Academic Journal
213 AB-X integrated circuit T cells demonstrate improved potency, expansion, and specificity compared to MSLN CAR T cells
| العنوان: | 213 AB-X integrated circuit T cells demonstrate improved potency, expansion, and specificity compared to MSLN CAR T cells |
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| المؤلفون: | Santoro, Stephen, Cooper, Aaron, Bezman, Natalie, Feng, Jun, Chawla, Kanika, Williams, Jaspar, Gagnon, John, Hall, Jason, Polyak, Dina, Boroughs, Angela, Nguyen, Michelle, Mohanty, Suchismita, Litterman, Adam, Granja, Jeff, DeTomaso, David, Zheng, Grace, Smith, Jenessa, LeFace, Drake, Mikkelsen, Tarjei, Jun, Susie |
| المصدر: | Journal for ImmunoTherapy of Cancer ; volume 9, issue Suppl 2, page A226-A226 ; ISSN 2051-1426 |
| بيانات النشر: | BMJ |
| سنة النشر: | 2021 |
| الوصف: | Background In solid tumors, CAR T cell efficacy is limited by off-tumor toxicity and suppression by the tumor microenvironment (TME). AB-X is an integrated circuit T cell (ICT cell) intended for the treatment of ovarian cancer. AB-X includes a transgene cassette with two functional modules: 1) an ”AND” logic gate designed to limit off-tumor toxicity through dual tumor antigen recognition; 2) a dual shRNA-miR to resist TME suppression and improve ICT cell function. The AB-X logic gate consists of a priming receptor that induces expression of an anti-mesothelin (MSLN) CAR upon engagement of a ALPG/P (alkaline phosphatase germ-line/placental). The dual shRNA-miR mediates downregulation of FAS and PTPN2. The AB-X DNA cassette is inserted into the T cell genome at a defined novel genomic site via CRISPR-based gene editing. Methods Dual-antigen specificity of the logic gate was assessed in mice harboring MSLN+ and ALPG/P+MSLN+ K562 tumors established on contralateral flanks. Potency was measured in a subcutaneous MSTO xenograft model. Logic-gated ICT cells were compared with MSLN CAR T cells in both models. In vitro, expansion of ICT cells with the FAS/PTPN2 shRNA-miR was evaluated in a 14 day repetitive stimulation assay (RSA). In vivo, expansion and potency were measured in the MSTO xenograft model. An in vitro FAS cross-linking assay was conducted to assess the impact of FAS knockdown on FAS-mediated apoptosis. Results Logic-gated ICT cells demonstrated specific activity against ALPG/P+MSLN+ tumors, but had no effect against MSLN+ tumors in the K562 in vivo specificity model. In addition, logic-gated ICT cells demonstrated greater in vivo potency than MSLN CAR T cells in the MSTO xenograft model. In our RSA, ICT cells containing the FAS/PTPN2 shRNA-miR had 8-fold greater expansion than the MSLN CAR T cells. Enhanced expansion was confirmed in vivo with ICT cells demonstrating >10-fold expansion in tumors and peripheral blood, enabling comparable growth inhibition in MSTO xenografts at less than one quarter the ... |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| DOI: | 10.1136/jitc-2021-sitc2021.213 |
| DOI: | 10.1136/jitc-2021-SITC2021.213 |
| الاتاحة: | http://dx.doi.org/10.1136/jitc-2021-sitc2021.213 https://syndication.highwire.org/content/doi/10.1136/jitc-2021-SITC2021.213 |
| رقم الانضمام: | edsbas.925BF49D |
| قاعدة البيانات: | BASE |
| DOI: | 10.1136/jitc-2021-sitc2021.213 |
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