Risk analysis of leachables in cell and gene therapy using a CAR-T model process

Budde, Dana; Jurkiewicz, Elke

doi:10.1016/j.ijpharm.2021.121015

Cited by 9 publications

(7 citation statements)

References 33 publications

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“…The other three compounds with an observed biological activity in the CPA (Table 1 ) did not impact cell growth of U2OS cells at concentrations ≤ 50 µM. When tested with different industrial cell lines, bD t BPP showed EC 50 values below 1 µM, which is in agreement with the observed EC 50 value for our CHO and other cell lines 18 , 58 , 63 . The observed differences in CPA versus CHO test results can be regarded as influenced by both cell-specific and test-specific differences, as described elsewhere 64 .…”

Section: Resultssupporting

confidence: 87%

“…Methods are not yet established to investigate the biological effects of PERLs on therapeutic cells, such as impaired cell proliferation or viability. Budde et al 18 reported detrimental effects on T-cell growth and loss of potency caused by compounds migrating from plastic materials used in AT applications. Another highly relevant problem expressed by various stakeholders, including authorities, is the formation of degenerated cells due to ex vivo manipulations of cells in the artificial environment of plastics, as associated with SUS.…”

Section: Introductionmentioning

confidence: 99%

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Assessing biologic/toxicologic effects of extractables from plastic contact materials for advanced therapy manufacturing using cell painting assay and cytotoxicity screening

Pahl,

Hauk

et al. 2024

Sci Rep

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Plastic components are essential in the pharmaceutical industry, encompassing container closure systems, laboratory handling equipment, and single-use systems. As part of their material qualification process, studies on interactions between plastic contact materials and process solutions or drug products are conducted. The assessment of single-use systems includes their potential impact on patient safety, product quality, and process performance. This is particularly crucial in cell and gene therapy applications since interactions with the plastic contact material may result in an adverse effect on the isolated therapeutic human cells. We utilized the cell painting assay (CPA), a non-targeted method, for profiling the morphological characteristics of U2OS human osteosarcoma cells in contact with chemicals related to plastic contact materials. Specifically, we conducted a comprehensive analysis of 45 common plastic extractables, and two extracts from single-use systems. Results of the CPA are compared with a standard cytotoxicity assay, an osteogenesis differentiation assay, and in silico toxicity predictions. The findings of this feasibility study demonstrate that the device extracts and most of the tested compounds do not evoke any measurable biological changes on the cells (induction ≤ 5%) among the 579 cell features measured at concentrations ≤ 50 µM. CPA can serve as an important assay to reveal unique information not accessible through quantitative structure–activity relationship analysis and vice versa. The results highlight the need for a combination of in vitro and in silico methods in a comprehensive assessment of single-use equipment utilized in advanced therapy medicinal products manufacturing.

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Section: Resultssupporting

confidence: 87%

Section: Introductionmentioning

confidence: 99%

Assessing biologic/toxicologic effects of extractables from plastic contact materials for advanced therapy manufacturing using cell painting assay and cytotoxicity screening

Pahl,

Hauk

et al. 2024

Sci Rep

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“…Earlier research involving 60 Co radiation at 40–60 kGy indicates that plasticizers with aromatic esters are more stable than aliphatic esters or phosphates, , with trioctyl trimellitate (TOTM) providing somewhat better protection than dialkyl phthalates against radiation-induced modification of PVC . Furthermore, in a risk analysis of leachates from plastic products, TOTM was found to be less toxic than dialkyl phthalates against T-cells and other cell types. , We thus selected TOTM as the primary plasticizer in PVC-based ISMs.…”

Section: Results and Discussionmentioning

confidence: 99%

“…15 Furthermore, in a risk analysis of leachates from plastic products, TOTM was found to be less toxic than dialkyl phthalates against T-cells and other cell types. 16,17 We thus selected TOTM as the primary plasticizer in PVC-based ISMs.…”

Section: ■ Introductionmentioning

confidence: 99%

Radiation-Tolerant Thin-Film Electrodes for pH Monitoring in Sterile Media

2022

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Thin-film pH electrodes on thermoplastic substrates can be subjected to γ-radiation (up to 45 kGy) without loss of stability or sensing performance, with important ramifications for monitoring analytes in sterile environments. pH-sensing membranes composed of polyvinyl chloride (PVC), trioctyl trimellitate (TOTM), and a standard hydrogen ionophore were cast onto screen-printed carbon electrodes with exfoliated graphene as a solid contact. Irradiated thin-film electrodes were conditioned in phosphate buffers and monitored for up to 3 months for changes in voltage readout and pH sensitivity, relative to untreated controls. The sensitivities of both irradiated and control electrodes were consistently Nernstian over a 100 day window, with both types exhibiting logarithmic voltage decays but in opposite directions. The γ-irradiated electrodes had excellent long-term stability with quasi-linear voltage drifts of +0.28 mV (∼0.005 pH) per day. Voltage readouts from sterilized thin-film electrodes in cell culture media could be converted by single-point calibration into pH values that fell within 0.07 units relative to a commercial pH meter (calibrated daily).

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“…Immunotherapy for advanced and metastatic cancers has attracted widespread attention in recent years. − Important examples of this include immune checkpoint blockade (ICB) therapy, targeting either programed death ligand-1 (PD-L1) or programed death-1 (PD-1), which has triggered long-term antitumor immune responses and achieved durable tumor regression in clinical trials. , Despite its promise, the development of complementary strategies to enhance the proportion of patients achieving benefits from ICB therapy remains a formidable challenge. , Several small-molecule therapeutics that target relevant signaling pathways in the immunosuppressive tumor microenvironment have been exploited in combination with ICB treatment. − …”

Section: Introductionmentioning

confidence: 99%

Targeting Ibrutinib to Tumor-Infiltrating T Cells with a Sialic Acid Conjugate-Modified Phospholipid Complex for Improved Tumor Immunotherapy

et al. 2022

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Immune checkpoint blockade (ICB) treatment for the clinical therapy of numerous malignancies has attracted widespread attention in recent years. Despite being a promising treatment option, developing complementary strategies to enhance the proportion of patients benefiting from ICB therapy remains a formidable challenge because of the complexity of the tumor microenvironment. Ibrutinib (IBR), a covalent inhibitor of Bruton's tyrosine kinase (BTK), has been approved as a clinical therapy for numerous B-cell malignancies. IBR also irreversibly inhibits interleukin-2 inducible T cell kinase (ITK), an essential enzyme in Th2-polarized T cells that participates in tumor immunosuppression. Ablation of ITK by IBR can elicit Th1-dominant antitumor immune responses and potentially enhance the efficacy of ICB therapy in solid tumors. However, its poor solubility and rapid clearance in vivo restrict T cell targetability and tumor accumulation by IBR. A sialic acid derivative-modified nanocomplex (SA-GA-OCT@PC) has been reported to improve the efficacy of IBR-mediated combination immunotherapy in solid tumors. In vitro and in vivo experiments showed that SA-GA-OCT@PC effectively accumulated in tumor-infiltrating T cells mediated by Siglec-E and induced Th1-dominant antitumor immune responses.

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Risk analysis of leachables in cell and gene therapy using a CAR-T model process

Cited by 9 publications

References 33 publications

Assessing biologic/toxicologic effects of extractables from plastic contact materials for advanced therapy manufacturing using cell painting assay and cytotoxicity screening

Assessing biologic/toxicologic effects of extractables from plastic contact materials for advanced therapy manufacturing using cell painting assay and cytotoxicity screening

Radiation-Tolerant Thin-Film Electrodes for pH Monitoring in Sterile Media

Targeting Ibrutinib to Tumor-Infiltrating T Cells with a Sialic Acid Conjugate-Modified Phospholipid Complex for Improved Tumor Immunotherapy

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