Most commonly, HSV thymidine-kinase has been used to convert the non-toxic pro-drug ganciclovir into the cytotoxic triphosphate ganciclovir [Ginn et al. 2017]. Therapies that are targeting CD19, an antigen present in most B-cell malignancies but absent in normal tissues other than the B-cell lineage, are at the forefront of CAR-based technology. A turning point occurred when the positive outcomes from three CAR therapy trials were published in 2010 and 2011. These studies showed unprecedented antitumor activity in patients with B-cell lymphoma, chronic lymphocytic leukemia (NCT01029366, NCT00466531) or B-cell acute lymphoblastic leukemia. This success concluded with the recent USFDA and EMA approval of two CAR T-cell therapies targeting CD19-expressing B cells.
Genome Editing and Gene Therapies: Complex and Expensive Drugs
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2020
The three TALEN-based ex vivo studies NCT02808442, NCT02735083, and NCT02746952 center around the application of gene-edited “off-the-shelf” universal chimeric antigen receptor (CAR) T (UCART) cells expressing anti-CD19 CAR for the treatment of pediatric patients with relapsed or refractory CD19-positive B-cell acute lymphoblastic leukemia (B-ALL). All three are multi-center international (France USA, Belgium, Spain, UK, and in part Japan) clinical trials, organized by the French Institut de Recherches Internationales Servier ADIR, a Servier Group company. Whereas in NCT02808442 from June 2016 until April 2020 safety and feasibility of UCART19 administering are evaluated, NCT02735083 is a long-term follow-up study to investigate the long-term safety of patients with advanced lymphoid malignancies who have been treated with the UCART drug before; this means that patients participating in this trial are not administered the drug for the duration of the study. Clinical trial NCT02746952 (June 2016 until April 2020) investigates how patients tolerate increasing doses of UCART, administered intravenously. Car T cell immunotherapy is discussed in the previous chapter, and the question how the potency of CAR-based therapies can be enhanced by combination with gene editing techniques is separately treated in Subsection 10.4.6.3. Zhao et al. (2019) have recently reviewed the results of clinical trials presented at the American Society of Hematology (ASH) annual meeting 2018 with a focus on CAR T and universal CAR T cell trials.
Effects of long-term high-level lead exposure on the immune function of workers
Published in Archives of Environmental & Occupational Health, 2022
Jianrui Dou, Le Zhou, Yi Zhao, Wu Jin, Huanxi Shen, Feng Zhang
CD19 is a surface differentiation protein of B-cells that can be used as a specific B-cell marker. These cells participate in humoral immune responses by secreting serum Ig, mature in the bone marrow and are mainly differentiated in the blood. Under normal physiological conditions, the proportion of B-cells in the peripheral blood is 10–15%. Boscolo et al. found that blood Pb levels in 30 men negatively correlated with CD19+ cell levels (r = −.506, p < .01). However, in the current study, there was no significant difference in the number of B-cells (CD3−CD19+) between the high-Pb and low-Pb groups. This outcome may have been caused by inconsistent blood Pb levels in the bodies of the study subjects.13
A calibration-free method for biosensing in cell manufacturing
Published in IISE Transactions, 2021
Jialei Chen, Zhaonan Liu, Kan Wang, Chen Jiang, Chuck Zhang, Ben Wang
Cell therapy is one of the most promising treatment approaches to have emerged over the last decades, demonstrating great potential in treating cancers, including leukemia and lymphoma (Kim and de Vellis, 2009; Yin, 2017). Among those therapies, Chimeric Antigen Receptor (CAR) T-cell therapy (Bonifant et al., 2016; June et al., 2018), involving the reprogramming of a patient’s T cells to effectively target and attack tumor cells, has shown innovative therapeutic effects in clinical trials, leading to a recent approval (i.e., the treatment of CD19+ hematological malignancies, see Prasad (2018)) by the FDA as a new cancer treatment modality. As illustrated in Figure 1, a typical CAR T-cell therapy involves four steps: deriving cells from a patient, genetically modifying the cells, culturing the cells, and re-administering back to the patient. With increasingly mature gene modification technology, more and more researchers focus on the culturing step (i.e., the red box in Figure 1), where the goal is to substantially increase the cell amount from a small batch to one dose for delivery to the patient. However, a key challenge is the intrinsic patient-to-patient variability in the starting material, i.e., cells derived from different patients vary in their viabilities, acceptance rates of genetic modification, and reactions to culture media (Hinrichs and Restifo, 2013). These variabilities introduce difficulties in cell culturing scale-up (i.e., cell manufacturing), and therefore, the current CAR T-cell therapy is hindered by low scalability, labor-intensive processes, and extremely high cost (Harrison et al., 2019). To achieve high quality and acceptable vein-to-vein cost, we present in this work a statistical framework for online monitoring in cell manufacturing, which can alleviate the negative effect of the intrinsic patient-to-patient variability.