Abstract 4058: In vitro binding, efficacy and safety studies to support engineered T cell therapies

Engineered T cell therapies such as Chimeric Antigen Receptor (CAR) T cells and T cell receptor (TCR)-engineered T cells have emerged as a promising cancer therapy. To date, four anti-CD19 CAR-T and two anti-BCMA CAR-T products have been approved by the FDA for the treatment of hematological maligna...

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Veröffentlicht in:Cancer research (Chicago, Ill.) Ill.), 2023-04, Vol.83 (7_Supplement), p.4058-4058
Hauptverfasser: Vermond, Sophie, Quist, Benita, Hazenoot, Monique, McLaughlin, Rene, Lopez, David Cobeta, Jayanth, Namrata, Verkaar, Folkert, Aziz, Omar, Vlaming, Maria LH, de Munnik, Sabrina, Moiset, Gemma
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Sprache:eng
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Zusammenfassung:Engineered T cell therapies such as Chimeric Antigen Receptor (CAR) T cells and T cell receptor (TCR)-engineered T cells have emerged as a promising cancer therapy. To date, four anti-CD19 CAR-T and two anti-BCMA CAR-T products have been approved by the FDA for the treatment of hematological malignancies. Many more T cell therapy products are currently being explored, directed towards both liquid and solid tumors as well as for other clinical indications. High-quality and robust in vitro and in vivo assays are essential for the discovery and characterization of lead T cell therapy products. Furthermore, despite demonstrating therapeutically successful, the further development of T cell immunotherapies has been hindered by safety concerns. Selected target antigens might be expressed in healthy tissues or engineered T cells may non-specifically bind to antigens in healthy tissues, potentially resulting in severe side effects. In addition, the random integration of the CAR- or TCR-encoding DNA cassettes in the host cell genome has the potential risk of causing insertional mutagenesis and may contribute to oncogenic transformation of the T cells. The aim of this study was to develop several in vitro assays for the assessment of target cell binding, efficacy and safety of T cell therapies using CAR-T cells targeting the Human Epidermal growth factor Receptor 2 (HER2) as a model system. The z-Movi cell avidity analyzer was used to study the binding strength between the CAR-T cells and target tumor cells. Cytotoxicity co-culture assays were developed using increasing effector:target cells ratios and an impedance-based readout to quantify the viability of HER2-positive and -negative cancer cell lines in real-time, to confirm the activity and selectivity of the HER2-CAR-T cells. Furthermore, co-culture assays were also developed for a variety of primary or iPSC-derived healthy human cells (representing various tissues) to assess potential off-tumor effects of the HER2-CAR-T cells against healthy cells. In addition, an oncogenicity assay was developed to quantify the survival and proliferation of the HER2-CAR-T cells in the absence and presence of cytokines by flow cytometry, to determine whether the genomic editing of the T cells affected their cytokine-dependency. In conclusion, Charles River Laboratories developed several in vitro assays for the preclinical assessment of T cell therapy binding, efficacy, potency, specificity and safety to aid early-stage lead dis
ISSN:1538-7445
1538-7445
DOI:10.1158/1538-7445.AM2023-4058