| Autor: |
Ilaria M. Michelozzi, Eduardo Gomez Castaneda, Ruben V.C. Pohle, Ferran Cardoso Rodriguez, Jahangir Sufi, Pau Puigdevall Costa, Meera Subramaniyam, Efstratios Kirtsios, Ayad Eddaoudi, Si Wei Wu, Aleks Guvenel, Jonathan Fisher, Sara Ghorashian, Martin A. Pule, Christopher J. Tape, Sergi Castellano, Persis J. Amrolia, Alice Giustacchini |
| Rok vydání: |
2020 |
| Předmět: |
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| Popis: |
We recently described a low-affinity second-generation CD19 chimeric antigen receptor (CAR) CAT that showed enhanced expansion, cytotoxicity, and anti-tumour efficacy compared to the high-affinity (FMC63 based) CAR used in Tisagenlecleucel, in pre-clinical models. Furthermore, CAT demonstrated an excellent toxicity profile, enhanced in vivo expansion, and long-term persistence in a Phase I clinical study. To understand the molecular mechanisms behind these properties of CAT CAR T-cells, we performed a systematic in vitro characterization of the transcriptomic (RNA-seq) and protein (CyTOF) changes occurring in T-cells expressing low-affinity vs high-affinity CD19 CARs following stimulation with CD19-expressing cells. Our results show that CAT CAR T-cells exhibit enhanced activation to CD19 stimulation and a distinct transcriptomic and protein profile, with increased activation and cytokine polyfunctionality compared to FMC63 CAR T-cells. We demonstrate that the enhanced functionality of low-affinity CAT CAR T-cells is a consequence of an antigen-dependent priming induced by residual CD19-expressing B-cells present in the manufacture. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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