IPSC-derived anti-KIT CAR-T cell generation: functional optimization and in vivo application in a transplantable mouse gastrointestinal stromal tumor (GIST) model
Final Report Abstract
The goal of the present research project was to a) develop and evaluate novel cellular therapies for T cell malignancies, and b) improve current iPSC to T cell differentiation protocols. For these purposes, novel CARs targeting the constant or variable region of the TCR beta subunit, as well as PD-1, were designed. All CARs displayed in vitro and in vivo antitumor functionality. Moreover, the efficacy of the αTRBV-CARs was improved by implementing a cleavable CAR system. It was observed that αTCR-CAR/TCR interaction has possible side effects, such as activation of the malignant cell, enhanced proliferation, and downregulation of TCR/CD3, which require further research. The novel αPD-1-CAR, which recognizes PD-1 expressed by several TCL subentities, did not interfere negatively with T cell expansion after transduction and showed target-specific activity without signs of hyperprogression in vivo. This represents a novel approach to treating PD-1+ tumors such as angioimmunoblastic T cell lymphoma or T follicular helper cell lymphoma. In the second part, the impact of a TCR-like construct – HLA-independent TCR (HIT) – on T cell differentiation from iPSCs was investigated. Both αWT1- and αCD19-HIT could substitute for a normal TCR, were functional, and compared to the conventional CAR, resulted in higher levels of T cell markers on iPSC-derived T cells. They were also able to produce higher numbers of CD4/CD8 double-positive T cells. Thus, the HIT format holds promise for improving T cell differentiation from iPSCs while simultaneously increasing sensitivity towards antigens at low frequency, such as the difficult-to-target oncogene-derived peptides presented by HLA.
Publications
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Early assessment of circulating tumor DNA after curative‐intent resection predicts tumor recurrence in early‐stage and locally advanced non‐small‐cell lung cancer. Molecular Oncology, 16(2), 527-537.
Waldeck, Silvia; Mitschke, Jan; Wiesemann, Sebastian; Rassner, Michael; Andrieux, Geoffroy; Deuter, Max; Mutter, Jurik; Lüchtenborg, Anne‐Marie; Kottmann, Daniel; Titze, Laurin; Zeisel, Christoph; Jolic, Martina; Philipp, Ulrike; Lassmann, Silke; Bronsert, Peter; Greil, Christine; Rawluk, Justyna; Becker, Heiko; Isbell, Lisa ... & von Bubnoff, Nikolas
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Monoclonal gammopathy of renal significance (MGRS): Real‐world data on outcomes and prognostic factors. American Journal of Hematology, 97(7), 877-884.
Gozzetti, Alessandro; Guarnieri, Andrea; Zamagni, Elena; Zakharova, Elena; Coriu, Daniel; Bittrich, Max; Pika, Tomáš; Tovar, Natalia; Schutz, Natalia; Ciofini, Sara; Peña, Camila; Rocchi, Serena; Rassner, Michael; Avivi, Irit; Waszczuk‐Gajda, Anna; Chhabra, Saurabh; Usnarska‐Zubkiewicz, Lidia; González‐Calle, Verónica; Mateos, Maria‐Victoria ... & Jurczyszyn, Artur
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Multidisciplinary tumor board analysis: validation study of a central tool in tumor centers. Annals of Hematology, 102(3), 603-611.
Frank, Benedikt; Ihorst, Gabriele; Herget, Georg; Schäfer, Henning; Neubauer, Jakob; Calba, Marc-Antoine; Textor, Daniel; Möller, Mandy-Deborah; Wenger, Sina; Jung, Johannes; Waldschmidt, Johannes; Miething, Cornelius; Rassner, Michael; Greil, Christine; Wäsch, Ralph & Engelhardt, Monika
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Development of Highly Sensitive Digital Droplet PCR for Detection of cKIT Mutations in Circulating Free DNA That Mediate Resistance to TKI Treatment for Gastrointestinal Stromal Tumor International Journal of Molecular Sciences, 24(6), 5411.
Rassner, Michael; Waldeck, Silvia; Follo, Marie; Jilg, Stefanie; Philipp, Ulrike; Jolic, Martina; Wehrle, Julius; Jost, Philipp J.; Peschel, Christian; Illert, Anna Lena; Duyster, Justus; Scherer, Florian & von Bubnoff, Nikolas
