Structural design of engineered costimulation determines tumor rejection kinetics and persistence of CAR T cells
By Zeguo Zhao, M. Condomines, Sjoukje J. C. van der Stegen, F. Perna, Christopher C. Kloss, Gertrude Gunset, J. Plotkin, Michel Sadelain. Cancer Cell, 2015
779 citations recorded by the source corpus.
Summary T cell engineering is a powerful means to rapidly generate anti-tumor T cells. The costimulatory properties of second-generation chimeric antigen receptors (CARs) determine the overall potency of adoptively transferred T cells. Utilizing an in vivo “stress test” to challenge CD19-targeted T cells, we studied the functionality and persistence imparted by 7 different CAR structures providing CD28 and/or 4-1BB costimulation. One configuration, which utilizes two signaling domains (CD28 and CD3ζ) and the 4-1BB ligand, provided the highest therapeutic efficacy, showing balanced tumoricidal function and increased T cell persistence accompanied by an elevated CD8/CD4 ratio and decreased exhaustion. Remarkably, induction of the IRF7/IFNβ pathway was required for optimal anti-tumor activity. Thus, 1928z-41BBL T cells possess strikingly potent intrinsic and immunomodulatory qualities.
Subfields: Molecular Biology, Oncology
View Paper: https://www.semanticscholar.org/paper/9a8b648a927c5775ab8ea97a22d80215e8bbae34
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Citations in the corpus
- Axicabtagene Ciloleucel CAR T-Cell Therapy in Refractory Large B-Cell Lymphoma (2017, neutral): “(%) ≥Three prior lines of therapy 49 (64) 21 (88) 70 (69) History of primary refractory disease** 23 (30) 3 (12) 26 (26) History of resistance to two consecutive lines 39 (51) 15 (62) 54 (53) Table 1.”
- Engineering strategies to overcome the current roadblocks in CAR T cell therapy (2019, background): “For example, seeking to combine the rapid activatory kinetics afforded by the CD28 co-stimulatory domains and the better persistence associated with the 4-1BB domain, Zhao et al. 127 demonstrated that co-expression of 4-1BBL on CAR T cells with CD28 co-stimulatory domains results in armoured CAR T c”
- Universal Chimeric Antigen Receptors for Multiplexed and Logical Control of T Cell Responses (2018, positive): “Recently, several studies have demonstrated the importance of regulating CD3z and the different costimulatory pathways independently to achieve optimal T cell response (Kloss et al., 2013; Lanitis et al., 2013; Zhao et al., 2015).”